EGFR inhibitors for the treatment of head and neck cancer

Abstract

The present invention relates to treating recurrent and / or metastatic head and neck squamous cell carcinoma (preferably recurrent head and neck squamous cell carcinoma) with the compound (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof. The present invention also relates to treating head and neck cancer with the compound (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof, wherein treating head and neck cancer comprises reducing the size of one or more tumors associated with the head and neck cancer.

Description

Field of the Invention

[0001] The present invention relates to the treatment of head and neck cancer. Background of the Invention

[0003] In recent years, there have been significant advances in the treatment of solid tumors, however, many forms of cancer remain incurable and resistant to standard treatments, head and neck cancer is a very stubborn cancer with limited treatment options, and a particularly stubborn cancer is recurrent head and neck squamous cell carcinoma. This cancer has a high mortality rate, high morbidity (particularly by reducing the ability to speak and swallow), and there is no successful treatment.

[0004] Head and neck cancer and recurrent and / or metastatic head and neck squamous cell carcinoma (particularly, wherein the recurrent and / or metastatic head and neck squamous cell carcinoma is recurrent head and neck squamous cell carcinoma) are difficult to treat for a number of reasons. The cancer is invasive and multifocal, which may prevent effective resection. Head and neck cancer and recurrent and / or metastatic head and neck squamous cell carcinoma (particularly, wherein the recurrent and / or metastatic head and neck squamous cell carcinoma is recurrent head and neck squamous cell carcinoma) may also be resistant to standard therapies.

[0005] (3-Ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The structure of NRC-2694 is shown below:

[0006]

[0007] NRC-2694 has been found to be effective in certain cancer types (WO 2009 / 090661 A1 and WO 2011 / 021212 A1). NRC-2694 has also been found to cause low to moderate inhibition of the growth of head and neck cancer cell lines transplanted into athymic female mice (Parkinson et al., Antiviral Research 74 (2007) 43-50).

[0008] NRC-2694 can be administered as NRC-2694 dihydrochloride (referred to as NRC-2694-A).

[0009] The efficacy of specific therapeutic agents for different cancers is unpredictable. Kinase inhibitors that have been found to be active against some cancers are inactive against other cancer types. There is still a need to identify agents that are effective in treating head and neck cancer, particularly agents that can cause tumor regression and reduce tumor size. In head and neck cancer, the reduction of tumor size is particularly important because it may make it easier for patients to speak and swallow. Therefore, there is still a need to identify an agent that is effective in treating recurrent head and neck squamous cell carcinoma.

[0010] Brief description of the invention

[0011] NRC-2694 has been found to be an effective therapeutic agent for head and neck cancer and head and neck squamous cell carcinoma. NRC-2694 is able to reduce the size of tumors associated with head and neck cancer and improve patient outcomes. This is an important advance in the treatment of head and neck cancer. NRC-2694 is also able to inhibit tumor growth and / or reduce the size of tumors associated with head and neck squamous cell carcinoma and improve patient outcomes. This is an important advance in the treatment of head and neck squamous cell carcinoma, a cancer with a high mortality rate and few effective treatment options.

[0012] Therefore, the present invention provides a compound for treating recurrent and / or metastatic head and neck squamous cell carcinoma (R / MHNSCC) in a patient, wherein the compound is (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof. Preferably, the recurrent and / or metastatic head and neck squamous cell carcinoma is recurrent head and neck squamous cell carcinoma.

[0013] Therefore, the present invention also provides a compound for treating head and neck cancer in a patient, wherein: the compound is (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof; and treating head and neck cancer includes reducing the size of one or more tumors associated with head and neck cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Kaplan–Meier estimates of progression-free survival are shown.

[0016] Figure 2 Efficacy results are shown for patients continuing Phase II (monotherapy).

[0017] Table Description

[0018] Table 1 provides a summary of tumor evaluations for five patients with recurrent head and neck squamous cell carcinoma as discussed in Example 1 .

[0019] Table 2 provides the patient demographics in the study of Example 2.

[0020] Table 3 provides progression-free survival (PFS) data for the study of Example 2.

[0021] Table 4 provides objective response rate (ORR) data for the study of Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0023] NRC-2694 has the systematic name (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine. NRC-2694 may also be referred to as N-(3-ethynylphenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy)-4-quinazolinamine. NRC-2694 and its salts can be prepared by standard synthetic techniques. The synthesis of NRC-2694 is described in WO2011 / 021212A1.

[0024] The compound is NRC-2694 or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt is typically a pharmaceutically acceptable acid addition salt. Typically, the compound is a hydrochloride salt of NRC-2694, for example, the compound may be a monohydrochloride salt of NRC-2694 (NRC-2694-B) or a dihydrochloride salt of NRC-2694 (NRC-2694-A). Preferably, the compound is NRC-2694 dihydrochloride salt (NRC-2694-A).

[0025] The cancer treated is head and neck cancer. The head and neck cancer can be head and neck carcinoma, head and neck lymphoma, head and neck adenocarcinoma or head and neck sarcoma. Typically, the cancer is head and neck carcinoma.

[0026] The cancer treated can be, for example, squamous cell carcinoma of the head and neck. Other forms of head and neck cancer include head and neck lymphoma, head and neck adenocarcinoma, and head and neck sarcoma.

