Method of treatment of drug-induced skin toxicity

Abstract

A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib, naporafenib, or a combination thereof in a subject in need thereof; the method comprising pre-emptively administering to the subject an effective amount of a rash treatment.

Description

WSGR Docket No.59457-795.601METHOD OF TREATMENT OF DRUG-INDUCED SKIN TOXICITYCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 743,993, filed January 10, 2025, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] The RAS / RAF / MEK / ERK or MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of this pathway underlies many instances of tumorigenesis. This pathway is activated by extracellular signals that in turn induces the small G protein RAS to exchange GDP for GTP. The activated RAS small guanidine triphosphatase (GTPase) promotes the activation of the RAF (also referred to as Raf herein) family proteins (ARAF, BRAF and CRAF, also known as RAFI). Activated RAF proteins lead to the phosphorylation and activation of MEK1 / 2 proteins, which subsequently phosphorylate and activate extracellular signal regulated kinases (ERKs). ERK1 / 2 proteins phosphorylate a variety of substrates, including multiple transcription factors, and regulate key cellular activities, including proliferation, differentiation, migration, survival, and angiogenesis.SUMMARY

[0003] Disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, the therapeutic treatment further comprises naporafenib. In some embodiments, naporafenib is not a salt. In some embodiments, the skin toxicity is a dermatologic reaction. In some embodiments, the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE). In some embodiments, the antibiotic is an oral antibiotic. In some embodiments, the antibiotic is a tetracycline antibiotic. In some embodiments, the antibiotic is doxycycline, minocycline, or oxytetracycline. In some embodiments, the antibiotic is a cephalosporin antibiotic. In some embodiments, the antibiotic is cephadroxil. In some embodiments, wherein the antibiotic is a folate synthesis inhibitor. In some embodiments, the antibiotic is trimethoprimsulfamethoxazole. In some embodiments, the administration of the antibiotic is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment. In some embodiments, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed. In some embodiments, theWSGR Docket No.59457-795.601antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed. In some embodiments, the antibiotic is administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises administering a topical corticosteroid. In some embodiments, the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream. In some embodiments, the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself. In some embodiments, the topical corticosteroid is applied to the face, scalp, and chest. In some embodiment^ the administration of the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment. In some embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed. In some embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed. In some embodiments, the topical corticosteroid is administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises daily administration of skin moisturizer. In some embodiments, the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreen. In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, wherein naporafenib is administered in an amount of 100 mg daily. In some embodiments, wherein naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).

[0004] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic. In some embodiments, naporafenib is not a salt. In some embodiments, the therapeutic treatment further comprises trametinib. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, the skin toxicity is a dermatologic reaction. In some embodiments, the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE). In some embodiments, the antibiotic is an oral antibiotic. In someWSGR Docket No.59457-795.601embodiments, the antibiotic is a tetracycline antibiotic. In some embodiments, the antibiotic is doxycycline, minocycline, or oxytetracycline. In some embodiments, the antibiotic is a cephalosporin antibiotic. In some embodiments, the antibiotic is cephadroxil. In some embodiments, the antibiotic is a folate synthesis inhibitor. In some embodiments, the antibiotic is trimethoprim-sulfamethoxazole. In some embodiments, the administration of the antibiotic is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment. In some embodiments, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed. In some embodiments, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed. In some embodiments, the antibiotic is administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises administering a topical corticosteroid. In some embodiments, the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream. In some embodiments, the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself. In some embodiments, the topical corticosteroid is applied to the face, scalp, and chest. In some embodiments, the administration of the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment. In some embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed. In some embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed. In some embodiments, the topical corticosteroid is administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises daily administration of skin moisturizer. In some embodiments, the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreen. In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiment^ naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib isWSGR Docket No.59457-795.601administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).

[0005] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, naporafenib is not a salt. In some embodiments, the skin toxicity is a dermatologic reaction. In some embodiments, the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE). In some embodiments, the antibiotic is an oral antibiotic. In some embodiments, the antibiotic is a tetracycline antibiotic. In some embodiments, the antibiotic is doxycycline, minocycline, or oxytetracy cline. In some embodiments, the antibiotic is a cephalosporin antibiotic. In some embodiments, the antibiotic is cephadroxil. In some embodiment^ the antibiotic is a folate synthesis inhibitor. In some embodiments, the antibiotic is trimethoprimsulfamethoxazole. In some embodiments, the administration of the antibiotic is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment. In some embodiments, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed. In some embodiments, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed. In some embodiments, the antibiotic is administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises administering a topical corticosteroid. In some embodiments, the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream. In some embodiments, the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself. In some embodiments, the topical corticosteroid is applied to the face, scalp, and chest. In some embodiment^ the administration of the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment. In someWSGR Docket No.59457-795.601embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed. In some embodiments, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed. In some embodiments, the topical corticosteroid is administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises daily administration of skin moisturizer. In some embodiments, the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreen. In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiments, naporafenib is administered in an amount of 400 mg daily. In some embodiment^ naporafenib is administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).

[0006] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and a topical corticosteroid. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, the therapeutic treatment further comprises naporafenib. In some embodiments, naporafenib is not a salt. In some embodiments, the skin toxicity is a dermatologic reaction. In some embodiments, the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE). In some embodiments, the antibiotic is an oral antibiotic. In some embodiments, the antibiotic is a tetracycline antibiotic. In some embodiments, the antibiotic is doxycycline, minocycline, or oxytetracycline. In some embodiments, the antibiotic is a cephalosporin antibiotic. In some embodiments, the antibiotic is cephadroxil. In some embodiments, the antibiotic is a folate synthesis inhibitor. In some embodiments, the antibiotic is trimethoprim-sulfamethoxazole. In some embodiments, the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream. In some embodiments, the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself. In some embodiments, the topical corticosteroid is applied to the face, scalp, and chest. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of theWSGR Docket No.59457-795.601therapeutic treatment. In some embodiments, the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued if no skin toxicity is observed. In some embodiments, the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued when the skin toxicity is no longer observed. In some embodiments, the antibiotic and the topical corticosteroid are administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises daily administration of skin moisturizer. In some embodiments, the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreor In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiments, naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).

