METIMGAST: Combination of Capmatinib + Spartalizumab in Advanced Oesogastric Adenocarcinoma
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
- 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
- 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
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
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Histologically or cytologically documented locally advanced or metastatic oesogastric adenocarcinoma.
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Unresectable tumor.
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Patients must have received at least one prior systemic chemotherapy based on platinium salt and fluoropyrimidine with documented progression during chemotherapy.
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Patients must have received trastuzumab in case of HER2 positive tumor (HER2 +++ or HER2++ and FISH or SISH+)
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Determination of tumor MET amplification by FISH available
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ECOG Performance Status ≤ 1.
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Measurable tumoral disease according to RECIST 1.1 criteria.
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Patients must be willing and able to swallow and retain oral medication.
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Age ≥18 years.
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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
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Consent to participate in the trial after information
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Affiliated to a social security system
Exclusion Criteria:
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Previous treatment with immunotherapy or MET inhibitor
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Impossibility to take oral medication
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Persistent toxicities related to prior treatment of grade greater than 1
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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.
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Use of any live vaccines within 4 weeks of initiation of study treatment.
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History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
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History or current interstitial lung disease or non-infectious pneumonitis
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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).
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Allogenic bone marrow or solid organ transplant
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Uncontrolled active infection
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Human Immunodeficiency Virus (HIV) infection
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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).
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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)
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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
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Clinically significant, uncontrolled heart diseases
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Recent acute coronary syndrome or unstable ischemic heart disease
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Congestive heart failure ≥ Class III or IV as defined by New York Heart Association
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Long QT syndrome (> 480 ms in women and 470 ms in men), family history of idiopathic sudden death or congenital long QT syndrome.
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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
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Surgery less than 4 weeks
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Radiotherapy less than 2 weeks
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Pregnancy or breastfeeding or women of child-bearing potential, unless they are using highly effective methods of contraception.
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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.
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Participants receiving treatment with strong inducers of CYP3A and could not be discontinued ≥ 1 week prior to the start of treatment.
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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.
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Patient having out of range laboratory values defined as:
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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
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Alanine aminotransferase (ALT) > 3 x ULN
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Aspartate aminotransferase (AST) > 3 x ULN
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Coagulation: Prothrombin Time (PT) >4 seconds more than the ULN or International Normalized Ratio (INR) >1.7
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Absolute neutrophil count (ANC) <1.5 x 109/L
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Platelet count <75 x 109/L
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Hemoglobin <9 g/dL
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Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) <45 mL/min
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Serum lipase >1 ULN
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Cardiac troponin I (cTnI) elevation >2 x ULN
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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)
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Patients under legal protection
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Participation to another interventional study with treatment
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hôpital Jean Minjoz | Besançon | France | 25030 | |
| 2 | Centre François Leclerc | Dijon | France | ||
| 3 | Centre Léon Bérard | Lyon | France | 69008 | |
| 4 | AP-HP Hôpital Saint Louis | Paris | France | 75010 | |
| 5 | Hôpital Haut Lévêque | Pessac | France | 33604 | |
| 6 | Institut Universitaire du Cancer | Toulouse | France | 31059 | |
| 7 | Institut Gustave Roussy | Villejuif | France | 94805 |
Sponsors and Collaborators
- Assistance Publique - Hôpitaux de Paris
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- APHP201152