[0027] The cancer treated can be a recurrent and / or metastatic cancer, and particularly a recurrent and / or metastatic head and neck squamous cell carcinoma. Therefore, the head and neck squamous cell carcinoma can be a head and neck squamous cell carcinoma with recurrent and / or metastatic properties after the previous treatment of the head and neck squamous cell carcinoma of the patient. Preferably, the cancer treated can be a recurrent cancer, and particularly a recurrent head and neck squamous cell carcinoma. Thus, the head and neck squamous cell carcinoma can be a head and neck squamous cell carcinoma that recurs after the previous treatment of the head and neck squamous cell carcinoma of the patient. Typically, recurrent tumors or lesions develop within ten years after completing treatment to remove, destroy or reduce the size of early tumors or lesions. For example, before starting to treat recurrent head and neck squamous cell carcinoma with a compound, the patient may have previously suffered from head and neck squamous cell carcinoma within ten years, within five years, or within two years.

[0028] The recurrent head and neck squamous cell carcinoma can be a head and neck squamous cell carcinoma that recurs after a previous treatment of the head and neck squamous cell carcinoma. For example, the patient may have previously been treated with an EGFR inhibitor (e.g., erlotinib, gefitinib, lapatinib, cetuximab or vandetanib, preferably cetuximab), with an immunotherapy (e.g., pembrolizumab or nivolumab), with a tumour-agnostic therapy (e.g., larotrectinib) or with chemotherapy (e.g., 5-fluorouracil, gemcitabine, cisplatin, carboplatin, paclitaxel or docetaxel) for head and neck squamous cell carcinoma.

[0029] For example, the patient may have previously been treated with cetuximab, pembrolizumab, or nivolumab for head and neck cancer (e.g., head and neck squamous cell carcinoma). The patient may have previously been treated with radiation therapy or surgery for head and neck cancer or head and neck squamous cell carcinoma, and the patient may have previously been treated with chemotherapy, such as chemotherapy with paclitaxel in combination with cisplatin or carboplatin.

[0030] Patients with head and neck cancer (e.g., recurrent head and neck squamous cell carcinoma) typically have one or more tumors (lesions or cancers) in the head and neck. Patients may have one or more tumors selected from laryngeal tumors, hypopharyngeal tumors, nasal cavity tumors, paranasal sinus tumors, nasopharyngeal tumors, oral tumors, oropharyngeal tumors, and salivary gland tumors. Patients may have laryngeal cancer, hypopharyngeal cancer, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, or salivary gland cancer.

[0031] The head and neck cancer may be a metastatic cancer, for example, the head and neck cancer may be a metastatic recurrent head and neck squamous cell carcinoma. The head and neck cancer may have metastasized to the lymph nodes, lungs, brain, liver or bones or any other organ of the human body.

[0032] The head and neck cancer can be at any stage. The head and neck cancer can be stage I, stage II, stage III, or stage IV cancer, for example, the head and neck cancer can be stage III or stage IV cancer.

[0033] The recurrent head and neck squamous cell carcinoma may be a metastatic recurrent head and neck squamous cell carcinoma. The recurrent head and neck squamous cell carcinoma may have metastasized to the lymph nodes, lungs, brain, liver or bones or any other organ of the human body.

[0034] Recurrent head and neck squamous cell carcinoma can be at any stage. Recurrent head and neck squamous cell carcinoma can be stage I, stage II, stage III, or stage IV cancer, for example, recurrent head and neck squamous cell carcinoma can be stage III or stage IV cancer.

[0035] Treating head and neck cancer may include reducing the size of one or more tumors associated with head and neck cancer. Thus, treatment may cause regression of tumors in head and neck cancer. Treating head and neck cancer may include reducing the number of tumors or lesions present in the patient's head and neck. Treating head and neck cancer may further include alleviating, ameliorating or preventing an increase in the symptoms of head and neck cancer. Treating head and neck cancer may further include reducing the progression of head and neck cancer. Treating head and neck cancer may further include preventing the metastasis of head and neck cancer. Treating head and neck cancer may include reducing the size of tumors associated with metastasis of head and neck cancer.

[0036] Treatment of recurrent and / or metastatic head and neck squamous cell carcinoma may include alleviating, improving or preventing the aggravation of the symptoms of recurrent and / or metastatic head and neck squamous cell carcinoma. Treatment of recurrent head and neck squamous cell carcinoma may include alleviating, improving or preventing the aggravation of the symptoms of recurrent head and neck squamous cell carcinoma. Typically, treatment of recurrent head and neck squamous cell carcinoma includes reducing the progression of recurrent head and neck squamous cell carcinoma. Treatment of recurrent head and neck squamous cell carcinoma may include preventing or inhibiting the growth of a tumor associated with recurrent head and neck squamous cell carcinoma or reducing the size of a tumor associated with recurrent head and neck squamous cell carcinoma. Treatment of recurrent head and neck squamous cell carcinoma may include preventing the metastasis of recurrent head and neck squamous cell carcinoma. Preferably, treatment of recurrent head and neck squamous cell carcinoma includes reducing the size of a tumor associated with recurrent head and neck squamous cell carcinoma. Therefore, treatment may cause tumor regression of recurrent head and neck squamous cell carcinoma. Treatment of recurrent head and neck squamous cell carcinoma may include reducing the number of tumors or lesions present in the patient's head and neck. Treating recurrent head and neck squamous cell carcinoma may include reducing the size of a tumor associated with recurrent head and neck squamous cell carcinoma metastasis.