[0007] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and a topical corticosteroid. In some embodiments, naporafenib is not a salt. In some embodiments, the therapeutic treatment further comprises trametinib. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, the skin toxicity is a dermatologic reaction. In some embodiments, the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE). In some embodiments, the antibiotic is an oral antibiotic. In some embodiments, the antibiotic is a tetracycline antibiotic. In some embodiments, the antibiotic is doxycycline, minocycline, or oxytetracycline. In some embodiments, the antibiotic is a cephalosporin antibiotic. In some embodiments, the antibiotic is cephadroxil. In some embodiments, the antibiotic is a folate synthesis inhibitor. In some embodiments, the antibiotic is trimethoprim-sulfamethoxazole. In some embodiments, the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream. In some embodiments, the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself. In some embodiments, the topical corticosteroid is applied to the face, scalp, and chest. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the antibiotic andWSGR Docket No.59457-795.601the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment. In some embodiments, the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued if no skin toxicity is observed. In some embodiments, the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued when the skin toxicity is no longer observed. In some embodiments, the antibiotic and the topical corticosteroid are administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises daily administration of skin moisturizer. In some embodiments, the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreor In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiments, naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).

[0008] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and a topical corticosteroid. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, naporafenib is not a salt. In some embodiments, the skin toxicity is a dermatologic reaction. In some embodiments, the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE). In some embodiments, the antibiotic is an oral antibiotic. In some embodiments, the antibiotic is a tetracycline antibiotic. In some embodiments, the antibiotic is doxycycline, minocycline, or oxytetracycline. In some embodiments, the antibiotic is a cephalosporin antibiotic. In some embodiments, the antibiotic is cephadroxil. In some embodiments, the antibiotic is a folate synthesis inhibitor. In some embodiments, the antibiotic is trimethoprim-sulfamethoxazole. In some embodiments, the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream. In some embodiments, the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself. In some embodiments, the topical corticosteroid is applied to the face, scalp, and chest. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the antibiotic and the topical corticosteroid is initiated 3 days before theWSGR Docket No.59457-795.601administration of the therapeutic treatment. In some embodiments, the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment. In some embodiments, the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued if no skin toxicity is observed. In some embodiments, the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued when the skin toxicity is no longer observed. In some embodiments, the antibiotic and the topical corticosteroid are administered daily from the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises daily administration of skin moisturizer. In some embodiments, the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreen. In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiment^ naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).

[0009] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of a rash treatment. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, naporafenib is not a salt. In some embodiments, the skin toxicity is a dermatologic reaction. In some embodiments, the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia(PPE). In some embodiments, the rash treatment is administered orally. In some embodiments, the rash treatment is administered topically. In some embodiments, the rash treatment is administered orally and topically. In some embodiments, the administration of the rash treatment is initiated between 1 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the rash treatment is initiated between 3 and 7 days before the administration of the therapeutic treatment. In some embodiments, the administration of the rash treatment is initiated 3 days before the administration of the therapeutic treatment. In some embodiments, the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment. In some embodiments, the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed. In some embodiments, the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed. In some embodiments, the rash treatment is administered daily fromWSGR Docket No.59457-795.601the time the administration is initiated to the time the administration is discontinued. In some embodiments, the method further comprises daily administration of skin moisturizer. In some embodiments, the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreen. In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiments, naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).DETAILED DESCRIPTION

[0010] Although disruption of the MAPK pathway is a frequent fundamental finding in many tumors, targeting the RAS / RAF / MEK / ERK nodes of this pathway has been difficult for a variety of reasons ranging from protein structures resistant to drug targeting (e. g. , RAS) to the rapid generation of resistance mechanisms. For example, inhibition of BRAF V600E / K mutant melanoma tumors with monomeric-selective BRAF inhibitors (e.g., dabrafenib, vemurafenib, encorafenib) quickly leads to the generation of RAF inhibitor-resistant RAF dimers resulting in adaptive resistance. One strategy to address the rapid onset of resistance is to target multiple nodes of the RAS / MAPK pathway with combination therapy. This approach has been successful in BRAF V600E / K mutant melanoma and BRAF V600E mutant NSCLC where the combination of a monomeric-selective BRAF inhibitor administered with a MEK inhibitor led to improved clinical activity compared to each class of drugs administered as monotherapy (Tafinlar®).

[0011] An additional strategy to combat the rapid onset of resistance is naporafenib, which inhibits dimeric versions of wild type BRAF, CRAF, and BRAF V600E / K mutant enzymes and is predicted to abrogate the onset of drug-resistant dimers, paired with a MEK inhibitor like trametinib, which inhibits a downstream node of the RAS / MAPK pathway, which is predicted to enhance clinical activity by delaying the onset of resistance.

[0012] However EGFR / MEK inhibitor-related skin toxicities (e. g., rash) has been observed as one of the major adverse events leading to dose modification and / or treatment discontinuation which may affect clinical outcomes. Management of skin toxicities is critical to ensure dose intensity and maintain Quality of Life (QOL).Methods of treating and / or preventing a skin toxicity

[0013] Disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, i. e., a cancer treatment, comprising trametinib, naporafenib, or a combination thereof, in a subject in need thereof; the method comprising pre-emptively and / or concurrently administering to the subject, an effective amount of a rash treatment. In someWSGR Docket No.59457-795.601embodiments, the rash treatment is administered pre-emptively, i.e., before therapeutic treatment commences. In some embodiments, the rash treatment is administered concurrently with the therapeutic treatment. In some embodiments, the rash treatment is continued throughout the course of the therapeutic treatment. In some embodiments, rash treatment is reduced or eliminated during the course of the therapeutic treatment.

[0014] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib in a subject in need thereof; the method comprising administering to the subject an effective amount of rash treatment. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib, the therapeutic treatment further comprises naporafenib.

[0015] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of a rash treatment. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib, the therapeutic treatment further comprises trametinib.

[0016] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of a rash treatment.

[0017] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib, the therapeutic treatment further comprises naporafenib. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib, the method further comprises administering a topical corticosteroid.

[0018] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib, the therapeutic treatment further comprises trametinib. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib, the method further comprises administering a topical corticosteroid.WSGR Docket No.59457-795.601

[0019] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib, the method further comprises administering a topical corticosteroid.

[0020] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and atopical corticosteroid. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib, the therapeutic treatment further comprises naporafenib.

[0021] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and atopical corticosteroid. In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib, the therapeutic treatment further comprises trametinib.

[0022] Also disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and a topical corticosteroid.Therapeutic Treatment

[0023] Disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment; the method comprising administering to the subject an effective amount of a rash treatment. In some embodiments, the therapeutic treatment is a cancer treatment. In some embodiments, the therapeutic treatment comprises naporafenib. In some embodiments, the therapeutic treatment comprises trametinib. In some embodiments, the therapeutic treatment comprises naporafenib and trametinib.Naporafenib

[0024] Naporafenib is an adenosine triphosphate (ATP)-competitive inhibitor of the CRAF and BRAF protein kinases. In vitro data indicate that naporafenib inhibits wild-type BRAF (>99% inhibition), mutant BRAF V600E (>99%), and wild-type CRAF (99%) at similar, sub-nanomolar potencies. Naporafenib is also highly selective with only 5 out of 456 kinases tested showing greater than or equal to 99% of inhibition by naporafenib at 1 pM concentration compared to control.WSGR Docket No.59457-795.601

[0025] Naporafenib has the following structure. In some embodiments, naporafenib is not a salt.

