| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with advanced solid tumor |
| Patients atteints de tumeurs solides avancées |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
The primary objective is to evaluate the antitumor activity of each matched therapies in small subject populations as a signal finding study.
For Module I, the primary objective will be the overall response rate by RECIST 1.1 of atezolizumab in each of the arms of module. |
L’objectif principal est d’évaluer l’activité antitumorale de chaque thérapie appariée dans de petites populations de patients dans le cadre d’une étude de recherche de signaux.
Pour le module I, l’objectif principal sera le taux de réponse global à l’atézolizumab, évalué d’après la version 1.1 des critères d’évaluation de la réponse dans les tumeurs solides (RECIST) dans chacun des bras du module. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the clinical benefit of matching therapies in small patient populations.
Specific Secondary objective for Module 1:
To characterize the safety and tolerability of atezolizumab as assessed by the incidence and severity of adverse events.
|
Evaluer le bénéfice clinique des thérapies d’appariement dans de petites populations de patients.
Objectif secondaire spécifique pour le module 1 :
Caractériser la sécurité d’emploi et la tolérance de l’atézolizumab, évaluées en fonction de l’incidence et de la sévérité des effets indésirables.
|
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A:
1. Subjects must have histologically or cytologically confirmed malignancy that is metastatic or unresectable, who have progressed to standard therapy, who are receiving a standard anticancer treatment but no subsequent approved treatment would be available upon progression, who are unable to receive standard therapy, or for whom standard therapy does not exist.
2. Subjects must have ECOG performance status of 0 or 1.
3. Subjects must be 18 year-old or older.
4. Subjects must have measurable disease according to RECIST 1.1.
5. Subjects must have enough tumor tissue for molecular analysis
• Subjects providing formalin-fixed paraffin embedded tissue (FFPE) must provide a minimum amount of tissue ranging from 20 to 28 slides depending on the sample tumor cellularity. If there is not enough archival tissue to meet this criterion, the subject must undergo a tumor biopsy.
• Subjects providing fresh frozen tissue (FFT) must provide 4 core biopsies or equivalent. FFT must be preferentially collected from a tumor biopsy; hence, patients must have disease amenable to be biopsied. Otherwise, the subject should have FFT stored in a biobank or biorepository.
• Efforts will be made to provide FFT in at least one quarter of the participating subjects. The proportion of subjects that might provide FFT might change based on the results from the molecular analysis.
• Since some of the tests are performed in FFPE tissue, patients providing FFT from a recent biopsy will have part of the sample processed in FFPE tissue as per Laboratory manual.
6. Subjects must have adequate hematological function: absolute granulocyte count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L.
7. Subject must have adequate renal and hepatic function: creatinine clearance ≥ 30ml/min, serum bilirubin ≤ 1.5 × ULN; unless due to Gilbert’s syndrome, AST/ALT ≤ 5 × ULN if liver metastases are present or AST/ALT ≤ 3 × ULN if
the subject has no liver involvement.
8. For subjects requiring a tumor biopsy: patients must have adequate coagulation function quick time ≥ 60%
9. Subjects must be willing to participate in a clinical trial with a matched therapy according to the molecular profile of his/her tumor
10.For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per year (when used consistently and correctly) during the treatment period and for at least 5 months after the last dose of atezolizumab, in case of being included in Part B of the study. Please see protocol for more details.
11.For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined in the protocol
12. Ability to understand and the willingness to sign a written informed consent document.
Part B:
Inclusion criterion 1/2/3/4 from part A
5. Subjects must be willing to participate in a clinical trial with a matched therapy according to the molecular profile of his/her tumor
6. Subjects must have adequate hematological function: absolute granulocyte count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L
7. Subjects must have adequate renal and hepatic function:
• Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 − age) × (weight in kg) × (0.85 if female)/72 × (serum creatinine in mg/dL)
• Serum bilirubin ≤ 1.5 × ULN; with the following exception: subjects with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled
• AST/ALT ≤ 5 × ULN if liver metastases are present or AST/ALT ≤ 2.5 × ULN if the subject has no liver involvement.
• Subjects receiving therapeutic anticoagulation (such as low−molecular weight heparin or warfarin) should be on a stable dose
8. Specific liver function requirement for module 1: subjects with liver or bone metastases: alkaline phosphatase ≤ 5 × ULN
9. and 10.Women of child-bearing potential and men must agree to use contraception: same as part A.
11. Ability to understand and the willingness to sign a written informed consent document.
12. Tumor must harbor the following alterations
• Arm 1A: BRCA1 or BRCA2 mutations
• Arm 1B: MLH1, MSH2, MSH6, or PMS2 mutations
• Arm 1C: tumors with POLE mutation, POLD1 mutation.
• Arm 1D: hypermutated tumors
• Subjects will be enrolled in this cohort if their tumors do not harbor any mutation required for arms 1A, 1B, 1C or 1F and their tumor mutational load meet the specified criteria.
i. High mutational load (>=16 mutation per Megabase as per FoundationOne test).
ii. Intermediate mutational load (12-<16 mutations per Megabase per FoundationOne test).