[0037] When treatment reduces the size of the tumor associated with head and neck cancer or recurrent and / or metastatic head and neck squamous cell carcinoma (wherein, preferably, recurrent and / or metastatic head and neck squamous cell carcinoma is recurrent head and neck squamous cell carcinoma), the size of the tumor is usually reduced by at least 10% from the baseline. The baseline can be the size of the tumor when or before the first treatment with the compound. For example, the baseline can be the size of the tumor measured by CT, MRI or PET scans before the first treatment is started (for example, within two weeks before the first treatment is started). The size of the tumor is usually measured according to the 1.1 version of the RECIST standard (for example, as described in Eisenhauer et al., European Journal of Cancer 45 (2009) 228-247). Therefore, the size of the tumor can be reduced by at least 10mm.

[0038] According to version 1.1 of the RECIST criteria, the response to compound treatment can be a complete response, a partial response, or stable disease, preferably, the response is a partial response or a complete response. A complete response can include the disappearance of all target lesions. A partial response can include a reduction of at least 30% in the sum of the diameters of target lesions.

[0039] Treatment can achieve progression-free survival of at least 45 days, at least 60 days, at least 120 days, or at least 180 days.

[0040] The reduction in tumor size may be a reduction of greater than 20%, greater than 30%, or greater than 50% relative to baseline.The reduction in tumor size may be observed after 30 days of treatment, after 45 days of treatment, or after 60 days of treatment.

[0041] The compound can effectively treat head and neck cancer in patients for whom other treatments have not been successful. Thus the head and neck cancer can be a head and neck cancer that is resistant to radiotherapy and / or chemotherapy. For example, the patient may have previously received radiotherapy or chemotherapy to treat the head and neck cancer, and the response to the radiotherapy or chemotherapy may be an unresponsive or stable disease.

[0042] It has been found that the compound can effectively treat recurrent head and neck squamous cell carcinoma in patients for whom other treatments have not been successful. Therefore, recurrent head and neck squamous cell carcinoma may be a recurrent head and neck squamous cell carcinoma that is resistant to radiotherapy and / or chemotherapy. For example, a patient may have previously received radiotherapy or chemotherapy to treat recurrent head and neck squamous cell carcinoma, and the response to radiotherapy or chemotherapy may be no response or stable disease.

[0043] Head and neck cancer may be resistant to treatment with erlotinib and / or gefitinib. Recurrent head and neck squamous cell carcinoma may be resistant to treatment with erlotinib and / or gefitinib.

[0044] The treatment may reduce multidrug resistance, for example during chemotherapy. For example, the treatment may reduce resistance to cisplatin, carboplatin or paclitaxel.

[0045] Prior to treatment with the compound, the patient may receive at least one cancer therapy line. Prior to treatment with the compound, the patient may receive at least two cancer therapy lines. The cancer therapy line may be selected from treatment with non-NRC-2694 EGFR inhibitors (e.g., erlotinib, gefitinib, lapatinib, cetuximab or vandetanib, preferably cetuximab), treatment with immunotherapy (e.g., pembrolizumab or nivolumab), treatment with tumor-agnostic therapy (e.g., larotrectinib), and treatment with chemotherapy (e.g., gemcitabine, 5-fluorouracil, cisplatin, carboplatin, paclitaxel or docetaxel).

[0046] The patient may have been diagnosed with head and neck cancer for more than six months, more than one year, more than two years, or more than three years. The patient may have been diagnosed with recurrent and / or metastatic head and neck squamous cell carcinoma for more than one month, more than six months, more than one year, more than two years, or more than three years. In particular, the patient may have been diagnosed with recurrent head and neck squamous cell carcinoma for more than one month, more than six months, more than one year, more than two years, or more than three years.

[0047] The patient is typically a human patient, the patient can be male or female, and the patient is typically at least 18 years old, such as 30-70 years old or 40-60 years old.

[0048] The compound can be administered in various dosage forms. The compound can be administered orally, for example, as a tablet, capsule, lozenge, pastille, aqueous or oily suspension, dispersible powder or as a granule. Alternatively, the compound can be administered parenterally, for example, subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion. The compound can also be administered as a suppository.

[0049] The compound is usually administered orally. The compound is preferably administered in the form of a tablet.

[0050] The compound is usually formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, a solid oral form may contain a diluent such as lactose, glucose, sucrose, cellulose, corn starch or potato starch together with the active compound; a lubricant such as silicon dioxide, talc, stearic acid, magnesium stearate or calcium stearate and / or polyethylene glycol; a binder; such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; a disintegrant such as starch, alginic acid, alginate or sodium starch glycolate; an effervescent mixture; a dye; a sweetener; a wetting agent such as lecithin, polysorbate, lauryl sulfate; and a non-toxic and pharmacologically inactive substance commonly used in a pharmaceutical preparation. Such a pharmaceutical preparation can be prepared in a known manner, for example by mixing, granulating, tabletting, sugar coating or film coating methods.

[0051] Liquid dispersions for oral administration may be syrups, emulsions or suspensions. Syrups may contain as carriers, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol.

[0052] Suspensions and emulsions may contain, as carriers, for example, natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycol (e.g. propylene glycol), and, if desired, an appropriate amount of lidocaine hydrochloride.

[0053] Solutions for injection or infusion may contain, for example, sterile water as a carrier, or, preferably, they may be in the form of sterile, aqueous, isotonic saline solutions.

