| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced oesogastric adenocarcinoma that have received at least one previous chemotherapy line with platinium salt and fluoropyrimidin and with a documented progression. |
| Patients atteints d’un adénocarcinome oesogastrique métastatique ou localement avancé ayant reçu au moins une ligne de chimiothérapie à base de sel de platine et de fluoropyrimidine avec une progression documentée sous chimiothérapie |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced oesogastric adenocarcinoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084873 |
| E.1.2 | Term | Gastrooesophageal junction cancer metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the tumor response to the regimen at 6 months after inclusion |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety of the regimen during the first and second cycles of administration (up to day 42 (D42)) (cf chap 4.1.2.)
- To evaluate the safety and tolerability of the regimen during the whole course of treatment for all kind of toxicities and up to 2 years for immunotherapy-related toxicity (cf chap 10.3.2.)
- To characterize the tumor response to the regimen (duration, time to response)
- To estimate the progression free survival, up to 2 years after inclusion
- To estimate the overall survival, up to 2 years after inclusion
- According to the results of interim analysis: to evaluate tolerance and efficacy of spartalizumab monotherapy in patient with non-amplified MET tumor
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
|
|
| E.4 | Principal exclusion criteria |
- Previous treatment with immunotherapy or MET inhibitor
- Impossibility to take oral medication
- 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) ≥ 160 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.
- 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) >5 x ULN
- Aspartate aminotransferase (AST) >5 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 whith treatment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (ORR) defined as the proportion of patients with at least one objective tumor response (complete or partial) according RECIST v1.1 criteria, within 6 months (8 treatment cycles) after inclusion. Response will be evaluated by thoraco-abdomino-pelvic CT-scan (or abdominal MRI and thoracic CT-scan without injection if contraindication) CT-scan every 9 weeks, with independent centralized reading |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| within 6 months (8 treatment cycles) after inclusion |
|
| E.5.2 | Secondary end point(s) |
Unacceptable toxicity within the first and second treatment cycle (occurrence of the event between D1 to D42 included), defined using the NCI-CTCAE v 4.0 criteria, as follows:
- Adverse event which is considered a toxicity > grade 3 at least possibly related to the study treatment.
AND - Adverse event > grade 3 which is unrelated to disease, disease progression, intercurrent illness, or concomitant medications
AND - Any of the following events:
- Any non-hematological toxicity ≥ grade 3 (except for nausea, vomiting, fatigue)
- Recurring grade 2 pneumonitis
- Myocarditis grade ≥2
- Autoimmune hemolytic anemia, hemolytic uremic syndrome, or acquired hemophilia grade ≥3
- Guillain-Barre, severe peripheral or autonomic neuropathy, or transverse myelitis
- Encephalitis or aseptic meningitis
- Laboratory abnormality ≥ grade 3 lasting >7 consecutive days (except for Nephritis (Grade 3 and 4: Creatinine >3x ULN), for combined elevations of AST or ALT and Total Bilirubin (see details in section 7.1.2 «Criteria for dose reduction / interruption») and for hyperglycaemia and changes in serum electrolytes/enzymes without clinical impact)
- Hematological toxicities defined as: Febrile neutropenia (absolute neutrophil count [ANC] <1.0 x109/L and fever ≥38.5°C) and/or documented infection with ANC <1.0 x 109/L, grade 3 neutropenia lasting >7 consecutive days, grade 4 neutropenia, grade 4 thrombocytopenia or bleeding requiring a platelet transfusion
- Adverse event requiring permanent treatment discontinuation more than 21 days
- Any other study drug related toxicity considered significant enough to be qualified as unacceptable toxicity in the opinion of the investigators after discussion with the sponsor.
Unacceptable toxicity during the whole treatment course (occurrence of the event between D1 to treatment discontinuation), defined using the NCI-CTCAE v 4.0 criteria as above (see below).
All adverse events during the whole treatment course, graded according to the NCI-CTCAE v 4.0 criteria before each cycle.
Duration of overall response (DOR), defined as the time between the first occurrence of tumor objective response, partial or complete (as defined in the primary endpoint above, using RECIST 1.1) and the first radiological progression, with response assessment every 9 weeks, up to 24 months.
Time to response (TTR) defined as the time between inclusion and the first occurrence of tumor objective response (complete or partial, as defined in the primary endpoint above, according to RECIST 1.1) or the end of the study, with response assessment every 9 weeks, up to 24 months.
Progression-free survival up to 24 months after inclusion, defined as the time between inclusion and the date of the first radiological progression (according to RECIST 1.1), death (any cause), or last follow-up (max=24 months), whichever occurs first.
Overall survival (OS) up to 24 months after inclusion, defined as the time between inclusion and death (any cause) or last follow-up (max=24 months), whichever occurs first. Patients alive will be censored at date of last record.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| during participation (18 months) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | |
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