Study to Evaluate Safety & Tolerability of BMS-906024 in Combination With Chemotherapy & to Define DLTs & MTD of BMS-906024 in Combination With One of the Following Chemotherapy Regimens; Weekly Paclitaxel, 5FU+Irinotecan or Carboplatin+Paclitaxel in Subjects With Advanced / Metastatic Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to identify a safe and tolerable dose of BMS-906024 in combination with each of the following three chemotherapy regimens: Paclitaxel, 5FU plus Irinotecan (FOLFIRI), or Carboplatin plus Paclitaxel in subjects with advanced or metastatic solid tumors

Detailed Description
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DLTs = dose-limiting toxicities MTD = Maximum tolerated dose

Official Title
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A Phase Ib Ascending Multi-arm, Dose Escalation Study of BMS-906024 Combined With Several Chemotherapy Regimens in Subjects With Advanced or Metastatic Tumors

Conditions
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Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: 5-Fluorouracil (5FU)
* Drug: Carboplatin
* Drug: Leucovorin
* Drug: Irinotecan
* Drug: Paclitaxel
* Drug: BMS-906024


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: Subjects with advanced or metastatic solid tumors for whom a chemotherapy regimen is considered appropriate Subjects with non-small cell lung cancer and triple-negative breast cancer are preferred Biopsy accessible tumor (may use archived tumor samples under certain circumstances) Life expectancy of at least 3 months Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 Measurable disease Exclusion Criteria: Uncontrolled brain metastases Infection Gastrointestinal (GI) disease with increased risk of diarrhea (e.g. inflammatory bowel disease) Uncontrolled or significant cardiovascular disease Subjects taking medications known to increase risk of Torsades de Pointes

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Paclitaxel + BMS-906024<br>Paclitaxel 80 mg/m2 solution and BMS-906024 4 mg or 6 mg solution intravenously once weekly continuously until disease progression or unacceptable toxicity | Drug: Paclitaxel<br> <br> * Other names: Taxol;Drug: BMS-906024<br> <br> * Other names: Notch inhibitor;|
| Experimental: Arm B: FOLFIRI (5FU, Leucovorin, Irinotecan) + BMS-906024<br>5FU Bolus 400 mg/m2, 5FU Infusion 2400 mg/m2, Irinotecan 180 mg/m2 solution, Leucovorin 400 mg/m2 solution intravenously once every 2 weeks and BMS- 906024 4 mg or 6 mg solution intravenously once weekly continuously until disease progression or unacceptable toxicity | Drug: 5-Fluorouracil (5FU)<br> <br> * Other names: Fluoroplex;Drug: Leucovorin<br> <br> Drug: Irinotecan<br> <br> * Other names: Camptosar;Drug: BMS-906024<br> <br> * Other names: Notch inhibitor;|
| Experimental: Arm C: Carboplatin/Paclitaxel + BMS-906024<br>Carboplatin AUC 6 / Paclitaxel 200 mg/m2 solution once every 3 weeks and BMS-906024 4 mg or 6 mg solution once weekly intravenously continuously until disease progression or unacceptable toxicity | Drug: Carboplatin<br> <br> * Other names: Paraplatin;Drug: Paclitaxel<br> <br> * Other names: Taxol;Drug: BMS-906024<br> <br> * Other names: Notch inhibitor;|
| Experimental: Arm D: Paclitaxel + BMS-906024<br>Paclitaxel 80 mg/m2 solution once weekly and BMS-906024 4 mg or 6 mg solution once every 2 weeks intravenously continuously until disease progression or unacceptable toxicity | Drug: Paclitaxel<br> <br> * Other names: Taxol;Drug: BMS-906024<br> <br> * Other names: Notch inhibitor;|
| Experimental: Arm F: Carboplatin/Paclitaxcel and BMS-906024<br>Carboplatin AUC 6 / Paclitaxel 200 mg/m2 solution once every 3 weeks and BMS-906024 4 mg or 6 mg solution once every 3 weeks intravenously continuously until disease progression or unacceptable toxicity | Drug: Carboplatin<br> <br> * Other names: Paraplatin;Drug: Paclitaxel<br> <br> * Other names: Taxol;Drug: BMS-906024<br> <br> * Other names: Notch inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessment based on reports of adverse events and clinical laboratory tests as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) |  | Up to 30 days after the last dose of study medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) of BMS-906024 and BMS-911557 (the active metabolite of BMS-906024), Paclitaxel, Irinotecan, SN-38 (the active metabolite of Irinotecan) and Carboplatin | Duration of first 3 cycles for Arm A: 10 weeks; Arm B: 6 weeks; Arm C: 9 weeks | 16 time points up to first 3 cycles | 
| Trough observed plasma concentration (Cmin) of BMS-906024 and BMS-911557 (the active metabolite of BMS-906024), Paclitaxel, Irinotecan, SN-38 (the active metabolite of Irinotecan) and Carboplatin | Duration of first 3 cycles for Arm A: 10 weeks; Arm B: 6 weeks; Arm C: 9 weeks | 16 time points up to first 3 cycles | 
| Time of maximum observed plasma concentration (Tmax) of BMS-906024 and BMS-911557 (the active metabolite of BMS-906024), Paclitaxel, Irinotecan, SN-38 (the active metabolite of Irinotecan) and Carboplatin | Duration of first 3 cycles for Arm A: 10 weeks; Arm B: 6 weeks; Arm C: 9 weeks | 16 time points up to first 3 cycles | 
| Area under the concentration-time curve during a dosing interval of tau [AUC(TAU)] of BMS-906024 and BMS-911557 (the active metabolite of BMS-906024) | Duration of first 3 cycles for Arm A: 10 weeks; Arm B: 6 weeks; Arm C: 9 weeks | 16 time points up to first 3 cycles | 
| Area under the concentration-time curve from time 0 to the time of the last sample collected in the dosing interval [AUC(0-T)] of Paclitaxel, Irinotecan, SN-38 (the active metabolite of Irinotecan) and Carboplatin | Duration of first 3 cycles for Arm A: 10 weeks; Arm B: 6 weeks; Arm C: 9 weeks | 16 time points up to first 3 cycles | 
| Steady-state infusion concentration (Css) of 5-Fluorouracil (5-FU) | Duration of first 3 cycles for Arm A: 10 weeks; Arm B: 6 weeks; Arm C: 9 weeks | 16 time points up to first 3 cycles | 
| Tumor response [as defined by Response Evaluation Criteria in Solid Tumors (RECIST) (v.1.1) criteria], best overall response (BOR), duration of response, and progression free survival (PFS) will be assessed |  | Every 6 weeks until confirmed disease progression, death or discontinuation for other reasons (whichever comes first) [Approximately 24 months] | 
| Gene mutation status of Notch activation markers as well as other genes of interest in relevant indications, in tumor, and gene expression levels of Notch activation markers, such as but not limited to Hes1, Deltex1, in tumor |  | Baseline (study days -28 to -1) |