Ph Ib/BGJ398/Cervix and Other Solid Tumors

Study Overview
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Brief Summary
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This study will be conducted using 3+3 design and includes, a dose escalation part to define the MTDfRP2D for the combination of BGJ398 and carboplatin/paclitaxel, and a dose expansion part to treat another 12 patients (only cervix cancer) to further evaluate safety of this combination. Safety, tolerability and MTD will be determined in the dose escalation part of the study. The dose expansion will additionally investigate preliminary anti-tumor efficacy in cervical cancer. The dosing cycle is 21 days.

Official Title
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A Phase Ib Study Evaluating BGJ398 in Combination With Chemotherapeutic Regimen in Patients With Stage IV, Recurrent or Persistent Carcinoma of The Cervix and Other Solid Tumors

Conditions
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Tumors, Cancer of Cervix

Intervention / Treatment
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* Drug: BGJ398
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects age >18 years at the time of informed consent Histologically/cytologically confirmed locally advanced or metastatic solid tumors for which no curable therapy exists. In dose expansion part of this study, only patients with stage IV or recurrent/persistent cervical cancer will be enrolled. Confirmation of FGF/FGFR aberration is not required. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Adequate marrow function as defined below: absolute neutrophil count ≥ 1.5 x 10 9/L platelets ≥ 100,000 x 10 9/L hemoglobin ≥ 9.0 g/dL Adequate liver function as evidenced by bilirubin <1.5 times the upper limit of normal (ULN); alanine aminotransferase (AL T) and aspartate aminotransferase (AST) <3 times the ULN Evidence of measurable or evaluable disease, as determined by RECIST v 1.1 Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy, or has not been naturally postmenopausal for at least 12 consecutive months (Le., has had menses at any time in the preceding 12 consecutive months). Oral contraceptives (OC), injected or implanted hormonal methods are not allowed as the sole method of contraception because BGJ398 has not been characterized with respect to its potential to interfere with PK and/or the effectiveness of OCs. It is preferred that archival tumor sample is available for molecular testing, if not available, a newly obtained tumor biopsy may be submitted instead (not mandatory) Exclusion Criteria: For patients enrolled in dose escalation, any number of prior treatments allowed. For patients enrolled in dose expansion, no prior chemotherapy is allowed (previous single agent cisplatin concurrent with radiotherapy is accepted). No prior therapy with paclitaxel, BGJ398 or other FGFR targeting agents. Preexisting> grade 2 peripheral neuropathy Patients with brain metastases are allowed provided that they are clinically stable for a period of 30 days prior to study entry and there is not a requirement for steroids or anti epileptics. History of pancreatitis in last 6 months prior to enrollment. History and/or current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis, or patients with other phosphate regulating abnormalities. Because hyperphosphatemia is a frequent occurrence with BGJ398 treatment, pretreatment and concurrent treatment with phosphate regulating agents is allowed. Current evidence of corneal or retinal disorder/ keratopathy such as bullous/ band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits, etc Since BGJ398 is a likely inhibitor of CYP3A4, patients who are currently receiving treatment with agents that are known sting inducers or inhibitors CYP3A4 are not allowed Treatment with any of the following anti-cancer therapies prior to the first dose of the of BGJ398 within the stated timeframes: intravenous chemotherapy within a period of 4 weeks ( 6 weeks for nitrosourea, mitomycin-C), biological therapy (e,g. antibodies) within a period of time that is   5 t1/2 or less than 4 weeks, whichever is shorter, prior to starting study drug, any other investigational agents within a period of time that is < 5 tl/2 or 4 weeks (whichever is shortest) prior to starting study drug, wide field radiotherapy < 4 weeks or limited field radiation for palliation < 2 weeks prior to starting study drug. Use of medications that increase serum levels of phosphorus and/or calcium. History of cardiac disease (Congestive heart failure NYHA grade> 2, LVEF < 50% as determined by MUGA scan or ECHO, history of clinically significant ventricular arrhythmias, unstable angina pectoriS or acute myocardial infarction <6 months prior to starting study drug, QTcF > 450 msec) Pregnant or nursing (lactating) women.

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: Dose Escalation<br>To determine the MTD/RP2D of BGJ398 when combined with carboplatin and paclitaxel in subjects with locally advanced for metastatic solid tumors. | Drug: BGJ398<br>* BGJ398 will be administered orally once daily on each day of the 21 day cycle.<br>* Other names: BGJ 398;Drug: Carboplatin<br>* Carboplatin will be administered in combination with paclitaxel intravenously on the first day of each 21-day cycle.<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* Paclitaxel will be administered in combination with carboplatin intravenously on the first day of each 21-day cycle.<br>* Other names: Taxol;|
| Experimental: Expansion Cervical Cancer<br>To assess the anti-tumor effect of BGJ398 when combined with carboplatin and paclitaxel in cervix cancer. | Drug: BGJ398<br>* BGJ398 will be administered orally once daily on each day of the 21 day cycle.<br>* Other names: BGJ 398;Drug: Carboplatin<br>* Carboplatin will be administered in combination with paclitaxel intravenously on the first day of each 21-day cycle.<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* Paclitaxel will be administered in combination with carboplatin intravenously on the first day of each 21-day cycle.<br>* Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose (MTD) based on toxicity analysis. | Toxicity will be monitored according to NCI Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.0. | approximately 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time vs. concentration profile of BGJ398 | Plasma concentration versus time profiles. Plasma PK parameters will be used to characterize the PK profiles of BGJ398 when combined with certain chemotherapies. | At Cycle 1 Day 1 and Cycle 2 Day 1 |