Combination of Capmatinib + Spartalizumab in Advanced Oesogastric Adenocarcinoma

Overview

Immunotherapy with anti-PD1 antibodies provides encouraging results on a subset of patients. Capmatinib, a MET inhibitor, has shown an imunomodulatory effect and a synergy with spartalizumab a PD-1 inhibitor. The purpose of this phase II trial is to evaluate the efficacy and safety of the combination of capmatinib + spartalizumab in adult patients with advanced oesogastric adenocarcinoma.

Full Title of Study: “Phase II Trial to Evaluate the Combination of Capmatinib + Spartalizumab in Advanced Oesogastric Adenocarcinoma”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2023

Interventions

  • Drug: Capmatinib
    • Capmatinib 400mg BID for a maximum of 12 months or until progression, patient’s refusal or unacceptable toxicity
  • Drug: Spartalizumab
    • Spartalizumab 300mg Q3W for a maximum of 12 months or until progression, patient’s refusal or unacceptable toxicity

Clinical Trial Outcome Measures

Primary Measures

  • Tumor response
    • Time Frame: 6 months
    • Overall response rate defined as the proportion of patients with at least one objective tumour response (complete or partial) according to response evaluation criteria in solid tumours (RECIST) v1.1 within 6 months.

Secondary Measures

  • Proportion of unacceptable toxicity of the regimen during the first and second cycles of administration
    • Time Frame: Day 42
    • Presence of at least one of (composite endpoint): Adverse event (AE) grade >3 (NCI-CTCAE v5), at least possibly related to the treatment or unrelated to disease, progression, intercurrent illness, concomitant medications Non-hematological AE grade ≥3 Recurring grade 2 pneumonitis, Myocarditis grade ≥2 Autoimmune hemolytic anemia, hemolytic uremic syndrome, acquired hemophilia grade ≥3 Guillain-Barre, severe peripheral or autonomic neuropathy, transverse myelitis, encephalitis, aseptic meningitis Laboratory abnormality grade ≥3 for >7days (except nephritis grade 3-4, combined elevations of aspartate or alanine transaminase and total bilirubin, hyperglycemia, serum electrolytes/enzymes changes without clinical impact) Febrile neutropenia, documented infection with absolute neutrophil count<10^9/L, grade 3 neutropenia >7days, grade 4 neutropenia or thrombocytopenia, or bleeding with platelet transfusion AE with discontinuation >21days Significant drug-related AE
  • Proportion of unacceptable toxicity of the regimen during the whole treatment course
    • Time Frame: 12 months or treatment discontinuation
    • Presence of at least one of (composite endpoint): Adverse event (AE) grade >3 (NCI-CTCAE v5), at least possibly related to the treatment or unrelated to disease, progression, intercurrent illness, concomitant medications Non-hematological AE grade ≥3 Recurring grade 2 pneumonitis, Myocarditis grade ≥2 Autoimmune hemolytic anemia, hemolytic uremic syndrome, acquired hemophilia grade ≥3 Guillain-Barre, severe peripheral or autonomic neuropathy, transverse myelitis, encephalitis, aseptic meningitis Laboratory abnormality grade ≥3 for >7days (except nephritis grade 3-4, combined elevations of aspartate or alanine transaminase and total bilirubin, hyperglycemia, serum electrolytes/enzymes changes without clinical impact) Febrile neutropenia, documented infection with absolute neutrophil count<10^9/L, grade 3 neutropenia >7days, grade 4 neutropenia or thrombocytopenia, or bleeding with platelet transfusion AE with discontinuation >21days Significant drug-related AE
  • Proportion of patients with adverse events during the whole treatment course
    • Time Frame: 12 months or treatment discontinuation
    • All adverse events during the whole treatment course
  • Duration of overall response
    • Time Frame: 24 months
    • Time between the first occurrence of tumor objective response, partial or complete (RECIST 1.1) and the first radiological progression, with response assessment every 9 weeks, up to 24 months
  • Time to response
    • Time Frame: 24 months
    • Time between inclusion and the first occurrence of tumor objective response (complete or partial, according to RECIST 1.1) or the end of the study, with response assessment every 9 weeks, up to 24 months
  • Progression-free survival
    • Time Frame: 24 months
    • Time between inclusion and the date of the first radiological progression (according to RECIST 1.1), death (any cause), or last follow-up (maximum=24 months), whichever occurs first.
  • Overall survival
    • Time Frame: 24 months
    • Time between inclusion and death (any cause) or last follow-up (maximum=24 months), whichever occurs first

