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

• ClinicalTrials.gov Identifier: NCT02978755
• Recruitment Status: Completed
• First Posted: December 1, 2016
• Last Update Posted: April 6, 2022
• Sponsor: GamaMabs Pharma
• Information provided by (Responsible Party): GamaMabs Pharma

Tracking Information

• First Submitted Date: November 23, 2016
• First Posted Date: December 1, 2016
• Last Update Posted Date: April 6, 2022
• Study Start Date: June 2016
• Actual Primary Completion Date: June 10, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 27, 2022)

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

Original Primary Outcome Measures (submitted: November 30, 2016)

• Phase I part: incidence of Dose Limiting Toxicities (DLTs) [ Time Frame: Four weeks ]
• Phase Ib part: incidence of Serious Adverse Events (SAEs) and Treatment-Emergent Adverse Events (TEAEs) at Recommended Phase 2 Dose (RP2D) [ Time Frame: Through study completion, an average of 1 year ]

Current Secondary Outcome Measures (submitted: March 27, 2022)

• PK: Maximum Serum Concentration [Cmax] [ Time Frame: up to 16 weeks ]
  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
• PK: Area Under the Curve [AUC] [ Time Frame: up to 16 weeks ]
  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
• Response Rate using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 [ Time Frame: Through study completion ]
  Percentage of patients who achieved a Complete Response (CR) or a Partial Response (PR) based on RECIST version 1.1
• Clinical benefit rate [ Time Frame: up to 3 months ]
  Percentage of patients achieving Complete Response (CR), Partial Response (PR) or Stable Disease (SD) superior to 3 months
• Duration of response [ Time Frame: Through study completion ]
  Duration of overall response in months for patients who achieved PR and/or CR
• Time to progression (TTP) [ Time Frame: Through study completion ]
  Time from first dose received until objective tumor progression

Original Secondary Outcome Measures (submitted: November 30, 2016)

• Maximum Serum Concentration [Cmax] [ Time Frame: up to 16 weeks ]
  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
• Area Under the Curve [AUC] [ Time Frame: up to 16 weeks ]
  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
• Response Rate using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 [ Time Frame: Through study completion, an average of 1 year ]
• Clinical benefit rate defined as percentage of patients achieving Complete Response (CR), Partial Response (PR) or Stable Disease (SD) superior to 3 months [ Time Frame: up to 3 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: First In Human Safety, Pharmacokinetics and Anti-tumoral Activity of GM102 in Gynecological Cancers
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment

• Condition: Neoplasm, Gynecologic

Intervention

• Drug: GM102
  GM102 escalating doses (phase1)
• Drug: GM102 escalating doses
  GM102 escalating doses combined with paclitaxel and carboplatin
• Drug: GM102
  GM102 single agent at recommended dose in 3 parallel cohorts (sex cord, epithelial ovarian, cervix cancers)

Study Arms

• Experimental: GM102 escalating doses
  8 successive cohorts
  Intervention: Drug: GM102
• Experimental: GM102 escalating doses + carboplatin+paclitaxel
  2 successive cohorts
  Intervention: Drug: GM102 escalating doses
• Experimental: GM102 recommended dose
  3 parallel cohorts in sex cord stromal, epithelial ovarian and cervix cancers
  Intervention: Drug: GM102

• Publications *: Prat M, Le Naour A, Coulson K, Lemee F, Leray H, Jacquemin G, Rahabi MC, Lemaitre L, Authier H, Ferron G, Barret JM, Martinez A, Ayyoub M, Delord JP, Gladieff L, Tabah-Fisch I, Prost JF, Couderc B, Coste A. Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression. J Immunother Cancer. 2020 Jun;8(1):e000472. doi: 10.1136/jitc-2019-000472.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 30, 2019): 78
• Original Estimated Enrollment (submitted: November 30, 2016): 51
• Actual Study Completion Date: June 10, 2020
• Actual Primary Completion Date: June 10, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, United Kingdom

Administrative Information

• NCT Number: NCT02978755
• Other Study ID Numbers: C101
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: GamaMabs Pharma
• Original Responsible Party: Same as current
• Current Study Sponsor: GamaMabs Pharma
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Alexandra Leary, MD/PhD; Gustave Roussy center, Villejuif, France

• PRS Account: GamaMabs Pharma
• Verification Date: March 2022