The definition of intermediate mutational load might be adjusted after an Interim analysis based on the available data.
• Arm 1E: tumors with other mutations in DNA-repair genes.
• Arm 1F: tumors with amplified PDL1. |
Partie A.
1. Les patients doivent présenter une tumeur maligne confirmée sur le plan histologique ou cytologique, métastatique ou non résécable, ayant progressé sous une thérapie standard, qui reçoivent un traitement anticancéreux standard, mais pour lesquels aucun traitement ultérieur autorisé ne serait disponible en cas de progression, qui ne peuvent pas recevoir de thérapie standard ou pour lesquels il n’existe pas de thérapie standard.
2. Indice de performance ECOG de 0 ou 1.
3. Patients âgés de 18 ans ou plus.
4. Les patients doivent être atteints d’une maladie mesurable selon les critères RECIST 1.1.
5. L’échantillon de tissu tumoral du patient doit être disponible en quantité suffisante pour permettre l’analyse moléculaire.
• Les patients qui fournissent un échantillon de tissu fixé au formol et inclus en paraffine (FFPE) doivent fournir une quantité minimale de tissu allant de 20 à 28 lames en fonction de la cellularité de la tumeur de l’échantillon. Si la quantité d’échantillons de tissu archivé est insuffisante pour répondre à ce critère, le patient réalisera une biopsie tumorale.
• Les patients qui fournissent des tissus frais congelés doivent fournir 4 échantillons obtenus par microbiopsie ou équivalent.
• On s’efforcera de fournir des tissus frais congelés chez au moins un quart des patients qui participent à l’étude.
6. Les patients doivent présenter une fonction hématologique adéquate : nombre absolu de granulocytes ≥ 1,5 × 109/l et numération plaquettaire ≥ 100 × 109/l.
7. Le patient doit présenter une fonction rénale et hépatique adéquate :
• Clairance de la créatinine ≥ 30 ml/min.
• Bilirubine sérique ≤ 1,5 × LSN ; sauf en cas de syndrome de Gilbert.
• ASAT/ALAT ≤ 5 × LSN si des métastases hépatiques sont présentes ou ASAT/ALAT ≤ 3 × LSN si le patient ne présente aucune atteinte hépatique.
8. Pour les patients nécessitant une biopsie tumorale : les patients doivent présenter une fonction de coagulation adéquate.
• Taux de prothrombine ≥ 60 %
9. Les patients doivent être disposés à participer à un essai clinique sur une thérapie appariée en fonction du profil moléculaire de leur tumeur.
10. Pour les femmes en âge de procréer : consentement à faire abstinence (s’abstenir d’avoir des rapports hétérosexuels) ou à utiliser des méthodes de contraception ayant un taux d’échec < 1 % par an (lorsqu’elles sont utilisées systématiquement et correctement) pendant la période de traitement et pendant au moins 5 mois après la dernière dose d’atézolizumab, en cas d’inclusion dans la partie B de l’étude.
11. Pour les hommes : consentement à faire abstinence (s’abstenir d’avoir des rapports hétérosexuels) ou à utiliser des moyens de contraception ayant un taux d’échec < 1 % par an (lorsqu’ils sont utilisés systématiquement et correctement) pendant la période de traitement et pendant au moins 5 mois après la dernière dose d’atézolizumab, en cas d’inclusion dans la partie B de l’étude. Les hommes doivent s’abstenir de faire don de sperme pendant cette même période.
12. Capacité de comprendre et volonté de signer un document de consentement éclairé par écrit.
Partie B:
Critères d'inclusion 1-4 de la partie 1.
5. Les patients doivent être disposés à participer à un essai clinique sur une thérapie appariée en fonction du profil moléculaire de leur tumeur.
6. Les patients doivent présenter une fonction hématologique adéquate : nombre absolu de granulocytes ≥ 1,5 × 109/l et numération plaquettaire ≥ 100 × 109/l
7. Le patient doit présenter une fonction rénale et hépatique adéquate :
• Créatinine sérique ≤ 1,5 × LSN et clairance de la créatinine ≥ 30 ml/min d’après le taux de filtration glomérulaire estimé par la formule de Cockcroft-Gault.
• Bilirubine sérique ≤ 1,5 × LSN sauf les patients atteints de la maladie de Gilbert et présentant un taux de bilirubine sérique ≤ 3 × LSN peuvent être inclus.
• ASAT/ALAT ≤ 5 × LSN si des métastases hépatiques sont présentes ou ASAT/ALAT ≤ 2,5 × LSN si le patient ne présente aucune atteinte hépatique.
• Les patients recevant un traitement anticoagulant à visée thérapeutique (comme de l’héparine de faible poids moléculaire ou de la warfarine) doivent recevoir une dose stable.
8. Exigence spécifique concernant la fonction hépatique pour le module 1
• Patients ayant des métastases hépatiques ou osseuses : phosphatase alcaline ≤ 5 × LSN
9. et 10. Les femmes en âge de procréer et les hommes doivent utiliser des méthodes de contraception (voir partie A).