[0026] In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiments, naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID).Trametinib

[0027] Trametinib is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 and is approved for use as a single agent for the treatment of BRAF -inhibitor treatment-naive adult patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Trametinib is also approved for use, in combination with dabrafenib, for the treatment of adult patients with unresectable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC), locally advanced or metastatic anaplastic thyroid cancer, and unresectable or metastatic solid tumors with BRAF V600Eor V600K mutations. Trametinib has the following structure. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate.

[0028] In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).

[0029] The most common side effects following administration of trametinib include rash, diarrhea, tiredness, peripheral edema (swelling, especially of ankles and feet), nausea, and acneiform dermatitis (acne-like inflammation of the skin).Rash Treatments

[0030] Disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment; the method comprising administering to the subject an effective amount of a rash treatment.

[0031] In some embodiments, the rash treatment comprises one agent. In some embodiments, the rash treatment comprises more than one agent. In some embodiments, the rash treatment comprises two agents. In some embodiments, the rash treatment is administered orally. In some embodiments,WSGR Docket No.59457-795.601the rash treatment is administered topically. In some embodiments, the rash treatment, when comprising more than one agent, is administered both orally and topically.

[0032] In some embodiments, the rash treatment comprises an antibiotic. In some embodiments, the rash treatment comprises atopical corticosteroid. In some embodiments, the rash treatment comprises an antibiotic and a topical corticosteroid.

[0033] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 1 and 7 days before the administration of the therapeutic treatment.

[0034] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 1 and 6 days before the administration of the therapeutic treatment.

[0035] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 1 and 5 days before the administration of the therapeutic treatment.

[0036] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 1 and 4 days before the administration of the therapeutic treatment.

[0037] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 1 and 3 days before the administration of the therapeutic treatment.

[0038] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 3 and 4 days before the administration of the therapeutic treatment.

[0039] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 3 and 5 days before the administration of the therapeutic treatment.

[0040] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 3 and 6 days before the administration of the therapeutic treatment.

[0041] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated between 3 and 7 days before the administration of the therapeutic treatment.

[0042] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated 1 day before the administration of the therapeutic treatment.WSGR Docket No.59457-795.601

[0043] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated 2 days before the administration of the therapeutic treatment.

[0044] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated 3 days before the administration of the therapeutic treatment.

[0045] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated 4 days before the administration of the therapeutic treatment.

[0046] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated 5 days before the administration of the therapeutic treatment.

[0047] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated 6 days before the administration of the therapeutic treatment.

[0048] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the rash treatment is initiated 7 days before the administration of the therapeutic treatment.

[0049] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment.

[0050] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered for at least 9 weeks after the first administration of the therapeutic treatment.

[0051] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered for at least 10 weeks after the first administration of the therapeutic treatment.

[0052] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered for at least 11 weeks after the first administration of the therapeutic treatment.

[0053] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered for at least 12 weeks after the first administration of the therapeutic treatment.

[0054] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.WSGR Docket No.59457-795.601

[0055] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.

[0056] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed but is resumed if the skin toxicity re-appears.

[0057] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the rash treatment is administered daily from the time the administration is initiated to the time the administration is discontinued.Antibiotics

[0058] In some embodiments, the rash treatment is an antibiotic.

[0059] In some embodiments, the antibiotic is an oral antibiotic. In some embodiments, the antibiotic is a tetracycline antibiotic. In some embodiments, the antibiotic is aminocy cline, doxycycline, or oxytetr acy cline.

[0060] In some embodiments, the antibiotic is aminocycline. In some embodiments, the antibiotic is doxycycline. In some embodiments, the antibiotic is oxytetracycline.

[0061] In some embodiments, the antibiotic is aminocycline administered at a dose of 100 mg QD, doxycycline administered at a dose of 100 mg BID, or oxytetracycline administered at a dose of 500 mg BID.

[0062] In some embodiments, the antibiotic is a cephalosporin antibiotic. In some embodiments, the antibiotic is cephadroxil. In some embodiments, the antibiotic is cephadroxil administered at a dose of 500 mg BID.

[0063] In some embodiments, the antibiotic is a folate synthesis inhibitor. In some embodiments, the oral antibiotic is trimethoprim-sulfamethoxazole. In some embodiments, the antibiotic is trimethoprim-sulfamethoxazole administered at a dose of 160 / 800 mg BID.

[0064] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 1 and 7 days before the administration of the therapeutic treatment.

[0065] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 1 and 6 days before the administration of the therapeutic treatment.

[0066] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 1 and 5 days before the administration of the therapeutic treatment.WSGR Docket No.59457-795.601

[0067] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 1 and 4 days before the administration of the therapeutic treatment.

[0068] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 1 and 3 days before the administration of the therapeutic treatment.

[0069] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 3 and 4 days before the administration of the therapeutic treatment.

[0070] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 3 and 5 days before the administration of the therapeutic treatment.

[0071] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 3 and 6 days before the administration of the therapeutic treatment.

[0072] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated between 3 and 7 days before the administration of the therapeutic treatment.

[0073] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated 1 dry before the administration of the therapeutic treatment.

[0074] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated 2 days before the administration of the therapeutic treatment.

[0075] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated 3 days before the administration of the therapeutic treatment.

[0076] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated 4 days before the administration of the therapeutic treatment.

[0077] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated 5 days before the administration of the therapeutic treatment.

[0078] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated 6 days before the administration of the therapeutic treatment.WSGR Docket No.59457-795.601

[0079] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic is initiated 7 days before the administration of the therapeutic treatment.

[0080] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment.

[0081] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered for at least 9 weeks after the first administration of the therapeutic treatment.

[0082] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered for at least 10 weeks after the first administration of the therapeutic treatment.

[0083] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered for at least 11 weeks after the first administration of the therapeutic treatment.

[0084] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered for at least 12 weeks after the first administration of the therapeutic treatment.

[0085] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.

[0086] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.

[0087] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed but is resumed if the skin toxicity re-appears.

[0088] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic is administered daily from the time the administration is initiated to the time the administration is discontinued.Topical Corticosteroid

[0089] In some embodiments, the rash treatment is a topical corticosteroid.WSGR Docket No.59457-795.601

[0090] In some embodiments, the topical corticosteroid is a topical low-potency corticosteroid. In some embodiments, the topical corticosteroid is hydrocortisone, alclometasone, or fluocinonide.

