| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with advanced solid tumor |
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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 | 21.1 |
| 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. |
|
| 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.
|
|
| 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% or INR ≤ 1.5
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, and alkaline phosphatase < 2.5 x ULN, with the following exceptions:
oPatients with documented liver metastases: AST and ALT < 5 x ULN
oPatients with documented liver or bone metastases: alkaline phosphatase < 5 x ULN
8. Subjects receiving therapeutic anticoagulation (such as low−molecular weight heparin or warfarin) should be on a stable dose
9.For subjects requiring a tumor biopsy: subjects must have adequate coagulation function
•Quick time ≥ 60% or INR ≤ 1.5
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.
11.For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures 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. Men must refrain from donating sperm during this same period
12.Ability to understand and the willingness to sign a written informed consent document.
13.Tumor must harbor the following alterations.
(Please refer to section 4.2.1 Inclusion Criteria for full list) |
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| E.4 | Principal exclusion criteria |
Part A
1.Subjects with leptomeningeal disease should be excluded from this clinical trial.
2.Subjects with known unstable brain metastases should be excluded from this clinical trial.
•Exception: Subjects who have undergone surgery and/or radiotherapy and in which brain metastases remain stable or decrease in size for six months after having completed therapy.
3.Subjects with spinal cord compression not definitively treated with surgery and/or radiation.
4.Subjects with uncontrolled intercurrent illness including, but not limited to, active infection, symptomatic congestive heart failure, LVEF < 50%, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
5.Subjects with inability to swallow tablets or capsules.
6.Subjects with known HIV, hepatitis B or hepatitis C infection.
7.Subjects with known history of malabsorption.
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, including chemotherapy, hormonal therapy or radiotherapy, within 3 weeks prior to initiation of study treatment; however, the following are allowed:
•Hormone-replacement therapy or oral contraceptives.
•somatostatin analogues for the treatment of symptoms related with neuroendocrine tumors.
•Gonadotropin-releasing hormone agonists or antiandrogens for prostate cancer.
•Palliative 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 course of 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. Based on the half-life of monoclonal antibodies and the limited overlap on toxicities, a 4 week wash-out period will be allowed.
5.Subjects with known unstable brain metastases should be excluded from this clinical trial.
•Exception: Subjects with treated brain metastasis which remain stable or responding 6 weeks after completing radiotherapy can be included.
6.Uncontrolled intercurrent illness including, but not limited to, active infection, cardiovascular disease, or psychiatric illness/social situations that would limit compliance with study requirements.
7.Subjects with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C.
•Subjects with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.
•Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
8.Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to Cycle 1, Day 1, unstable arrhythmias or unstable angina.
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 (approximately 75 days) 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 (NCI CTCAE Grade 3 and 4).
11.Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-α) and interleukin-2 (IL-2) 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, fusion proteins or any excipient of the experimental product.
13.History of active autoimmune disease in the last three years, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
14.Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
(Please refer to section 4.2.2 Exclusion Criteria for full list) |
|
| 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 |
|
| 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).
Specific Secondary Endpoints for iPROFILER part.
•To determine the prevalence of genetic alterations in the iPROFILER screened population
|
|
| 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 |
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| 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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