Sponsor decision up DSMB advice due to unfavorable toxicity profile

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.

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