A First-In-Human trial of monoclonal antibody IMP in patients with Anti-Müllerian-Hormone-Receptor II (AMHRII) positive gynecological cancers
CASE STUDY TYPE
First-In-Human & pharmacokinetics trial in Oncology (Phase Ia/Ib)
BACKGROUND
Gynecological cancers represent about 50% of women’s cancers, and approximately 500 000 deaths each year. While early-stage tumors can usually be cured with current therapies, there is still a significant medical need for patients with advanced disease. In adults, Anti-Müllerian hormone receptor II (AMHRII) expression is restricted to Sertoli cells and Granulosa cells; but is highly expressed in approximately 70% in gynecological tumors.
The studied investigational medicinal product (IMP) is a glyco-engineered highly selective monoclonal antibody (mAb) targeting the AMHRII that had demonstrated both enhanced Antibody-Dependent Cellular Cytotoxicity and Antibody-Dependent Cellular Phagocytosis, as well as efficacy in preclinical models of cancer.
The goal of this first-in-human (FIH) study was to characterize accurately the safety, tolerability, pharmacokinetic and preliminary signs of activity of the IMP.
METHODS
A phase Ia dose escalation, open label, non-controlled, multicenter, prospective study, to determine the recommended phase II dose of IMP in monotherapy at different regimens (q2w or q1w) and in combination with chemotherapy using 3+3 dose-finding design in patients with advanced pretreated gynecological cancer.
A phase Ib, open label, non-controlled, multicenter, prospective study, to confirm the tolerance of the selected dose in monotherapy and evaluate the activity of IMP in three cohorts of patients.
OBJECTIVES
CO-PRIMARY OBJECTIVES
- Phase Ia: to determine the recommended phase II dose (RP2D)
- Phase Ib: to characterize the safety profile
EXPLORATORY OBJECTIVES
- Describe the tumor growth rate
- Document potential pharmacodynamics
- Assess potential circulating biomarkers predictive of sensitivity
- Identify any other biomarkers predictive of tumor response to IMP
SECONDARY OBJECTIVES
- Assess the pharmacokinetics parameters
- Characterize the safety profile in monotherapy and in combination with chemotherapy
- Evaluate anti-tumor activity
- Assess the potential immunogenicity
SCIENTIFIC and DATA vALORISATION
- Poster presentation at ASCO 2018 & 2019
- Poster presentation at EORTC, NCI, AACR join meeting 2018
Key factors of success
- ICTA’s rigorousness
- ICTA’s capability to propose innovative solutions for uncommon projects
- ICTA’s responsiveness and ability to develop adapted IT tools in a fast-paced and multidisciplinary environment.
LESSONS LEARNED to speed up the start-up phase of the next study
- The importance of a close collaboration between ICTA and Sponsor in order to allow for optimal anticipation of the Sponsor needs, particularly in term of IT tool development
- An accurate and reactive site management to closely follow each inclusion.
CHALLENGES
| KEY CHALLENGES | ICTA’s SOLUTIONS | ICTA’s ACHIEVEMENTS |
|---|---|---|
| Study implementation Multicenter FIH study carried out in 3 countries | Regulatory submissions and sites management in 3 European countries, France, Belgium, The United Kingdom thanks to ICTA’s European network of partners | Successful implementation of the study in the targeted sites and countries within the expected timelines, with 95 % active sites + Close collaboration with Gynecological network of investigators in France |
| Site follow-up during dose escalation phase due to very tight timelines | Close follow up of the sites on a daily basis for patient slots allocation, PK/PD samples handling. Detailed weekly status reports provided to sponsor | Up-to-date data provided to all SRC meetings and green lights obtained for this FIH phase Ia/Ib dose escalation Targeted timelines achieved to trigger Phase II trial in the expected timelines |
| Study design Modification of the study design further to Safety Review Committee (SRC) meeting Addition of new cohorts with different treatment schemes | Adaptation of the eCRF thanks to ICTA in-house EDC system and internal Biometrics and IT development teams | Up-to-date data provided to all SRC meetings and green lights obtained for this FIH phase Ia/Ib dose escalation Targeted timelines achieved to trigger Phase II trial in the expected timelines |
| Budget optimisation required since in the context of the IMP sale to another firm | Drafting of an abbreviated final CSR without appendixes | Drafting of one statistical report at the end of phase Ia and a final CSR at the end of the study |