Treatment of cancer with dihydropyrazino-pyrazines

• US 9,980,963 B2
• Filed: 10/21/2016
• Issued: 05/29/2018
• Est. Priority Date: 04/17/2013
• Status: Active Grant

• Current Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Original Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Inventors: Raymon, Heather, Xu, Shuichan, Lopez-Girona, Antonia, Tsuji, Toshiya, Hege, Kristen Mae
• Primary Examiner(s): TRAN, MY CHAU T
• Application Number:
  US15/299,589
• Publication Number:
  US 20170065583A1
• Time in Patent Office: 585 Days
• Field of Search: 514249
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574

Abstract

Provided herein are methods for treating or preventing chronic lymphocytic leukemia, comprising administering an effective amount of a Dihydropyrazino-Pyrazine Compound to a patient having chronic lymphocytic leukemia.

Claims

1. A method for treating CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to a patient having CLL or T-PLL, wherein said patient is administered about 0.5 mg once per day or about 4 mg, about 8 mg or about 10 mg twice per day of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

2. The method of claim 1, wherein said patient is administered about 0.5 mg once per day of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

3. The method of claim 1, wherein said patient is administered about 4 mg, about 8 mg or about 10 mg twice per day of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

4. The method of claim 1, wherein said patient is administered about 10 mg twice per day of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

5. The method of claim 1, wherein said patient is administered a unit dosage form comprising 0.25 mg, 1.0 mg, 5.0 mg, 7.5 mg, or 10 mg of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

9. The method of claim 1, 6, 7 or 8, wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q, loss or mutation of the gene encoding ATM, loss of ATM expression or function, mutation of IgVH, wild type IgVH, wild type p53/ATM, mutation of p53, dysfunctional p53 or Zap-70 positivity.

10. The method of claim 1, 6, 7 or 8, wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q or loss or mutation of the gene encoding ATM.

6. A method for achieving an International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response definition of complete response, complete response with incomplete marrow recovery, partial response or stable disease in a patient having CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient, wherein said patient is administered about 0.5 mg once per day or about 4 mg, about 8 mg or about 10 mg twice per day of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

7. A method for achieving a National Cancer Institute-sponsored Working Group on Chronic Lymphocytic Leukemia (NCI-WG CLL) response definition of complete response, complete response with incomplete marrow recovery, partial response or stable disease in a patient having CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient, wherein said patient is administered about 0.5 mg once per day or about 4 mg, about 8 mg or about 10 mg twice per day of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

8. A method for treating CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to a patient having CLL or T-PLL, wherein the treatment results in one or more of inhibition of disease progression, increased Time To Progression (TTP), increased Overall Survival (OS), increased Progression-free Survival (PFS), increased Event-free Survival, increased Disease-free Survival, increased Response Duration, increased Lymphoma-specific survival, and/or increased Time To Next Treatment, wherein said patient is administered about 0.5 mg once per day or about 4 mg, about 8 mg or about 10 mg twice per day of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

11. A method for treating CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in combination with etoposide to a patient having CLL or T-PLL.