A Clinical Trial Comparing Gemcitabine and Carboplatin With and Without P276-00 in Subjects With Metastatic Triple Negative Breast Cancer, With a Run-in of Escalating Dose of P276-00 Added to Gemcitabine and Carboplatin

An Open-Label Randomized Phase II Trial Comparing Gemcitabine and Carboplatin With and Without P276-00 in Subjects With Metastatic Triple Negative Breast Cancer, With a Phase I Run-in of Escalating Dose of P276-00 Added to Gemcitabine and Carboplatin

P276-00 is a novel, potent, small-molecule, flavone-derived Cdk 4 D1, Cdk1 B, and Cdk9 T inhibitor, with potent cytotoxic effects against chemosensitive and chemoresistant cancer cell lines.This study is planned to compare efficacy of the standard chemotherapy regimen of gemcitabine and carboplatin when administered with or without P276-00 in subjects with advanced triple negative breast cancer.

Inclusion Criteria:

1. Females of age ≥18 years.
2. Histologically documented metastatic triple negative breast cancer (any triple negative breast cancer for Phase I)
3. Two or fewer chemotherapy regimens for advanced disease (no limit of prior regimens for Phase I)
4. ECOG performance score of 1 or less
5. Presence of measurable disease by RECIST 1.1 criteria (not for the Phase I portion)
6. Ability to understand and the willingness to sign a written informed consent document (ICD)
7. Full recovery from all prior treatment toxicities to Common Terminology Criteria for Adverse Events (CTCAE V.4) Grade ≤ 1

Exclusion Criteria:

1. Prior chemotherapy or biologic/targeted anticancer agents within 4 weeks of study drug administration

2. Prior radiation therapy within 6 weeks of study drug administration

3. Subject with known active CNS metastases and/or carcinomatous meningitis. However, subjects with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 1 month prior to entry as defined as: (1) no evidence of new or enlarging CNS metastasis or new neurological symptoms attributable to CNS metastases (2) off steroids that are used to minimize surrounding brain edema.

4. Prior therapy with gemcitabine or a platinum agent (not for the Phase I part)

5. Prior therapy with a Cdk/cyclin inhibitor or any flavones derivative

6. QTc interval >450 msec (using Fridericia's formula)

7. Any acute illness including uncontrolled diabetes, symptomatic or otherwise uncontrolled cardiac disease (coronary artery disease, arrhythmias, congestive heart failure) or other illness that in the judgment of the investigator would introduce additional medical risks

8. Visceral crisis including extensive liver disease with>50% parenchymal involvement or lymphangitic pulmonary disease

9. History of other prior malignancies except for properly treated basal cell or squamous cell carcinoma of skin, in situ cervical cancer, or in situ breast cancer

10. Expected survival of less than 3 months

11. Hemoglobin <9.0 gm/dL

12. Absolute neutrophil count <1500/mm3

13. Platelet count <100,000/mm3

14. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >3 × institutional upper limit of normal (ULN)

15. Total bilirubin, >1.5 × institutional ULN

16. Serum creatinine >1.5 mg/dL

17. Subjects with known infection with human immunodeficiency virus (HIV), tuberculosis, Hepatitis C or Hepatitis B

18. Pregnant or lactating women

19. Women of childbearing potential not willing to use approved methods of contraception after signing the ICD, during the entire study and for at least 4 weeks after completion of study or following withdrawal from the study

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