[0054] The compound can be administered to the patient multiple times as needed to treat head and neck cancer or recurrent and / or metastatic head and neck squamous cell carcinoma (wherein, preferably, the recurrent and / or metastatic head and neck squamous cell carcinoma is recurrent head and neck squamous cell carcinoma). The compound can be administered once or twice a week, or once, twice, three or four times a day. Typically, the compound is administered to the patient once or twice a day. Preferably, the compound is administered to the patient once a day.

[0055] The compound of therapeutically effective amount is applied to the patient. According to the age and weight of the patient to be treated, the severity of recurrent head and neck squamous cell carcinoma and the frequency and route of administration, a typical dosage is 1mg / day to 1000mg / day. Usually, the compound is applied to human patients with a dosage of 50mg / day to 500mg / day. Preferably, the compound is applied to patients with a dosage of 100mg / day to 400mg / day. For example, the daily dose can be 75mg / day to 125mg / day, 125mg / day to 175mg / day, 175mg / day to 225mg / day, 225mg / day to 275mg / day, 275mg / day to 325mg / day, 325mg / day to 375mg / day, 375mg / day to 425mg / day or 425mg / day to 475mg / day. The daily dose can be about 100 mg / day, about 125 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, about 275 mg / day, about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day or about 500 mg / day. The compound can be applied to human patients under fasting or feeding conditions. The compound can be applied to human patients with or without considering food.

[0056] The compound can be administered to a patient at a dosage of 200 mg / day to 400 mg / day. The compound can be administered to a patient at a dosage of 250 mg / day to 350 mg / day. Preferably, the compound is administered to a patient at a dosage of 275 mg / day to 325 mg / day. For example, about 300 mg of the compound can be administered every day. The compound can be administered once or multiple times a day. Typically, the compound is administered to a patient as a single dose once a day in an amount of 275 mg to 325 mg. The compound can be administered once a day for at least 5 days, for example, once a day for 1 month to 6 months.

[0057] The compound can be used as a monotherapy. Alternatively, the compound can be used as part of a combination therapy, for example, with radiotherapy, immunotherapy (e.g., pembrolizumab or nivolumab), with unlimited tumor type therapy (e.g., larotrectinib), chemotherapy (e.g., 5-fluorouracil, gemcitabine, cisplatin, carboplatin, paclitaxel or docetaxel) or a combination thereof. The compound can be used as part of a combination therapy with chemotherapy, for example, as part of a combination therapy with one or more of 5-fluorouracil, gemcitabine, cisplatin, carboplatin, paclitaxel and docetaxel. The chemotherapy may include the administration of one or more of cisplatin, carboplatin and paclitaxel. The compound can be used, for example, in combination with (a) cisplatin and paclitaxel or (b) carboplatin and paclitaxel.

[0058] Combination therapy can include simultaneous or separate administration of two treatments. For example, the patient can undergo chemotherapy while the compound is administered. Chemotherapy can, for example, be administered separately from the compound treatment, for example, once every 2 weeks to 5 weeks.

[0059] Therefore, the present invention provides a compound for treatment as defined herein in combination with chemotherapy. The compound can be used for treatment as defined herein in combination with, for example, (a) cisplatin and paclitaxel or (b) carboplatin and paclitaxel. The present invention also provides chemotherapy for treatment as defined herein in combination with the compound. Also provided is a product comprising (i) the compound and (ii) cisplatin and paclitaxel or carboplatin and paclitaxel for simultaneous, sequential or separate treatment of a disease as defined herein, wherein when the compound is administered, the patient may receive chemotherapy with (a) cisplatin and paclitaxel or (b) carboplatin and paclitaxel.

[0060] Cisplatin or carboplatin can be given at 25 mg / m 2 Up to 175 mg / m 2 Total surface area, e.g. 75 mg / m 2 Up to 125 mg / m 2 Paclitaxel can be administered at a dose of 100 mg / m 2 Up to 250 mg / m 2 Total surface area, e.g. 150 mg / m 2 Up to 200 mg / m 2 The dose is administered over the total body surface area.

[0061] The present invention also provides a method for treating head and neck cancer in a patient, the method comprising administering to the patient a compound, the compound being (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof, wherein treating the head and neck cancer comprises reducing the size of one or more tumors associated with the head and neck cancer. The present invention also provides the use of a compound in the preparation of a medicament for treating head and neck cancer in a patient, the compound being (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof, and wherein treating the head and neck cancer comprises reducing the size of one or more tumors associated with the head and neck cancer. The cancer, the patient, the compound and the treatment may be as defined herein for the compound for use according to the present invention.

[0062] The present invention also provides a method for treating recurrent and / or metastatic head and neck squamous cell carcinoma in a patient, the method comprising administering to the patient a compound, the compound being (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof. In particular, the present invention also provides a method for treating recurrent head and neck squamous cell carcinoma in a patient, the method comprising administering to the patient a compound, the compound being (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof. The present invention also provides the use of a compound in the preparation of a medicament for treating recurrent and / or metastatic head and neck squamous cell carcinoma in a patient, the compound being (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof. In particular, the present invention also provides the use of a compound in the preparation of a medicament for treating recurrent head and neck squamous cell carcinoma in a patient, the compound being (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof. The cancer, patient, compound and treatment may be as defined herein for the compound for use according to the present invention.

