First In Human Safety, Pharmacokinetics and Anti-tumoral Activity of GM102 in Gynecological Cancers

Study Overview
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Brief Summary
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First in Human study, assessing the safety profile, the pharmacokinetics and preliminary antitumor activity of GM102, a new compound (a monoclonal antibody), in patients with previously treated gynecological cancers bearing the AMHRII (anti-mullerian Hormone Receptor II) receptor. The primary objective of the study is to determine the GM102 recommended dose.

Detailed Description
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AMHRII, an embryonic receptor, is reexpressed in a subset of gynecological cancers. GM102 is a humanized low fucose monoclonal antibody with a high affinity to AMHRII receptor. GM102 acts through enhanced capability to engage immune effector cells (macrophages, natural killer (NK) cells) to trigger ADCC (antibody dependent cellular cytotoxicity) and phagocytosis of tumor cells. Patients with gynecological tumors expressing AMHRII receptor on the tumor cells in archived tissue as determined prior to study entry will be eligible for C101 study. C101 consists in a phase I part (dose and schedule escalation) and a phase Ib part (expansion). The phase I part is designed to determine the recommended phase 2 dose (RP2D) using the classical 3+3 dose-finding design. In six successive escalating dose cohorts, patients will receive GM102 infusions every 2 weeks until progression or toxicity. In 4 additional cohorts, patients will receive GM102 infusions weekly until progression or toxicity and GM102 infusions combined with chemotherapy until progression or toxicity. A Trial Steering Committee (TSC) will analyze and qualify the toxicities and will provide recommendations according to the dose administration rules defined in the protocol. At the end of the phase I part, the RP2D will be determined, taking into account dose limiting toxicities (DLTs), overall toxicity, pharmacokinetics and pharmacodynamic effects of GM102. The Phase Ib part of the study will confirm the tolerance of the selected dose (RP2D) and will assess antitumoral activity of GM102 in three parallel cohorts of patients with Sex Cord-Stromal tumors, and AMHRII positive ovarian and cervix cancers. Patients will be treated until progression or toxicity.

Official Title
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Open, Non Controlled, Multicenter, First-in-Human Study for the Evaluation of the Safety, Pharmacokinetics and Preliminary Antitumor Activity of GM102 in Patients With Advanced Pretreated Gynecological Cancer

Conditions
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Neoplasm, Gynecologic

Intervention / Treatment
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* Drug: GM102
* Drug: GM102 escalating doses
* Drug: GM102


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced, or metastatic recurrent gynecological cancer, for whom no standard alternative therapy is available, having received at least one line of therapy and expressing AMHRII on tumor cells. If possible at least one lesion should be identified for 2 biopsies: a baseline biopsy and an under-treatment biopsy for AMHRII expression and GM102 pharmacodynamics evaluation. Available tumor block or at least 10 slides from formalin-fixed paraffin-embedded (FFPE) archival tissue. At least one measurable lesion by RECIST (Response Evaluation Criteria in Solid Tumors) on screening CT-scan. Written Informed Consent forms. Willing and able to comply with the trial requirements. Covered by healthcare insurance in accordance with local requirements. For phase 1b, only patients with either Sex cord stromal tumors or epithelial ovarian cancer or cervix cancer will be eligible Exclusion Criteria: Age < 18 years old. Eastern Cooperative Oncology Group (ECOG) performance status > 1 Life expectancy < 12 weeks. Known or symptomatic brain metastasis (other than totally resected or previously irradiated and non-progressive/relapsing) or lepto-meningeal carcinomatosis. Concurrent treatment with any other anticancer therapy. Concurrent chronic corticosteroid treatment. Known severe anaphylactic or other hypersensitivity reactions secondary to a prior exposure to human antibodies or to any protein product. Washout period before treatment initiation: < 3 weeks or 5 times the half-life, whichever is shorter, for prior antitumor therapy (small molecules and/or antibody-drug conjugates, radiotherapy) or 6 weeks for monoclonal antibodies. Any active concomitant malignancy. Serious concomitant illness e.g. active infection requiring systemic antibiotic, antifungal or antiviral drug, or physical examination or laboratory abnormalities, that, in the opinion of the Investigator, would compromise protocol objectives. Poor bone marrow reserve as defined by neutrophils < 1.0 x 10E9/L or haemoglobin < 9.0 g/dL or platelet count < 100 x 10E9/L. Poor organ function as defined by any one of the following: left ventricular ejection fraction ≤ 40%, serum creatinine > 1.5 x upper limit of normal (ULN), total bilirubin > 1.5 x ULN, AST and ALT> 2.5 x ULN in the absence of liver metastasis or > 5 x ULN in case of documented liver metastasis. Non-resolution of any prior treatment related toxicity to < Grade 2, except for alopecia according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03. Pregnancy or breastfeeding. Patient with reproductive potential who do not agree to use an accepted effective method of contraception - investigator's judgment - during the study period and for at least 4 months following completion of study treatment. Patient participating in another clinical trial investigating a treatment during the study and within 30 days prior to first study treatment administration. Patient deprived of her liberty by a judicial or administrative decision, patient admitted to a hospital, social institution or who is under a measure of legal protection, patient hospitalized without consent or who is in an emergency situation.