[0091] In some embodiments, the topical corticosteroid is hydrocortisone. In some embodiments, the topical corticosteroid is alclometasone. In some embodiments, the topical corticosteroid is fluocinonide.

[0092] In some embodiments, the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05%.

[0093] In some embodiments, the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself. In some embodiments, the topical corticosteroid is applied to the face, scalp, and chest.

[0094] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment.

[0095] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 1 and 6 days before the administration of the therapeutic treatment.

[0096] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 1 and 5 days before the administration of the therapeutic treatment.

[0097] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 1 and 4 days before the administration of the therapeutic treatment.

[0098] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 1 and 3 days before the administration of the therapeutic treatment.

[0099] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 3 and 4 days before the administration of the therapeutic treatment.

[0100] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 3 and 5 days before the administration of the therapeutic treatment.

[0101] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 3 and 6 days before the administration of the therapeutic treatment.

[0102] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment.WSGR Docket No.59457-795.601

[0103] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated 1 day before the administration of the therapeutic treatment.

[0104] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated 2 days before the administration of the therapeutic treatment.

[0105] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment.

[0106] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated 4 days before the administration of the therapeutic treatment.

[0107] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated 5 days before the administration of the therapeutic treatment.

[0108] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated 6 days before the administration of the therapeutic treatment.

[0109] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the topical corticosteroid is initiated 7 days before the administration of the therapeutic treatment.

[0110] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment.

[0111] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered for at least 9 weeks after the first administration of the therapeutic treatment.

[0112] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered for at least 10 weeks after the first administration of the therapeutic treatment.

[0113] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered for at least 11 weeks after the first administration of the therapeutic treatment.

[0114] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered for at least 12 weeks after the first administration of the therapeutic treatment.WSGR Docket No.59457-795.601

[0115] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.

[0116] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.

[0117] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed but is resumed if the skin toxicity re-appears.

[0118] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the topical corticosteroid is administered daily from the time the administration is initiated to the time the administration is discontinued.Antibiotics and Topical Corticosteroid

[0119] In some embodiments, the rash treatment is an antibiotic and a topical corticosteroid.

[0120] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment.

[0121] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 1 and 6 days before the administration of the therapeutic treatment.

[0122] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 1 and 5 days before the administration of the therapeutic treatment.

[0123] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 1 and 4 days before the administration of the therapeutic treatment.

[0124] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 1 and 3 days before the administration of the therapeutic treatment.

[0125] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 3 and 4 days before the administration of the therapeutic treatment.WSGR Docket No.59457-795.601

[0126] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 3 and 5 days before the administration of the therapeutic treatment

[0127] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 3 and 6 days before the administration of the therapeutic treatment

[0128] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment

[0129] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated 1 day before the administration of the therapeutic treatment.

[0130] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated 2 days before the administration of the therapeutic treatment.

[0131] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment.

[0132] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated 4 days before the administration of the therapeutic treatment.

[0133] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated 5 days before the administration of the therapeutic treatment.

[0134] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated 6 days before the administration of the therapeutic treatment.

[0135] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the administration of the antibiotic and topical corticosteroid is initiated 7 days before the administration of the therapeutic treatment.

[0136] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment.

[0137] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered for at least 9 weeks after the first administration of the therapeutic treatment.WSGR Docket No.59457-795.601

[0138] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered for at least 10 weeks after the first administration of the therapeutic treatment.

[0139] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered for at least 11 weeks after the first administration of the therapeutic treatment.

[0140] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered for at least 12 weeks after the first administration of the therapeutic treatment.

[0141] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.

[0142] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.

[0143] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed but is resumed if the skin toxicity reappears.

[0144] In some embodiments of a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment, the antibiotic and topical corticosteroid are administered daily from the time the administration is initiated to the time the administration is discontinued.Skin Toxicity

[0145] Disclosed herein is a method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment; the method comprising administering to the subject an effective amount of a rash treatment.

[0146] In some embodiments, the skin toxicity is a dermatologic reaction. In some embodiments, the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE). In some embodiments, the dermatologic reaction is a rash. In some embodiments, the dermatologic reaction is dry skin. In some embodiments, the dermatologic reaction is dermatitis acneiform.WSGR Docket No.59457-795.601Definitions

[0147] As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and / or duration of a disorder, e.g., a proliferative disorder, or the amelioration of one or more symptoms, suitably of one or more discernible symptoms, of the disorder resulting from the administration of one or more therapies. In specific embodiments, the terms “treat,” “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient. In other embodiments the terms “treat,” “treatment” and “treating” refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms “treat,” “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.

[0148] Within the meaning of the present disclosure, the term “treat” also denotes to arrest, delay the onset (i. e. , the period prior to clinical manifestation of a disease) and / or reduce the risk of developing or worsening a disease. The term “protect” is used herein to mean prevent, delay, or treat, or all, as appropriate, development, continuance, or aggravation of a disease in a subject, e.g., a mammal or human.

[0149] The term “subject” or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a proliferative disease, such as cancer.

[0150] As used herein, the term “cancer” refers to a disease characterized by the undesired and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors. The term “cancer” is used herein to mean a broad spectrum of tumors, including all solid and hematological malignancies. In some embodiments, the cancer is melanoma.Numbered Embodiments

