Oesophageal Adenocarcinoma, Gastric Adenocarcinoma
Conditions
Brief summary
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.
Interventions
DRUGCapmatinib
Capmatinib 400mg BID for a maximum of 12 months or until progression, patient's refusal or unacceptable toxicity
DRUGSpartalizumab
Spartalizumab 300mg Q3W for a maximum of 12 months or until progression, patient's refusal or unacceptable toxicity
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Multicenter single-arm adaptive phase II trial with 2 cohorts according to MET amplification level : * Cohort 1: tumor without MET amplification (\< 6 copies); * Cohort 2: tumor with MET amplification (≥6 copies).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor response | 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
| Measure | Time frame | Description |
|---|---|---|
| Proportion of unacceptable toxicity of the regimen during the whole treatment course | 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 | 12 months or treatment discontinuation | All adverse events during the whole treatment course |
| Duration of overall response | 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 |
| Proportion of unacceptable toxicity of the regimen during the first and second cycles of administration | 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 |
| Progression-free survival | 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 | 24 months | Time between inclusion and death (any cause) or last follow-up (maximum=24 months), whichever occurs first |
| Time to response | 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 |
Countries
France
Outcome results
None listed