The aim of this study is to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of bemarituzimab given in combination with a fixed dose of bevacizumab and to assess the clinical activity of the proposed combination bemarituzumab and bevacizumab in 3 parallel and independent cohorts of gynecological cancer (endometrium, ovary and cervix).
This trial is a multicenter, single arm, open-label Phase I/II trial that include: * A centralised biological pre-screening to only select patients with FGFR2b overexpressing tumors. * First part : a dose escalation part to define the RP2D of bemarituzumab in combination with fixed dose of bevacizumab (12 to 18 patients independently of tumor types). Eligible patients will be treated with a escalating doses of bemarituzumab : 15 mg/kg cycle 1 day 1, then 11 mg/kg thereafter from cycle 2 day 1; 22 mg/kg cycle 1 day 1, then 15 mg/kg thereafter from cycle 2 day 1; 30 mg/kg cycle 1 day 1, then 22 mg/kg thereafter from cycle 2 day 1; and fixed dose of bevacizumab (15 mg/kg, IV infusion, every 3 weeks). To ensure adequate patient safety during the dose escalation part, there will be a 3-day delay between the first and subsequent patients enrolled in each DL cohort to maximize the safety of enrolled patients. \- Second part : an extension part to assess the clinical activity of the combination in 3 independent and parallel cohort (ovarian, endometrial or cervix carcinoma) (up 25 patients in total per cohort).The Phase II part will use a Simon's min-max two-stage design. Eligible patients will be treated by bemarituzumab (at RP2D defined in the phase I dose escalation, IV, every 3 weeks) and bevacizumab (15 mg/kg, IV, every 3 weeks).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Part 1 Dose escalation part : IV infusion, every 3 weeks with the dose : DL1 = 15 mg/kg cycle 1 day 1, then 11 mg/kg thereafter from cycle 2 day 1 DL2 = 22 mg/kg cycle 1 day 1, then 15 mg/kg thereafter from cycle 2 day 1 DL3 = 30 mg/kg cycle 1 day 1, then 22 mg/kg thereafter from cycle 2 day 1 Part 2 Extension part : IV infusion, every 3 weeks with the dose defined in the phase I dose escalation Treatment with both study drugs will continue until disease progression according to RECIST v1.1, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first
IV infusion, 15mg/kg, every 3 weeks. Treatment with both study drugs will continue until disease progression according to RECIST v1.1, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first
Dose escalation part : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
To Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of bemarituzimab given in combination with a fixed dose of bevacizumab. Dose Limiting toxicities (DLTs) are defined specific adverse events (AEs) graded using NCI-CTCAE v5.0 or specific grading for ocular AE occurring during the DLT period and assessed as related to bemarituzumab and/or bevacizumab
Time frame: 6 weeks
Extension part : Progression free rate (PFR)
To assess the clinical activity of the proposed combination bemarituzumab and bevacizumab in 3 parallel and independent cohorts of gynecological cancer (endometrium, ovary and cervix). PFR-12weeks is defined as the rate of patients with non-progressive disease i.e. complet response (CR)/partial response (PR)/stable disease (SD) as per RECIST v1.1. after 12 weeks of treatment.
Time frame: 12 weeks
Best overall response rate (BORR)
Best overall response rate is determined as the best response (CR/PR/SD or PD) recorded between the cycle 1 day 1 and the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first. For subjects without documented progression or subsequent anticancer therapy, all available response designations will contribute to the BORR determination.
Time frame: Every 6 weeks until 24 weeks post cycle 1 day 1 (each cycle is 21 days) then every 12 weeks, through study completion, an average of 5 years
Duration of response (DoR)
Duration of response will be calculated from date of first documented objective response (i.e., CR or PR) until date of first documented PD.
Time frame: Every 6 weeks until 24 weeks post cycle 1 day 1 (each cycle is 21 days) then every 12 weeks, through study completion, an average of 5 years
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Progression-Free Survival
Progression-Free Survival will be measured from cycle 1 day 1 to the date of the first disease progression or death.
Time frame: Every 6 weeks until 24 weeks post cycle 1 day 1 (each cycle is 21 days) then every 12 weeks, through study completion, an average of 5 years
Overall Survival
Overall Survival will be measured from cycle 1 day 1 to the date of death from any cause.
Time frame: Until up to 1 year follow-up of the last patient enrolled
Adverse events
Incidence of any adverse events graded according to NCI-CTCAE V5.0
Time frame: from the date of first intake of study drug until 100 days after study drug discontinuation, (at least up to 12 months for the last patient in)
Correlation between FGFR2b overexpression level and clinical outcome
To assess if there is a correlation between FGFR2b overexpression level (pre-screening) and clinical outcome.
Time frame: Before inclusion in therapeutic phase (before cycle 1 day 1 (each cycle is 21 days)