[0151] Some numbered examples of embodiments are presented below.1. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic.2. The method of embodiment 1, wherein trametinib is in the form of a dimethyl sulfoxide solvate.WSGR Docket No.59457-795.6013. The method of embodiment 1 or 2, wherein the therapeutic treatment further comprises naporafenib.4. The method of embodiment 3, wherein naporafenib is not a salt.5. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic.6. The method of embodiment 5, wherein naporafenib is not a salt.7. The method of embodiment 5 or 6, wherein the therapeutic treatment further comprises trametinib.8. The method of embodiment 7, wherein trametinib is in the form of a dimethyl sulfoxide solvate.9. The method of any one of embodiment 1-8, wherein the skin toxicity is a dermatologic reaction.10. The method of embodiment 9, wherein the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE).11. The method of any one of embodiments 1-10, wherein the antibiotic is an oral antibiotic.12. The method of any one of embodiments 1-11, wherein the antibiotic is a tetracycline antibiotic.13. The method of embodiment 12, wherein the antibiotic is doxycycline, minocycline, or oxytetracycline.14. The method of any one of embodiments 1-11, wherein the antibiotic is a cephalosporin antibiotic.15. The method of embodiment 14, wherein the antibiotic is cephadroxil.16. The method of any one of embodiments 1-11, wherein the antibiotic is a folate synthesis inhibitor.17. The method of embodiment 16, wherein the antibiotic is trimethoprim-sulfamethoxazole.18. The method of any one of embodiments 1-17, wherein the administration of the antibiotic is initiated between 1 and 7 days before the administration of the therapeutic treatment. 19. The method of any one of embodiments 1-17, wherein the administration of the antibiotic is initiated between 3 and 7 days before the administration of the therapeutic treatment. 20. The method of any one of embodiments 1-17, wherein the administration of the antibiotic is initiated 3 days before the administration of the therapeutic treatment.21. The method of any one of embodiments 1-20, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment.WSGR Docket No.59457-795.60122. The method of any one of embodiments 1-20, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.23. The method of any one of embodiments 1-20, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.24. The method of any one of embodiments 1-23, wherein the antibiotic is administered daily from the time the administration is initiated to the time the administration is discontinued.25. The method of any one of embodiments 1-24, wherein the method further comprises administering a topical corticosteroid.26. The method of embodiment 25, wherein the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream.27. The method of embodiment 25 or 26, wherein the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself.28. The method of embodiment 25 or 26, wherein the topical corticosteroid is applied to the face, scalp, and chest.29. The method of any one of embodiments 25-28, wherein the administration of the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment.30. The method of any one of embodiments 25-28, wherein the administration of the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment.31. The method of any one of embodiments 25-28, wherein the administration of the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment. 32. The method of any one of embodiments 25-31, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment.33. The method of any one of embodiments 25-31, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.34. The method of any one of embodiments 25-31, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.35. The method of any one of embodiments 25-34, wherein the topical corticosteroid is administered daily from the time the administration is initiated to the time the administration is discontinued.WSGR Docket No.59457-795.60136. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic.37. The method of embodiment 36, wherein trametinib is in the form of a dimethyl sulfoxide solvate.38. The method of embodiment 36, wherein naporafenib is not a salt.39. The method of any one of embodiments 36-38, wherein the skin toxicity is a dermatologic reaction.40. The method of embodiment 39, wherein the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE).41. The method of any one of embodiments 36-40, wherein the antibiotic is an oral antibiotic.42. The method of any one of embodiments 36-41, wherein the antibiotic is a tetracycline antibiotic.43. The method of embodiment 42, wherein the antibiotic is doxycycline, minocycline, or oxytetracycline.44. The method of any one of embodiments 36-41, wherein the antibiotic is a cephalosporin antibiotic.45. The method of embodiment 44, wherein the antibiotic is cephadroxil.46. The method of any one of embodiments 36-41, wherein the antibiotic is a folate synthesis inhibitor.47. The method of embodiment 46, wherein the antibiotic is trimethoprim-sulfamethoxazole.48. The method of any one of embodiments 36-47, wherein the administration of the antibiotic is initiated between 1 and 7 days before the administration of the therapeutic treatment. 49. The method of any one of embodiments 36-47, wherein the administration of the antibiotic is initiated between 3 and 7 days before the administration of the therapeutic treatment. 50. The method of any one of embodiments 36-47, wherein the administration of the antibiotic is initiated 3 days before the administration of the therapeutic treatment.51. The method of any one of embodiments 36-50, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment.52. The method of any one of embodiments 36-50, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.WSGR Docket No.59457-795.60153. The method of any one of embodiments 36-50, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.54. The method of any one of embodiments 36-53, wherein the antibiotic is administered daily from the time the administration is initiated to the time the administration is discontinued.55. The method of any one of embodiments 36-54, wherein the method further comprises administering a topical corticosteroid.56. The method of embodiment 55, wherein the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream.57. The method of embodiment 55 or 56, wherein the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself.58. The method of embodiment 55 or 56, wherein the topical corticosteroid is applied to the face, scalp, and chest.59. The method of any one of embodiments 55-58, wherein the administration of the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment.60. The method of any one of embodiments 55-58, wherein the administration of the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment.61. The method of any one of embodiments 55-58, wherein the administration of the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment. 62. The method of any one of embodiments 55-61, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment.63. The method of any one of embodiments 55-61, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.64. The method of any one of embodiments 55-61, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.65. The method of any one of embodiments 55-64, wherein the topical corticosteroid is administered daily from the time the administration is initiated to the time the administration is discontinued.66. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib in a subject in need thereof; the methodWSGR Docket No.59457-795.601comprising administering to the subject an effective amount of an antibiotic and atopical corticosteroid.67. The method of embodiment 66, wherein trametinib is in the form of a dimethyl sulfoxide solvate.68. The method of embodiment 66 or 67, wherein the therapeutic treatment further comprises naporafenib.69. The method of embodiment 68, wherein naporafenib is not a salt.70. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and a topical corticosteroid.71. The method of embodiment 70, wherein naporafenib is not a salt.72. The method of embodiment 70 or 71, wherein the therapeutic treatment further comprises trametinib.73. The method of embodiment 72, wherein trametinib is in the form of a dimethyl sulfoxide solvate.74. The method of any one of embodiments 66-73, wherein the skin toxicity is a dermatologic reaction.75. The method of embodiment 74, wherein the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE).76. The method of any one of embodiments 66-75, wherein the antibiotic is an oral antibiotic.77. The method of any one of embodiments 66-76, wherein the antibiotic is a tetracycline antibiotic.78. The method of embodiment 77, wherein the antibiotic is doxycycline, minocycline, or oxytetracycline.79. The method of any one of embodiments 66-76, wherein the antibiotic is a cephalosporin antibiotic.80. The method of embodiment 79, wherein the antibiotic is cephadroxil.81. The method of any one of embodiments 66-76, wherein the antibiotic is a folate synthesis inhibitor.82. The method of embodiment 81, wherein the antibiotic is trimethoprim-sulfamethoxazole.83. The method of any one of embodiments 66-82, wherein the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream.WSGR Docket No.59457-795.60184. The method of any one of embodiments 66-83, wherein the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself.85. The method of any one of embodiments 66-84, wherein the topical corticosteroid is applied to the face, scalp, and chest.86. The method of any one of embodiments 66-85, wherein the administration of the antibiotic and the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment.87. The method of any one of embodiments 66-85, wherein the administration of the antibiotic and the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment.88. The method of any one of embodiments 66-85, wherein the administration of the antibiotic and the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment.89. The method of any one of embodiments 66-88, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment.90. The method of any one of embodiments 66-88, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued if no skin toxicity is observed.91. The method of any one of embodiments 66-88, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued when the skin toxicity is no longer observed. 92. The method of any one of embodiments 66-91, wherein the antibiotic and the topical corticosteroid are administered daily from the time the administration is initiated to the time the administration is discontinued.93. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and a topical corticosteroid.94. The method of embodiment 93, wherein trametinib is in the form of a dimethyl sulfoxide solvate.95. The method of embodiment 93, wherein naporafenib is not a salt.96. The method of any one of embodiments 93-95, wherein the skin toxicity is a dermatologic reaction.WSGR Docket No.59457-795.60197. The method of embodiment 96, wherein the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE).98. The method of any one of embodiments 93-97, wherein the antibiotic is an oral antibiotic.99. The method of any one of embodiments 93-98, wherein the antibiotic is a tetracycline antibiotic.100. The method of embodiment 99, wherein the antibiotic is doxycycline, minocycline, or oxytetracycline.101. The method of any one of embodiments 93-98, wherein the antibiotic is a cephalosporin antibiotic.102. The method of embodiment 101, wherein the antibiotic is cephadroxil.103. The method of any one of embodiments 93-98, wherein the antibiotic is a folate synthesis inhibitor.104. The method of embodiment 103, wherein the antibiotic is trimethoprim-sulfamethoxazole.105. The method of any one of embodiments 93-104, wherein the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream. 106. The method of any one of embodiments 93-105, wherein the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself.107. The method of any one of embodiments 93-106, wherein the topical corticosteroid is applied to the face, scalp, and chest.108. The method of any one of embodiments 93-107, wherein the administration of the antibiotic and the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment.109. The method of any one of embodiments 93-107, wherein the administration of the antibiotic and the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment.110. The method of any one of embodiments 93-107, wherein the administration of the antibiotic and the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment.111. The method of any one of embodiments 93-110, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment.112. The method of any one of embodiments 93-110, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued if no skin toxicity is observed.WSGR Docket No.59457-795.601113. The method of any one of embodiments 93-110, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued when the skin toxicity is no longer observed. 114. The method of any one of embodiments 93-113, wherein the antibiotic and the topical corticosteroid are administered daily from the time the administration is initiated to the time the administration is discontinued.115. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of a rash treatment. 116. The method of embodiment 115, wherein trametinib is in the form of a dimethyl sulfoxide solvate.117. The method of embodiment 115, wherein naporafenib is not a salt.118. The method of any one of embodiments 115-117, wherein the skin toxicity is a dermatologic reaction.119. The method of embodiment 118, wherein the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE).120. The method of any one of embodiments 115-119, wherein the rash treatment is administered orally.121. The method of any one of embodiments 115-119, wherein the rash treatment is administered topically.122. The method of any one of embodiments 115-119, wherein the rash treatment is administered orally and topically.123. The method of any one of embodiments 115-122, wherein the administration of the rash treatment is initiated between 1 and 7 days before the administration of the therapeutic treatment.124. The method of any one of embodiments 115-122, wherein the administration of the rash treatment is initiated between 3 and 7 days before the administration of the therapeutic treatment.125. The method of any one of embodiments 115-122, wherein the administration of the rash treatment is initiated 3 days before the administration of the therapeutic treatment.126. The method of any one of embodiments 115-125, wherein the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment.WSGR Docket No.59457-795.601127. The method of any one of embodiments 115-125, wherein the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.128. The method of any one of embodiments 115-125, wherein the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.129. The method of any one of embodiments 115-128, wherein the rash treatment is administered daily from the time the administration is initiated to the time the administration is discontinued.130. The method of any one of embodiments 1-129, wherein the method further comprises daily administration of skin moisturizer.131. The method of any one of embodiments 1-130, wherein the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreen.132. The method of any one of embodiments 1-131, wherein naporafenib is administered in an amount of between 100 mg and 400 mg daily.133. The method of any one of embodiments 1-131, wherein naporafenib is administered in an amount of 100 mg daily.134. The method of any one of embodiments 1-131, wherein naporafenib is administered in an amount of 400 mg daily.135. The method of any one of embodiments 132-134, wherein naporafenib is administered twice daily (BID).136. The method of any one of embodiments 1-135, wherein trametinib is administered in an amount of between 0.5 mg and 1 mg daily.137. The method of any one of embodiments 1-135, wherein trametinib is administered in an amount of 0.5 mg daily.138. The method of any one of embodiments 1-135, wherein trametinib is administered in an amount of 1 mg daily.139. The method of any one of embodiments 136-138, wherein trametinib is administered once daily (QD).EXAMPLE

