A Multicentre, Open-label, Phase I-II Study Evaluating the Combination of a MEK Inhibitor and a PDL1 Inhibitor in Pediatric and Adult Patients With Locally Advanced and/or Metastatic Soft Tissue Sarcoma.
Overview
- Phase
- Phase 1
- Intervention
- Cobimetinib
- Conditions
- Sarcoma,Soft Tissue
- Sponsor
- Centre Leon Berard
- Enrollment
- 320
- Locations
- 6
- Primary Endpoint
- Phase II part
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
The proposed study conducted in adult and pediatric patients aims to evaluate the safety and clinical activity of atezolizumab + cobimetinib in advanced/metastatic soft tissue sarcomas (up to 80 patients).
Detailed Description
The hypothesis of the proposed combination is as follows: cobimetinib via MEK1/2 inhibition could modify the tumor microenvironment and improve the response of T cells against tumor cells. Therefore, the addition of cobimetinib to atezolizumab may improve immune recognition and result in improved anti-tumour activity. The combination of cobimetinib and atezolizumab showed clinical activity in a Phase I trial in patients with metastatic colorectal cancer (Atezolizumab 840 mg every 2 weeks and Cobimetinib 60 mg/d) with a disease control rate of 31%. Atezolizumab and cobimetinib are currently being tested in pediatrics in the iMatrix clinical trial with no major safety concerns to date. A molecular screening step is mandatory for all patients enrolled in this trial in order to document MAPK pathway status and Tumor Mutational Burden (TMB) using FoundationOne test (FOne Heme).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female patients aged of at least :
- •12 years on day of signing informed consent.
- •Histologically-confirmed diagnosis of soft tissue sarcomas, confirmed by a pathologist from RRePS Network, among the 2 cohorts:
- •Rhabdomyosarcomas (RMS).
- •Malign Peripheral Nerve Sheath Tumors (MPNST). I
- •Availability of a representative formalin-fixed paraffin-embedded (FFPE) primary and/or metastatic tumor tissue with an associated pathology report for molecular prescreening i.e. either an archival block or a dedicated freshly collected de novo tumor biopsy.
- •Documented MAPK pathway status and known Tumor Mutational Burden (TMB) before C1D
- •Previous treatment with anthracycline-based chemotherapy (in the neoadjuvant, adjuvant or metastatic setting). Note: this criteria not mandatory for rhabdomyosarcoma.
- •Previous treatment by at least one line of chemotherapy in the advanced/metastatic setting before C1D
- •Documented radiological disease progression as per RECIST V1.1 before C1D
Exclusion Criteria
- •Soft tissue sarcoma disease considered curable with surgery or radiotherapy.
- •Prior treatment with cobimetinib or other MEK inhibitors. NI
- •Prior treatment with immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapeutic antibodies.
- •Patients with history of severe allergic or other hypersensitivity reactions to:
- •Chimeric or humanized antibodies or fusion proteins,
- •Biopharmaceuticals produced in Chinese hamster ovary cells, or
- •Any component of the atezolizumab formulation.
- •Any component of Cobimetinib formulation.
- •History of malabsorption syndrome or other condition that would interfere with the absorption of oral medications.
- •Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
Arms & Interventions
Atezolizumab + Cobimetinib
Atezolimumab : * Adult Patient and patients ≥12 years-old with a BW ≥60kg: 840mg, Q2W * Pediatric Patient including patients ≥12 years-old with a BW \<60kg: 15mg/kg, Q2W with a maximum of 840mg. Cobimetinib : * Pediatric patients ≥ 12 and a BW \< 60kg:1mg/kg. Pediatric patients ≥ 12 and with a BW ≥ 60kg: 60mg/d. * Adult Patients: 60mg/d D1 to D21 over a 28-day cycle.
Intervention: Cobimetinib
Atezolizumab + Cobimetinib
Atezolimumab : * Adult Patient and patients ≥12 years-old with a BW ≥60kg: 840mg, Q2W * Pediatric Patient including patients ≥12 years-old with a BW \<60kg: 15mg/kg, Q2W with a maximum of 840mg. Cobimetinib : * Pediatric patients ≥ 12 and a BW \< 60kg:1mg/kg. Pediatric patients ≥ 12 and with a BW ≥ 60kg: 60mg/d. * Adult Patients: 60mg/d D1 to D21 over a 28-day cycle.
Intervention: Atezolizumab
Outcomes
Primary Outcomes
Phase II part
Time Frame: 16 weeks
The Progression Free rate after 16 weeks of treatment is defined as the rate of patients with a complete response or a partial response or a stable disease as per RECIST V1.1.
Secondary Outcomes
- Objective response rate(at 8 weeks and 16 weeks)
- Progression-free survival(Time from the first day of study treatment to the date of the first documented tumor progression or death up to 3 month.)
- Duration of response(Time interval from the date of first occurrence of a documented objective response until the date of documented progression or death in the absence of disease progression up to 3 month.)