[0063] The present invention is described in more detail by the following examples, which are not intended to limit the scope of the claims. Example

[0064] Example 1

[0065] Overview

[0066] A Phase I clinical study was conducted to evaluate the safety, pharmacokinetics, and antitumor activity of NRC-2694-A (NRC-2694 dihydrochloride) in patients with recurrent head and neck squamous cell carcinoma.

[0067] Purpose

[0068] Primary: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of NRC-2694-A given orally once daily.

[0069] Secondary: To evaluate the single-dose and multiple-dose pharmacokinetics and antitumor activity of NRC-2694-A.

[0070] Study population

[0071] There are no standard selection criteria for patients diagnosed with advanced solid malignancies.

[0072] Eligibility criteria

[0073] The inclusion criteria were as follows.

[0074] Patients ≥ 18 years old with a life expectancy of ≥ 8 weeks.

[0075] ECOG performance score less than or equal to 2.

[0076] Adequate bone marrow reserve (WBC at least 3,000 / mm 3 , neutrophil count ≥ 2000 / mm 3 , platelet count ≥1,00,000 mm 3 , hemoglobin level 8.0 g / dL), renal function (normal serum creatinine), liver function [total bilirubin level ≤ 2 times upper limit of normal (UNL) and serum aminotransferase level ≤ 2.5 times UNL / ≤ 5 times (for liver metastasis and / or obstructive jaundice)]. Subjects must have negative tests for HIV, HBsAg, and pregnancy (for female subjects).

[0077] Patients who have not received chemotherapy within 14 days (6 weeks for nitrosoureas or mitomycin C) and radiation therapy within 3 weeks, and have not undergone surgery within 2 weeks prior to dosing.

[0078] · The patient is willing to implement birth control measures during treatment and within 2 months after treatment. The exclusion criteria are as follows.

[0079] - Patients with major medical conditions that are not adequately controlled by current therapy, including active cardiac, hepatic, endocrine, renal, or psychiatric disease.

[0080] Patients with brain metastases or primary CNS malignancies.

[0081] · For concurrent cancer therapy (radiotherapy, chemotherapy, etc.).

[0082] · Pregnant or breastfeeding patients.

[0083] • Any condition, including laboratory abnormalities, the presence of which would place the subject at unacceptable risk if he / she participated in the study and which might obscure the assessment of toxicity or altered drug metabolism.

[0084] Gastrointestinal impairment that could significantly alter the absorption of study medications and the use of medications that alter gastric pH; (mild antacids are permitted if taken 4 hours before or after study medication administration)

[0085] Study Design

[0086] An open-label, prospective, non-randomized, multicenter, dose-escalation study was conducted. The starting dose selected for the study was 100 mg / day, the maximum received dose was 500 mg / day, and eligible subjects were admitted to a hospital unit for 12 days, beyond which patients who tolerated the drug were treated as outpatients (ambulatory).

[0087] Results Evaluation

[0088] Safety: Assessments were performed within 7 days prior to study drug administration and subsequently on Days 12, 18, 24, 30, 45, 60, 75, and 90. However, for the assessment of DLT and MTD, safety data from the first 30 days were considered.

[0089] Pharmacokinetic evaluation: Estimation of NRC-2694 in plasma was performed using a validated LC-MS / MS method. Based on the plasma concentration data, non-compartmental pharmacokinetic variables, namely, area under the curve (AUC), peak plasma concentration (Cmax), time to peak plasma concentration (Tmax) and elimination rate constant, volume of distribution, half-life and clearance were calculated for single dose (on day 1) and steady state (on day 12). Blood samples were collected in K2 EDTA pre-filled vacuum blood collection tubes before dosing, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours.

[0090] Tumor Assessment: Changes in tumor size from baseline were assessed according to RECIST criteria (version 1.1).

[0091] result

[0092] A summary of the tumor evaluations of five patients with recurrent head and neck squamous cell carcinoma is shown in Table 1 .

[0093] Table 1

[0094]

[0095] Four patients with recurrent head and neck squamous cell carcinoma completed the 120-day trial. A partial response (tumor regression) of tumor size reduction according to RECIST criteria was observed in one patient. The remaining patients showed stable disease.

[0096] Pharmacokinetic data showed a dose-dependent increase in concentration from 100 mg / day to 500 mg / day for both Day 1 and Day 12 concentrations.

[0097] in conclusion

[0098] NRC-2694-A was administered once daily and showed a tolerable safety profile. A dose proportionality relationship with respect to pharmacokinetics was observed with NRC-2694-A. The MTD of NRC-2694-A was 400 mg / day. In patients with recurrent head and neck squamous cell carcinoma, NRC-2694-A demonstrated a good objective response and caused a decrease in tumor size or stagnation of tumor size.

[0099] Example 2

[0100] A Phase II clinical study was conducted to evaluate the efficacy and safety of NRC-2694-A in patients with recurrent head and neck squamous cell carcinoma.

[0101] Background Information

[0102] Head and neck cancer begins in squamous cells of moist mucosal surfaces in the head and neck region (e.g., within the mouth, nose, and throat). It is estimated that approximately 66,470 new cases of oral, pharyngeal, or laryngeal cancer occur each year, accounting for approximately 3.5% of new cancer cases in the United States. An estimated 15,050 deaths from head and neck (H&N) cancer may occur during the same period. Squamous cell carcinoma or variants are the histopathological type of more than 90% of these tumors.