[0152] The present disclosure is further illustrated by the following comparative studies, which should not be construed as limiting in any way. The disclosure has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation.WSGR Docket No.59457-795.601Study 1

[0153] Patients were required to have advanced or metastatic KRAS or BRAF mutant NSCLC or NRASm melanoma with progression following Standard of Care (SOC treatment). Patients for whom no effective standard therapy existed, who were intolerant to standard therapy, or for whom the standard for care was considered equivalent to study treatment, were also eligible.

[0154] A total of 241 patients have been treated with naporafenib in combination with an ERK1 / 2 inhibitor (LTT462), trametinib, or riboci clib. A total of 115 patients were treated with naporafenib and trametinib in combination in 5 dose cohorts. Four cohorts received naporafenib (mg) BID and trametinib (mg) QD continuously: 200 / 0.5 (6 patients), 200 / 1 (54 patients), 400 / 0.5 (44 patients), 400 / 1 (5 patients), and a fifth cohort was administered 400 mg naporafenib BID continuously and trametinib 1 mg QD following a 2 weeks on / 2 weeks off schedule (6 patients). Mandatory primary rash treatment prior to administration of the study drugs for the management of dermatologic toxicity was not implemented in this study.

[0155] For those patients receiving naporafenib with trametinib (n=115), discontinuation of study treatments for TEAEs (treatment-emergent adverse events) was reported in 17 (14.8%) patients while dose reductions due to TEAEs were also reported in 17 (14.8%) patients. The most frequent (occurring in >25% of the 115 patients receiving naporafenib + trametinib) TEAEs regardless of causality, dose or grade were rash (51.3%), diarrhea (36.5%), blood creatine phosphokinase increased (32.2%), anemia (32.2%), dermatitis acneiform (27.8%), and nausea (27.8%). Treatment-related adverse events (TRAEs) were reported in 95.7% of all patients who received naporafenib with trametinib and Grade 3 or higher TRAEs reported in 58.3% of patients. The most frequent TRAEs (occurring in >15% of the 115 patients receiving naporafenib + trametinib), regardless of dose and grade were rash (50.4%), dermatitis acneiform (27%), blood creatine phosphokinase increased (25.2%), diarrhea (22.6%), pruritis (19.1%), dry skin (17.4%), nausea (17.4%), and stomatitis (16.5%). The most frequent (occurring in >3 patients) Grade 3 or Grade 4 TRAEs were rash (n=22; 19.1%), dermatitis acneiform (n=8; 7%), rash maculo-papular (n=7; 6.1%), blood creatine phosphokinase increased (n=7; 6.1%), lipase increased (n=6; 5.2%), amylase increased (n=4; 3.5%), gamma-glutamyltransferase (GGT) increased (n=4, 3.5%), asthenia (n=3, 2.6%) and stomatitis (n=3; 2.6%).Study 2

[0156] Patients with NRASm or BRAFm melanoma must have received prior systemic therapy for unresectable or metastatic melanoma with an anti-PD-l / Ll -based regimen and were restricted to a maximum of two prior lines of systemic ICI therapy for unresectable or metastatic melanoma.

