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Administration of mntor inhibitor to treat patients with cancer

An inhibitor and drug delivery technology, applied in pharmaceutical formulations, anti-tumor drugs, drug combinations, etc., can solve the problems of oral ulcer toxicity and affecting the therapeutic effect of mTOR inhibitors, etc.

Inactive Publication Date: 2009-02-04
ARIAD PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nonetheless, oral ulceration can attenuate and can constitute a dose-limiting toxicity with newer mTOR inhibitors, severe enough to warrant consideration by patients and caregivers, and in some cases severe enough to warrant execution, discontinuation, or reduction of mTOR inhibitors dosage, even though doing so may affect the therapeutic effect of mTOR inhibitors

Method used

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  • Administration of mntor inhibitor to treat patients with cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: Oral formulation AP23573

[0067] The following procedure was used to prepare tablets each containing 10 mg of AP23573 and the ingredients listed below. The tablets are coated with two different coatings - a film-coated tablet for immediate release and an enteric-coated tablet for delayed release. The composition of the tablet cores is shown in the table below. The tablet cores are film-coated and can be used as such, or they can also be enteric-coated.

[0068] components

weight percentage

AP23573

8.00％

BHT

0.08％

Hydroxypropyl Cellulose

8％

lactose monohydrate

50.57％

microcrystalline cellulose

30.85％

Croscarmellose Sodium

2.00％

Magnesium stearate

0.50％

Absolute Ethanol (Ethanol) *

-

[0069] * Used in the process but not present in the final product

[0070] Hydroxypropyl cellulose, lactose monohydrate, microcrystalline cellulose...

Embodiment 2

[0080] Example 2: Phase I dose-escalation trial of oral AP23573 in patients with unresponsive or progressive malignancies

[0081] Background: In a phase I clinical trial of an intravenous (IV) formulation of the mTOR inhibitor AP23573, the drug was well tolerated and active against a wide range of cancers. This trial is a safety, tolerability and maximum tolerated dose (MTD) test for oral dosage form of AP23573. Its secondary purpose is to study the antitumor activity, pharmacokinetics (PK) and pharmacodynamics (PD) of AP23573.

[0082] Methods: The selected patients were initially randomly grouped (at least 3 patients in each group), and the fixed initial dose of 20mg / day was one of the three 28-day dosing regimens, that is, once a day for 4 consecutive days a week (QDx4), 21 consecutive days in 28 days (QDx21), or 28 consecutive days (QDx28). Subsequent dose levels were determined based on the safety and tolerability of the first cycle of medication, and were recorded i...

Embodiment 3

[0086] Example 3: Other Studies

[0087] Additional clinical studies of AP23573 were conducted using 30, 40 or 50 mg of AP23573 / day according to the QDx5 dosing regimen. Patients receiving doses of 30 and 50 mg were given a loading dose on the first day of each week so that the dose on that day was doubled to 60 and 100 mg, respectively.

[0088] Methods: In a phase 1 / 2a trial of single-drug oral AP23573, 17 patients, 9 of whom were sarcoma patients, were studied with selected doses and dosing regimens (40mg QDx5). In addition, of the 7 patients who were initially given 50 mg QDx5, 4 patients (2 of whom were sarcoma patients) had their dose reduced to 40 mg. Therefore, 21 patients received the 40mg QDx5 regimen, 11 of whom were sarcoma patients.

[0089] In another study of QDx5, the dose was doubled on the first day of the week (to include the loading dose), and 7 patients (6 with sarcoma) received weekly doses of 60, 30, 30, 30 and 30 mg ( That is, a regimen of 30mg QDx5,...

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PUM

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Abstract

The invention features methods for treatment of a patient in need thereof with the administration of mammalian target of rapamycin (mTOR) inhibitors such as sirolimus, temsirolimus, everolimus or rapamycin analogs including AP23573, especially to a cancer patient for 4 or 5 consecutive days per week. The mTOR inhibitor therapy can be used for a wide range of cancers including prostrate, pancreas, ovary, lung, breast, bladder, colon, brain, head and neck, endometrium, leukemia, lymphoma and sarcoma.

Description

technical field [0001] The present invention relates to the administration of mTOR inhibitors to patients in need thereof, particularly cancer patients. Background technique [0002] Several mTOR inhibitors are currently being evaluated as single agents or as combination agents for various cancer treatments. Those mTOR inhibitors include rapamycin analogues, AP23573 (ARIAD Pharmaceuticals, Inc.), everolimus (Novartis, Novartis) and temsirolimu (Wyeth, Wyeth). )Wait. Other mTOR inhibitors, including sirolimus (rapamycin), and other analogs ABT-578 and biolimus. However, AP23573, everolimus, and Torisel all produced positive results in human studies, and oral ulcers were noted as a dose-limiting toxicity. [0003] Oral ulcers were previously classified simply as mucositis in some cases. For a review of the pathology of mucositis, see Stephen T. Sonis, Nature Reviews | Cancer vol. 4, 277-284 (April 2004). See also Rubenstein et al., Mucositis: Perspectives and Clinical Pra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/436A61P35/00
CPCA61K31/4353A61K31/502A61P35/00A61P35/02A61P43/00
Inventor 卡米尔·L·贝德罗塞安
Owner ARIAD PHARMA INC
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