[0103] NRC-2694-A is an organic small molecule with the IUPAC name N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine dihydrochloride. It is an orally administered tyrosine kinase inhibitor belonging to the quinazoline class of EGFR inhibitors. Amplified EGFR signaling is often found in human tumors and can be caused by various mechanisms. Since amplified EGFR signaling plays an important role in carcinogenesis, inhibiting this process is a reasonable approach to develop new chemical entities for the treatment of such malignancies.

[0104] Purpose of the study:

[0105] Primary objective: The primary objective is to evaluate the efficacy of NRC-2694-A in combination with platinum plus paclitaxel compared with platinum plus paclitaxel alone in terms of progression-free survival (PFS) in patients with recurrent and / or metastatic head and neck squamous cell carcinoma (R / MHNSCC).

[0106] Secondary objectives: The secondary objectives were to (a) compare the objective response rate in R / M HNSCC patients treated with NRC-2694-A in combination with platinum plus paclitaxel versus platinum plus paclitaxel alone, and (b) compare the safety and tolerability of the two regimens.

[0107] Methodology

[0108] This study is an open-label, prospective, randomized, active-controlled, multicenter Phase II study of NRC-2694-A in patients with histologically / cytologically confirmed HNSCC with radiographic progression (recurrent and / or metastatic).

[0109] Patients aged 18-65 years with recurrent and / or metastatic disease, a life expectancy of ≥3 months, and a planned regimen of cisplatin / carboplatin plus paclitaxel were eligible for this study. Patients who met all inclusion and exclusion criteria were randomized to receive chemotherapy plus NRC-2694-A (study drug group) or chemotherapy alone (control group).

[0110] Group-I (study drug group): NRC-2694-A + cisplatin / carboplatin and paclitaxel

[0111] Group-II (control group): cisplatin / carboplatin and paclitaxel

[0112] During the study, 300 mg of NRC-2694-A was administered once daily in the morning with or without food in 240 ml of water. The dose of cisplatin was 100 mg / m 2 body surface area, intravenously over 1 hour. Alternatively, carboplatin was dosed based on a target area under the curve (AUC) equivalent to 5 mg / ml / min, infused over 1 hour. The choice of platinum compound was based on the investigator's discretion and depended on the type of platinum received during prior therapy, avoiding duplication. Paclitaxel was administered at 175 mg / m 2 Doses are given by body surface area and infused over 3 hours.

[0113] Monotherapy: After completing 6 cycles of chemotherapy in the control or study drug groups, patients received 300 mg of NRC-2694-A once daily as monotherapy.

[0114] Eligibility criteria

[0115] Inclusion criteria:

[0116] 1. Between 18 and 65 years old, with a life expectancy of ≥ 3 months, with recurrent and / or

[0117] Or patients with metastatic disease who are planned to be treated with a cisplatin / carboplatin plus paclitaxel regimen. This is also in the palliative setting.

[0118] 2. ECOG (Eastern Cooperative Oncology Group) performance status ≤2.

[0119] 3. Histologically confirmed squamous cell carcinoma of the head and neck. The primary sites include the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx and paranasal sinuses.

[0120] 4. Adequate bone marrow reserve (WBC (white blood cells) at least 3,000 / mm 3 , neutrophil count ≥ 2000 / mm 3 , platelet count ≥ 1,00,000 / mm 3 , hemoglobin level 8.0 g / dL), renal function (normal serum creatinine), liver function [total bilirubin level ≤2 times upper limit of normal (UNL) and serum aminotransferase levels ≤2.5 times UNL / ≤5 times (for liver metastasis and / or obstructive jaundice)].

[0121] 5. Patients who have not received chemotherapy within 30 days (6 weeks for nitrosourea or mitomycin C) and radiotherapy within 3 weeks, and have not undergone surgery within 2 weeks prior to dosing.

[0122] 6. Measurable lesions according to the revised RECIST criteria (version 1.1).

[0123] 7. Patients who received primary radiation therapy were eligible if local recurrence was within the radiation field and occurred at least 6 months after completion of treatment. If recurrence was outside the radiation field, patients were eligible at least 3 months after completion of treatment.

[0124] 8. Willing to implement birth control measures during treatment and within 2 months after treatment.

[0125] 9. Patients who tested negative for HIV, HBsAg, HCV and pregnancy (for female subjects).

[0126] Exclusion criteria:

[0127] 1. Patients with major medical conditions that are not adequately controlled by current therapy, including active cardiac, hepatic, endocrine, renal or psychiatric disease.

[0128] 2. Patients with brain metastases or primary CNS (central nervous system) malignancies. Radiological evaluation of brain metastases is performed only if the patient is symptomatic.

[0129] 3. Previous EGFR-targeted therapy, previous investigational agents for recurrent or metastatic disease, other concurrent investigational agents, other concurrent anticancer treatments.

[0130] Evaluation Criteria

[0131] Efficacy evaluation:

[0132] After the start of treatment, assess tumor response by CT or MRI at baseline and at the end of each 6-week duration (before the start of the next cycle) until disease progression.

[0133] Progression-free survival was considered to be the time from the date of randomization to the date of progression or to the date of death, whichever occurred first.

[0134] Disease progression was assessed according to RECIST version 1.1 criteria2.

[0135] The objective response rate was considered the percentage of patients in each group who achieved a complete or partial response to treatment.

[0136] o Complete response (CR): disappearance of all target lesions.

[0137] o Partial response (PR): a reduction of at least 30% in the sum of the diameters of target lesions.