[0157] A total of 134 patients have been treated with naporafenib in combination with an ERK1 / 2 inhibitor (LTT462), trametinib, or ribociclib (LEE011). The combination of naporafenib and trametinib was evaluated in patients with either NRASm or BRAFm melanoma at the RDEs of 200 / 1 (30 patients) and 400 / 0.5 (22 patients) where both naporafenib and trametinib were administeredWSGR Docket No.59457-795.601continuously BID and QD, respectively; note that one patient assigned to a dosage of 400 / 0.5 received a dosage of 400 / 1 in error. Mandatory primary rash treatment prior to administration of the study drugs for the management of dermatologic toxicity was not implemented in this study.

[0158] For those patients receiving naporafenib with trametinib (n=53), discontinuation of study treatments for TEAEs was reported in 10 (18.9%) patients while dose reductions due to TEAEs were reported in 16 (30.2%) patients. The most frequent TEAEs (occurring in >25% of the 53 patients receiving naporafenib + trametinib) regardless of grade, causality, and dose were dermatitis acneiform (37.7%), rash (37.7%), fatigue (34%), nausea (34%), constipation (32.1%), pruritis (28.3%), blood creatine phosphokinase increased (28.3%), and diarrhea (26.4%). TRAEs were reported in 100% of all patients who received naporafenib with trametinib and Grade 3 or 4 TRAEs were reported in 60.4% of the patients. The most frequent TRAEs (occurring in >15% of the 53 patients receiving naporafenib + trametinib) regardless of dose and grade were rash (37.7%), dermatitis acneiform (35.8%), pruritis (26.4%), blood creatine phosphokinase increased (24.5%), fatigue (22.6%), nausea (20.8%), diarrhea (18.9%), rash maculopapular (17.0%), and skin fissures (15.1%). The most frequent (occurring in > 3 patients) Grade 3 or 4 TRAEs were rash (11.3%), dermatitis acneiform (7.5%), and rash maculo-papular (5.7%).SEACRAFT-1

[0159] SEACRAFT- 1 is an ongoing open-label study to assess the safety and efficacy of naporafenib administered with trametinib in previously treated patients with locally advanced unresectable or metastatic RAS Q61X solid tumor malignancies. A total of 88 adult patients have been enrolled: 84 patients with solid tumors harboring RAS Q61X mutation as well as an additional 4 patients with double wild type (WT) melanoma where ‘ double WT’ refers to patients with NRAS WT / BRAF V 600 WT melanoma. In particular, the study evaluated the safety and tolerability of naporafenib administered with trametinib in patients and characterize the pharmacokinetic (PK) profile of naporafenib and trametinib when administered to patients. In the study, naporafenib was administered 200 mg twice daily (BID) and trametinib was administered 1 mg once daily (QD). Outcome measures include the incidence and severity of treatment-emergent adverse events and serious adverse events, including dermatologic toxi cities. All patients received mandatory primary rash treatment prior to the first dose of the study drugs. The rash treatment was administered either as an oral antibiotic and / or topical low potency corticosteroids. The patients may continue the rash treatment for at least the first 8 weeks of study treatment. The oral antibiotic can be selected from, but not limited to, minocycline 100 mg QD, doxycycline 100 mg BID, or oxytetracy cline 500 mg BID. Other oral antibiotics, including cephalosporins(e. g. cephadroxil 500 mg BID) and trimethoprim-sulfamethoxazole (e.g.160 / 800 BID), can be selected in case of intolerance or history or allergy. The topical low potency corticosteroid can be selected from, but not limited to, hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream.

[0160] Preliminary results on dermatologic toxicities are illustrated in Table 1 below.WSGR Docket No.59457-795.601Table 1. Comparison Data between Study 1, Study 2, and SEACRAFT-1>>>200 / 1 = 200mgnaporafenib BID + tram etinib ImgQD; G=CTCAE grade; G=CTCAE grade;MedDRA=Medical Dictionary for Regulatory Activities; NEC=not elsewhere classified; PT=preferred term; Pts=patients; RDI=relative dose intensity; TEAE=treatment emergent adverse event*“Dermato logic” includes MedDRAHLTs (rashes, eruptions and exanthems NEC; bullous conditions; dermatitis and eczema; exfohative conditions) and the followingPTs: dermatitis acneiform, drugeruption, drug reactionwith eosinophilia and systemic symptoms, palmar-plantar erythrodysesthesia (PPE), severe cutaneous adverse reaction, toxic skin eruption, photosensitivity reaction, skin fissures, pruritis

[0161] As seen from the preliminary results, rash pre- treatment in SEACRAFT- 1 significantly decreased the incidence of> Grade 3 dermatological toxi cities, reduced drug discontinuations due to adverse events (especially skin-related TEAEs), and improved relative dose intensity (RDI). Only one patient (1.1%) permanently discontinued naporafenib (or trametinib) due to dermatologic toxicity TEAE.

Claims

WSGR Docket No.59457-795.601CLAIMSWhat is claimed is:

1. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic.

2. The method of claim 1, wherein trametinib is in the form of a dimethyl sulfoxide solvate.

3. The method of claim 1, wherein naporafenib is not a salt.

4. The method of any one of claims 1-3, wherein the skin toxicity is a dermatologic reaction.

5. The method of claim 4, wherein the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE).

6. The method of any one of claims 1-5, wherein the antibiotic is an oral antibiotic.

7. The method of any one of claims 1-6, wherein the antibiotic is a tetracycline antibiotic.

8. The method of claim 7, wherein the antibiotic is doxycycline, minocycline, or oxytetracycline.

9. The method of any one of claims 1-6, wherein the antibiotic is a cephalosporin antibiotic.

10. The method of claim 9, wherein the antibiotic is cephadroxil.

11. The method of any one of claims 1-6, wherein the antibiotic is a folate synthesis inhibitor.

12. The method of claim 11, wherein the antibiotic is trimethoprim-sulfamethoxazole.

13. The method of any one of claims 1-12, wherein the administration of the antibiotic is initiated between 1 and 7 days before the administration of the therapeutic treatment.