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: phase 1 escalation GM102 single agent phase 1 escalation GM102 combined with paclitaxel and carboplatin phase 1b: 3 parallel expansion cohorts at the recommended dose of GM102 single agent
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GM102 escalating doses<br>8 successive cohorts | Drug: GM102<br>* GM102 escalating doses (phase1)<br>|
| Experimental: GM102 escalating doses + carboplatin+paclitaxel<br>2 successive cohorts | Drug: GM102 escalating doses<br>* GM102 escalating doses combined with paclitaxel and carboplatin<br>|
| Experimental: GM102 recommended dose<br>3 parallel cohorts in sex cord stromal, epithelial ovarian and cervix cancers | Drug: GM102<br>* GM102 single agent at recommended dose in 3 parallel cohorts (sex cord, epithelial ovarian, cervix cancers)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I part: incidence of Dose Limiting Toxicities (DLTs) | Number of patients in the DLT evaluable population experiencing at least one DLT | Four weeks | 
| Phase Ib part: incidence of Serious Adverse Events (SAEs) and Treatment-Emergent Adverse Events (TEAEs) at Recommended Phase 2 Dose (RP2D) | Number of patients with at least one AE | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK: Maximum Serum Concentration [Cmax] | Cycle 1 Day 1 pre-dose, Cycle 1 Day 1 End Of Infusion (EOI), Cycle 1 Day 1 EOI + 3 hours, Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 8, Cycle 1 Day 15 pre-dose, Cycle 1 Day 15 EOI, Cycle 2 Day 1 pre-dose, Cycle 2 Day 1 EOI, Cycle 2 Day 15 pre-dose, Cycle 2 Day 15 EOI, Cycle 3 Day 1 pre-dose, Cycle 3 Day 1 EOI, Cycle 3 Day 15 pre-dose, Cycle 3 Day 15 EOI, Cycle 4 Day 1 pre-dose, Cycle 4 Day 1 EOI, Cycle 4 Day 15 pre-dose, Cycle 4 Day 15 EOI | up to 16 weeks | 
| PK: Area Under the Curve [AUC] | Cycle 1 Day 1 pre-dose, Cycle 1 Day 1 End Of Infusion (EOI), Cycle 1 Day 1 EOI + 3 hours, Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 8, Cycle 1 Day 15 pre-dose, Cycle 1 Day 15 EOI, Cycle 2 Day 1 pre-dose, Cycle 2 Day 1 EOI, Cycle 2 Day 15 pre-dose, Cycle 2 Day 15 EOI, Cycle 3 Day 1 pre-dose, Cycle 3 Day 1 EOI, Cycle 3 Day 15 pre-dose, Cycle 3 Day 15 EOI, Cycle 4 Day 1 pre-dose, Cycle 4 Day 1 EOI, Cycle 4 Day 15 pre-dose, Cycle 4 Day 15 EOI | up to 16 weeks | 
| Response Rate using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 | Percentage of patients who achieved a Complete Response (CR) or a Partial Response (PR) based on RECIST version 1.1 | Through study completion | 
| Clinical benefit rate | Percentage of patients achieving Complete Response (CR), Partial Response (PR) or Stable Disease (SD) superior to 3 months | up to 3 months | 
| Duration of response | Duration of overall response in months for patients who achieved PR and/or CR | Through study completion | 
| Time to progression (TTP) | Time from first dose received until objective tumor progression | Through study completion |