[0138] Safety evaluation:

[0139] Adverse events were monitored throughout the study and graded using the NCI CTCAE version 5.0 (November 27, 2017).

[0140] result

[0141] A total of 90 patients were recruited in this study. Among these patients, 45 patients were in Group I (NRC-2694-A + chemotherapy) and 45 patients were in Group II (chemotherapy only). Of the 45 patients in Group I, 40 patients were male, 5 patients were female, and the median age was 50 years old (31-66 years old). Of the 45 patients in Group-II, 41 patients were male, 4 patients were female, and the median age was 51 years old (30-64 years old). The average height and weight of Group-I patients before administration were 164.0cm (± 7.36) and 51.0kg (± 9.32), respectively. The average height and weight of Group-II patients before administration were 167.0cm (± 7.69) and 53.2kg (± 9.7), respectively. The details of patient demographics are listed in Table 2. Patients with ECOG performance status less than or equal to 2 and meeting the eligibility criteria were recruited. Of the 90 patients recruited, 67 patients who completed at least 2 cycles of chemotherapy or one radiographic assessment were considered for response assessment. Of these 67 patients, 34 patients were in Group I and 33 patients were in Group II.

[0142] Table 2: Patient Demographics

[0143]

[0144] Efficacy evaluation: progression-free survival (PFS)

[0145] The median progression-free survival (PFS) was found to be 4.38 months for patients in group I and 1.38 months for patients in group II (hazard ratio for PFS, 0.436; 95% CI, 0.264-0.722; p<0.0007). The inclusion of NRC-2694-A in the paclitaxel and platinum chemotherapy regimen was associated with a significant increase in PFS duration (Table 3). Kaplan-Meier estimates of progression-free survival according to treatment group are shown in Figure 1 middle.

[0146] Table 3: Progression-free survival (PFS)

[0147]

[0148] Efficacy evaluation: objective response rate (ORR)

[0149] The inclusion of NRC-2694-A in the chemotherapy regimen significantly increased the ORR in patients in Group I compared to patients in Group II. Complete responses were observed in 5 patients in Group I compared to 2 patients in Group II. Partial responses were observed in 12 patients in Group I compared to 5 patients in Group II. An ORR of 50% was observed in Group 1 and 21% in Group II, with a p-value of 0.016 (Table 4).

[0150] Table 4: Objective Response Rate (ORR)

[0151]

[0152] Efficacy evaluation: Patients were transferred from the chemotherapy-only group to the NRC-2694-A plus chemotherapy group

[0153] The study protocol allowed patients whose disease progressed in Group II (chemotherapy-only group) after two cycles of chemotherapy to receive NRC-2694-A in addition to chemotherapy. Seven such patients who progressed in Group II after two cycles subsequently received NRC-2694-A and chemotherapy. Of these patients, two patients achieved a complete response, while another two had stable disease and one had progressive disease. This suggests that patients who were unresponsive to chemotherapy and therefore had progressive disease exhibited a complete response after the inclusion of NRC-2694-A.

[0154] Efficacy Assessment: Patients proceed to Phase II (monotherapy)

[0155] In addition, 11 patients who completed Phase I treatment [Group I (9 patients) and Group II (2 patients)] continued into Phase II (monotherapy). Of the 9 patients in Group I, 2 patients had a complete response, 4 patients had a partial response, 2 patients had stable disease, and 1 patient had progressive disease at the start of monotherapy.

[0156] During Phase II, 2 patients maintained a complete response. Of the 4 patients who had a partial response in Phase I, 1 patient continued to have a partial response, while 2 patients had stable disease, and 1 patient had progressive disease. The 2 patients who had stable disease in Phase I continued to have stable disease. However, 1 patient who had progressive disease in Phase I continued to have progressive disease.

[0157] Notably, 2 patients from Group II who had partial responses and stable disease earlier achieved complete responses in Phase II. This suggests that NRC-2694-A has therapeutic benefits not only when given in combination with chemotherapy, but also when given as a monotherapy.

[0158] The results for patients who entered phase II are summarized in Figure 2 middle.

[0159] Discussion and Conclusion

[0160] A randomized phase II trial in recurrent head and neck squamous cell carcinoma showed that the addition of NRC-2694-A to paclitaxel and cisplatin / carboplatin chemotherapy significantly improved progression-free survival. Resistance to cisplatin in cancer treatment is determined by overexpression of the EGFR tyrosine kinase receptor, and in poor prognosis patients treated with neoadjuvant cisplatin, cell death is inhibited by upregulation of anti-apoptotic proteins. The phenomenon of multidrug resistance (MDR) during chemotherapy is one of the reasons for the limited clinical efficacy of chemotherapeutic drugs. Importantly, overexpression of the epidermal growth factor receptor (EGFR) or any of its related pathways occurs in more than 90% of head and neck cancers. Increased EGFR protein expression or EGFR gene copy number amplification is associated with poor prognosis, radioresistance, local regional treatment failure, and increased rate of distant metastasis. One of the reasons for EGFR overexpression may be due to radiotherapy, which is the standard line of treatment for head and neck cancer, and this overexpression further leads to disease recurrence.