11. Capacité de comprendre et volonté de signer un document de consentement éclairé par écrit.
12. La tumeur doit être porteuse des modifications suivantes:
• Bras 1A : mutations BRCA1 ou BRCA2
• Bras 1B : mutations MLH1, MSH2, MSH6 ou PMS2
• Bras 1C : tumeurs porteuses de la mutation POLE, mutation POLD1
• Bras 1D : tumeurs hypermutées
• Bras 1E : tumeurs portant d’autres mutations dans les gènes de réparation de l’ADN
• Bras 1F : tumeurs avec amplification du gène PDL1
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|
| E.4 | Principal exclusion criteria |
Part A:
1.Subjects with known brain metastases or leptomeningeal disease
2.Subjects with spinal cord compression not definitively treated with surgery and/or radiation
3.Subjects with uncontrolled intercurrent illness
4.Subjects with inability to swallow tablets or capsules
5.Subjects with known HIV, hepatitis B or hepatitis C infection
6.Subjects with known history of malabsorption
7.Pregnant and lactating women. Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to Day 1.
Part B:
1.Pregnant or breastfeeding women. Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to Day 1. This negative test will be valid for Cycle 1 day 1. In subsequent cycles, serum pregnancy test will be performed on day 1 of each cycle, with a +/- 3 day window, and prior to drug administration.
2.Any approved anticancer therapy within 3 weeks prior to initiation of study treatment. Exception: hormone-replacement therapy or oral contraceptives; alliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day 1.
3.Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the study
4.Treatment with an investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within five half-lives of the investigational product, whichever is longer), with the exception of monoclonal antibodies (4 week wash-out period)
5.Subjects with known unstable brain metastases. Exception: treated brain metastasis which remain stable or responding 6 weeks after completing radiotherapy
6.Uncontrolled intercurrent illness that would limit compliance with study requirements
7.Subjects with active hepatitis B (HBV) or hepatitis C (HCV). Subjects with past HBV infection or resolved HBV infection are eligible. Subjects positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
8.Significant cardiovascular disease within 3 months prior to Cycle 1, Day 1, unstable arrhythmias or unstable angina.
Known left ventricular ejection fraction (LVEF) < 40% will be excluded. Known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
Uncontrolled effusion requiring recurrent drainage procedures; subjects with indwelling catheters are allowed.
Uncontrolled hypercalcemia (>1.5mmol/L ionized calcium or Ca > 12mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
9.Another primary malignancy other than disease under study within 2 years prior to Cycle 1 Day 1, unless consider at low risk of relapse at Investigator discretion
10.Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD1, or anti−PDL1 therapeutic antibodies. Subjects who have received prior treatment with anti−CTLA-4 may be enrolled, provided at least 5 half-lives have elapsed from the last dose of anti-CTLA-4 to the first dose of Atezolizumab and there was no history of severe immune-mediated adverse effects from anti−CTLA-4
11.Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is longer) prior to Cycle 1, Day 1
12.History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins, fusion proteins or any excipient of the experimental product.
13.History of active autoimmune disease in the last three years (unless exceptions)
14.Prior allogeneic bone marrow transplantation or prior solid organ transplantation
15.Evidence of active pneumonitis on screening chest CT scan or history of idiopathic pulmonary fibrosis, drug-induced pneumonitis, or organizing pneumonia. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
16.Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study. Influenza vaccination can be given during influenza season only but patients must not receive live, attenuated influenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at any time during the study
17.Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to
C1D1, or anticipated requirement for systemic immunosuppressive medications during the trial. Exception: provided into the protocol
18.History of active tuberculosis
19.Contraindications included in the product information of the drugs used in the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Overall response rate (ORR) by RECIST 1.1 of different targeted agents in molecularly selected small patient populations.
Specific Primary Endpoint for Module 1
• Overall response rate by RECIST 1.1 of atezolizumab in each of the arms of module. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At Week 12 |
| A la semaine 12 |
|
| E.5.2 | Secondary end point(s) |
• Mean progression free survival (PFS by RECIST 1.1) of the patients participating in iBASKET evaluated at the end of the module.
• Progression Free Survival (PFS by RECIST 1.1) at 6 months of subjects treated with targeted therapy in iBASKET.
• Mean overall survival of subjects treated with targeted therapy in iBASKETevaluated at the end of the module.
Specific Secondary Endpoints for Module 1
• To evaluate the safety of atezolizumab in subjects with recurrent or metastatic solid tumors. Continued evaluation during the trial (Module 1). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Mean progression free survival at the end of the module.
- Progression Free Survival at 6 months
- Mean overall survival at the end of the module
-Safety, continued evaluation during the trial |
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| 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 | No |
| 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 | Yes |
| 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 | Yes |
| 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 |
| basket of basket study, modular study |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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
|
| End of the module will be considered 6 months after the last dose of the last participant patient in that specific module (after the Follow-up visit) or until all subjects have died, withdrawn consent or are lost to follow-up (whichever occurs first). A subject will be considered lost to follow up when reasonable attempts are made by the site to contact him/her without success. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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