Participating in This Clinical Trial

Inclusion Criteria

  • Histologically or cytologically documented locally advanced or metastatic oesogastric adenocarcinoma. – Unresectable tumor. – Patients must have received at least one prior systemic chemotherapy based on platinium salt and fluoropyrimidine with documented progression during chemotherapy. – Patients must have received trastuzumab in case of HER2 positive tumor (HER2 +++ or HER2++ and FISH or SISH+) – Determination of tumor MET amplification by FISH available – ECOG Performance Status ≤ 1. – Measurable tumoral disease according to RECIST 1.1 criteria. – Patients must be willing and able to swallow and retain oral medication. – Age ≥18 years. – Women of childbearing potential and males who are sexually active must agree to follow instructions for method(s) of contraception for the duration of study treatments with Capmatinib and Spartalizumab until 7 days after the last dose of Capmatinib and 150 days after the last dose of Spartalizumab – Consent to participate in the trial after information – Affiliated to a social security system Exclusion Criteria:

  • Previous treatment with immunotherapy or MET inhibitor – Impossibility to take oral medication – Persistent toxicities related to prior treatment of grade greater than 1 – Presence or history of another malignant disease that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type. – Use of any live vaccines within 4 weeks of initiation of study treatment. – History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs). – History or current interstitial lung disease or non-infectious pneumonitis – Active autoimmune disease or a documented history of autoimmune disease (Patients with vitiligo, controlled type I diabetes mellitus on stable insulin dose, residual autoimmune-related hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic treatment are permitted). – Allogenic bone marrow or solid organ transplant – Uncontrolled active infection – Human Immunodeficiency Virus (HIV) infection – Untreated active Hepatitis B infection (HBsAg positive) (Patients with active hepatitis B (HBsAg positive) may be enrolled provided viral load (HBV DNA) at screening is <100 UI/mL. Patients may receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents before the initiation of study treatment to suppress viral replication). – Untreated active hepatitis C (HCV RNA positive) (patients that achieved a sustained virological response after antiviral treatment and show absence of detectable HCV RNA ≥6 months after cessation of antiviral treatment are eligible) – Untreated or symptomatic central nervous system (CNS) lesion. However, patients are eligible if: a) all known CNS lesions have been treated with radiotherapy or surgery and b) patient remained without evidence of CNS disease progression ≥4 weeks after treatment and c) patients must be off corticosteroid therapy for ≥2 weeks – Clinically significant, uncontrolled heart diseases – Recent acute coronary syndrome or unstable ischemic heart disease – Congestive heart failure ≥ Class III or IV as defined by New York Heart Association – Long QT syndrome (> 480 ms in women and 470 ms in men), family history of idiopathic sudden death or congenital long QT syndrome. – Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥150 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening – Surgery less than 4 weeks – Radiotherapy less than 2 weeks – Pregnancy or breastfeeding or women of child-bearing potential, unless they are using highly effective methods of contraception. – Sexually active males unless they use a condom during intercourse while taking capmatinib and for 7 days after stopping treatment and should not father a child in this period. – Participants receiving treatment with strong inducers of CYP3A and could not be discontinued ≥ 1 week prior to the start of treatment. – Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned date of first dose of study treatment. – Patient having out of range laboratory values defined as: – Total bilirubin >2 mg/dL, except for patients with Gilbert's syndrome who are excluded if total bilirubin >3.0 x ULN or direct bilirubin >1.5 x ULN – Alanine aminotransferase (ALT) > 3 x ULN – Aspartate aminotransferase (AST) > 3 x ULN – Coagulation: Prothrombin Time (PT) >4 seconds more than the ULN or International Normalized Ratio (INR) >1.7 – Absolute neutrophil count (ANC) <1.5 x 109/L – Platelet count <75 x 109/L – Hemoglobin <9 g/dL – Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) <45 mL/min – Serum lipase >1 ULN – Cardiac troponin I (cTnI) elevation >2 x ULN – Potassium, Magnesium, Phosphorus, total Calcium (corrected for serum albumin) outside of normal limits (patients may be enrolled if corrected to within normal limits with supplements during screening) – Patients under legal protection – Participation to another interventional study with treatment

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Assistance Publique – Hôpitaux de Paris
  • Provider of Information About this Clinical Study
    • Sponsor

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