[0161] In a phase III clinical trial of pembrolizumab in R / M HNSCC, KEYNOTE-048, the ORR of the combination of pembrolizumab and platinum-based chemotherapy was 36% in the CPS>20 population, compared with an ORR of 26% for pembrolizumab alone (Burtness et al., The Lancet, 2019; 394(10212): 1915-1928). In addition, in the absence of targeted therapy, platinum-based chemotherapy alone showed only a 19.5% response. In the same study, cetuximab showed an ORR of 35.6% when combined with platinum-based chemotherapy (Vermorken et al., New England Journal of Medicine, 2008; 359(11): 1116-27).

[0162] In contrast, NRC-2694-A showed better efficacy in terms of PFS and ORR. The addition of NRC-2694-A to chemotherapy was associated with a significant increase in median progression-free survival by 3 months. The study confirmed a statistically significant improvement in PFS. In addition, NRC-2694-A in combination with platinum-based chemotherapy significantly increased ORR compared to chemotherapy alone, and had a favorable safety profile. After completion of chemotherapy, patients receiving NRC-2694-A as a monotherapy also showed objective responses. This finding is important because otherwise these patients would have disease progression if not treated. Therefore, continuing NRC-2694-A after chemotherapy will keep the disease under control in patients who have no other treatment options.

[0163] The response rates observed with NRC-2694-A are superior to those of approved monoclonal antibodies, namely cetuximab and pembrolizumab. Importantly, all currently approved R / M HNSCC treatment options are injectable products that require supervised drug administration in a hospital setting. In addition, there are no orally active treatment options approved to date for R / M HNSCC. NRC-2694-A is an orally active tyrosine kinase inhibitor for the treatment of R / M HNSCC.

[0164] In conclusion, NRC-2694-A in combination with platinum-based chemotherapy not only improved progression-free survival and objective response, but also benefited patients with recurrent head and neck squamous cell carcinoma when given as monotherapy. Clearly, NRC-2694-A may be an important treatment option in the recurrent and / or metastatic setting of head and neck cancer.

Claims

1. Use of a compound in the preparation of a medicament for treating recurrent and / or metastatic head and neck squamous cell carcinoma in a patient, wherein the compound is (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the recurrent and / or metastatic head and neck squamous cell carcinoma is recurrent head and neck squamous cell carcinoma.

3. The use according to claim 2, wherein the recurrent head and neck squamous cell carcinoma is metastatic recurrent head and neck squamous cell carcinoma.

4. The use according to claim 1, wherein treating recurrent and / or metastatic head and neck squamous cell carcinoma comprises reducing the size of a tumor associated with said recurrent and / or metastatic head and neck squamous cell carcinoma.

5. The use according to claim 4, wherein The tumor size is reduced by at least 10% from baseline, Optionally, wherein the size of the tumor is as measured according to RECIST criteria version 1.

1.

6. Use according to the preceding claim 1, wherein the recurrent and / or metastatic head and neck squamous cell carcinoma is resistant to radiotherapy and / or chemotherapy.

7. Use of a compound in the preparation of a medicament for treating recurrent and / or metastatic head and neck cancer in a patient, wherein: The compound is (3-ethynyl-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (NRC-2694) or a pharmaceutically acceptable salt thereof; and Treating head and neck cancer includes reducing the size of one or more tumors associated with the head and neck cancer.

8. The use according to claim 7, wherein the head and neck cancer is recurrent head and neck cancer.

9. Use according to claim 7, wherein the head and neck cancer is metastatic.

10. The use according to claim 7, wherein the head and neck cancer is head and neck squamous cell carcinoma.

11. The use according to claim 7, wherein The tumor size is reduced by at least 10% from baseline, Optionally, wherein the size of the tumor is measured according to RECIST criteria version 1.

1.

12. Use according to claim 7, wherein the head and neck cancer is resistant to radiotherapy and / or chemotherapy.

13. The use according to claim 1 or claim 7, wherein the patient has received at least one line of cancer therapy prior to treatment with the compound.

14. The use according to claim 1 or claim 7, wherein the patient has received at least two lines of cancer therapy prior to treatment with the compound.

15. The use according to claim 1 or claim 7, wherein the patient is a human patient.

16. The use according to claim 1 or claim 7, wherein the patient is male or female.

17. The use according to claim 1 or claim 7, wherein the patient is male.

18. The use according to claim 1 or claim 7, wherein the patient is between 18 and 90 years old.

19. The use according to claim 1 or claim 7, wherein the patient is between 30 and 70 years old.

20. The use according to claim 1 or claim 7, wherein the compound is NRC-2694 dihydrochloride (NRC-2694-A) or NRC-2694 monohydrochloride (NRC-2694-B).

21. The use according to claim 1 or claim 7, wherein the compound is NRC-2694 dihydrochloride (NRC-2694-A).

22. The use according to claim 1 or claim 7, wherein the compound is administered orally to the patient.

23. The use according to claim 1 or claim 7, wherein the compound is administered to the patient in the form of a tablet or capsule.

24. The use according to claim 1 or claim 7, wherein the compound is administered to the patient once or twice daily.

25. The use according to claim 1 or claim 7, wherein the compound is administered to the patient once daily.

26. The use according to claim 1 or claim 7, wherein the compound is administered to the patient at a dose of 50 mg / day to 500 mg / day.

27. The use according to claim 1 or claim 7, wherein the compound is administered to the patient at a dose of 100 mg / day to 400 mg / day.

28. The use according to claim 1 or claim 7, wherein the compound is for use in combination with (a) cisplatin and paclitaxel or (b) carboplatin and paclitaxel.

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