14. The method of any one of claims 1-12, wherein the administration of the antibiotic is initiated between 3 and 7 days before the administration of the therapeutic treatment.

15. The method of any one of claims 1-12, wherein the administration of the antibiotic is initiated 3 days before the administration of the therapeutic treatment.

16. The method of any one of claims 1-15, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment.

17. The method of any one of claims 1-16, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.

18. The method of any one of claims 1-16, wherein the antibiotic is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.

19. The method of any one of claims 1-18, wherein the antibiotic is administered daily from the time the administration is initiated to the time the administration is discontinued.WSGR Docket No.59457-795.60120. The method of any one of claims 1-19, wherein the method further comprises administering a topical corticosteroid.

21. The method of claim 20, wherein the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream.

22. The method of claim 20 or 21, wherein the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself.

23. The method of any one of claims 20-22, wherein the topical corticosteroid is applied to the face, scalp, and chest.

24. The method of any one of claims 20-23, wherein the administration of the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment.

25. The method of any one of claims 20-23, wherein the administration of the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment.

26. The method of any one of claims 20-23, wherein the administration of the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment.

27. The method of any one of claims 20-26, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment.

28. The method of any one of claims 20-26, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.

29. The method of any one of claims 20-26, wherein the topical corticosteroid is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.

30. The method of any one of claims 20-29, wherein the topical corticosteroid is administered daily from the time the administration is initiated to the time the administration is discontinued.

31. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of an antibiotic and a topical corticosteroid.

32. The method of claim 31, wherein trametinib is in the form of a dimethyl sulfoxide solvate.

33. The method of claim 31, wherein naporafenib is not a salt.

34. The method of any one of claims 31-33, wherein the skin toxicity is a dermatologic reaction.WSGR Docket No.59457-795.60135. The method of claim 34, wherein the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE).

36. The method of any one of claims 31-35, wherein the antibiotic is an oral antibiotic.

37. The method of any one of claims 31-36, wherein the antibiotic is a tetracycline antibiotic.

38. The method of claim 37, wherein the antibiotic is doxycycline, minocycline, or oxytetracycline.

39. The method of any one of claims 31-36, wherein the antibiotic is a cephalosporin antibiotic.

40. The method of claim 39, wherein the antibiotic is cephadroxil.

41. The method of any one of claims 31-36, wherein the antibiotic is a folate synthesis inhibitor.

42. The method of claim 41, wherein the antibiotic is trimethoprim-sulfamethoxazole.

43. The method of any one of claims 31-42, wherein the topical corticosteroid is hydrocortisone 1% cream, alclometasone 0.05% cream, or fluocinonide 0.05% cream.

44. The method of any one of claims 31-43, wherein the topical corticosteroid is applied to parts of the body where the skin toxicity is manifesting itself.

45. The method of any one of claims 31-44, wherein the topical corticosteroid is applied to the face, scalp, and chest.

46. The method of any one of claims 31-45, wherein the administration of the antibiotic and the topical corticosteroid is initiated between 1 and 7 days before the administration of the therapeutic treatment.

47. The method of any one of claims 31-45, wherein the administration of the antibiotic and the topical corticosteroid is initiated between 3 and 7 days before the administration of the therapeutic treatment.

48. The method of any one of claims 31-45, wherein the administration of the antibiotic and the topical corticosteroid is initiated 3 days before the administration of the therapeutic treatment.

49. The method of any one of claims 31-48, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment.

50. The method of any one of claims 31-48, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued if no skin toxicity is observed.

51. The method of any one of claims 31-48, wherein the antibiotic and the topical corticosteroid are administered for at least 8 weeks after the first administration of the therapeutic treatment and are discontinued when the skin toxicity is no longer observed.WSGR Docket No.59457-795.60152. The method of any one of claims 31-51, wherein the antibiotic and the topical corticosteroid are administered daily from the time the administration is initiated to the time the administration is discontinued.

53. A method of treating and / or preventing a skin toxicity associated with the administration of a therapeutic treatment comprising trametinib and naporafenib in a subject in need thereof; the method comprising administering to the subject an effective amount of a rash treatment.

54. The method of claim 53, wherein trametinib is in the form of a dimethyl sulfoxide solvate.

55. The method of claim 53, wherein naporafenib is not a salt.

56. The method of any one of claims 53-55, wherein the skin toxicity is a dermatologic reaction.

57. The method of claim 56, wherein the dermatologic reaction is a rash, dry skin, dermatitis acneiform, paronychia, or palmar-plantar erythrodysesthesia (PPE).

58. The method of any one of claims 53-56, wherein the rash treatment is administered orally.

59. The method of any one of claims 53-56, wherein the rash treatment is administered topically.

60. The method of any one of claims 53-56, wherein the rash treatment is administered orally and topically.

61. The method of any one of claims 53-60, wherein the administration of the rash treatment is initiated between 1 and 7 days before the administration of the therapeutic treatment.

62. The method of any one of claims 53-60, wherein the administration of the rash treatment is initiated between 3 and 7 days before the administration of the therapeutic treatment.

63. The method of any one of claims 53-60, wherein the administration of the rash treatment is initiated 3 days before the administration of the therapeutic treatment.

64. The method of any one of claims 53-63, wherein the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment.

65. The method of any one of claims 53-63, wherein the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued if no skin toxicity is observed.

66. The method of any one of claims 53-63, wherein the rash treatment is administered for at least 8 weeks after the first administration of the therapeutic treatment and is discontinued when the skin toxicity is no longer observed.

67. The method of any one of claims 53-66, wherein the rash treatment is administered daily from the time the administration is initiated to the time the administration is discontinued.

68. The method of any one of claims 1-67, wherein the method further comprises daily administration of skin moisturizer.WSGR Docket No.59457-795.60169. The method of any one of claims 1-68, wherein the method further comprises daily administration of a broad spectrum with sun protection factor (SPF) >15 sunscreen.

70. The method of any one of claims 1-69, wherein naporafenib is administered in an amount of between 100 mg and 400 mg daily.

71. The method of any one of claims 1-70, wherein naporafenib is administered in an amount of 100 mg daily.

72. The method of any one of claims 1-70, wherein naporafenib is administered in an amount of 400 mg daily.

73. The method of any one of claims 1-72, wherein naporafenib is administered twice daily (BID).

74. The method of any one of claims 1-73, wherein trametinib is administered in an amount of between 0.5 mg and 1 mg daily.

75. The method of any one of claims 1-74, wherein trametinib is administered in an amount of 0.5 mg daily.

76. The method of any one of claims 1-74, wherein trametinib is administered in an amount of 1 mg daily.

77. The method of any one of claims 74-76, wherein trametinib is administered once daily (QD).

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