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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Gemcitabine and Carboplatin
* Drug: P276-00 along with Gemcitabine and carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females of age ≥18 years. Histologically documented metastatic triple negative breast cancer (any triple negative breast cancer for Phase I) Two or fewer chemotherapy regimens for advanced disease (no limit of prior regimens for Phase I) ECOG performance score of 1 or less Presence of measurable disease by RECIST 1.1 criteria (not for the Phase I portion) Ability to understand and the willingness to sign a written informed consent document (ICD) Full recovery from all prior treatment toxicities to Common Terminology Criteria for Adverse Events (CTCAE V.4) Grade ≤ 1 Exclusion Criteria: Prior chemotherapy or biologic/targeted anticancer agents within 4 weeks of study drug administration Prior radiation therapy within 6 weeks of study drug administration 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. Prior therapy with gemcitabine or a platinum agent (not for the Phase I part) Prior therapy with a Cdk/cyclin inhibitor or any flavones derivative QTc interval >450 msec (using Fridericia's formula) 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 Visceral crisis including extensive liver disease with>50% parenchymal involvement or lymphangitic pulmonary disease 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 Expected survival of less than 3 months Hemoglobin <9.0 gm/dL Absolute neutrophil count <1500/mm3 Platelet count <100,000/mm3 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >3 × institutional upper limit of normal (ULN) Total bilirubin, >1.5 × institutional ULN Serum creatinine >1.5 mg/dL Subjects with known infection with human immunodeficiency virus (HIV), tuberculosis, Hepatitis C or Hepatitis B Pregnant or lactating women 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 -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gemcitabine and Carboplatin<br>Gemcitabine 1000 mg/m2/day on Days 1 & 8 and carboplatin at AUC 2 on Days 1 and 8 every 21 days. | Drug: Gemcitabine and Carboplatin<br>* Gemcitabine 1000 mg/m2/day on Days 1 & 8 and carboplatin at AUC 2 on Days 1 and 8 every 21 days.<br>|
| Experimental: P276-00 along with Gemcitabine and carboplatin<br>P276-00 will be administered at starting dose of 100 mg/m2/day (and higher if tolerated) in 200 mL of 5% dextrose as an iv infusion over 30 minutes, on Days 1 to 5, along with gemcitabine 1000 mg/m2/day and carboplatin at AUC 2 on Days 1 & 8 every 21 days.In Phase 2 component, P276-00 will be administered at recommended phase II dose of P276-00 in combination with standard dose of gemcitabine and carboplatin. | Drug: P276-00 along with Gemcitabine and carboplatin<br>* In phase I run in period, P276 00 will be administered at starting dose of 100 mg/m2/day (and higher if tolerated) in 200 mL of 5% dextrose as an iv infusion over 30 minutes, on Days 1 to 5, along with gemcitabine 1000 mg/m2/day and carboplatin at AUC 2 on Days 1 & 8 every 21 days. In Phase 2 component, P276-00 will be administered at recommended phase II dose of P276-00 in combination with standard dose of gemcitabine and carboplatin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression free survival | The primary efficacy endpoint will be median progression-free survival (PFS), defined as the time from the beginning of study treatment to the occurrence of documented disease progression or recurrence, or death from any cause | 1 year and above | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | at 3 years | 
| Overall survival at 6 months |  | at 6 months | 
| Progression Free Survival at 6 months |  | at 6 months | 
| Objective response rate |  | upto 3 years and above | 
| Duration of response |  | upto 3 years and above | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple negative breast cancer