| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with advanced solid tumour |
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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 antitumour activity of each matched therapy in small subject populations as a signal finding study.
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| E.2.2 | Secondary objectives of the trial |
• To determine the prevalence of genetic alteration in the iPROFILER screened population.
• To evaluate the clinical benefit of matching therapies in small patient populations.
• To evaluate the safety and tolerability of each investigational agent tested as assessed by the incidence and severity of adverse events.
Specific to Module 2&3:
• To assess the health-related quality of life (HRQoL) for all enrolled subjects.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Radiomics sub-study (Module 1 specific):
• The primary objective of this sub-study is to evaluate CT-radiomics signature of solid tumours that predicts response to atezolizumab.
• The secondary objectives are to evaluate early changes in CT-radiomics signatures as response to atezolizumab, to evaluate correlation of radiomics features with tumour mutational status to develop radiogenomics phenotypes, and to evaluate correlation of CT-radiomics features with histological features from tumour samples.
SIMPATHY sub-study (Module 1 specific):
• SIMPATHY sub-study aims to produce a detailed map of the tumour immune microenvironment before, during and after failure of ICI treatment with the anti-PDL1 monoclonal atezolizumab, contextualized with genomic and systemic immune features. |
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| 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. (for
M1: Subjects with non-prostate solid tumours must have measurable disease according to RECIST 1.1 and patients with prostate cancer must have a tumour amenable to assess biochemical and/or objective radiographic responses according to PCWG3 and RECIST 1.1.)
5. Subjects must have enough tumour 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 tumour cellularity. If there is not enough archival tissue to meet this criterion, the subject must undergo a tumour biopsy.
• Subjects providing fresh frozen tissue (FFT) must provide 4 core biopsies or equivalent. FFT must be preferentially collected from a tumour 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 × 10 9/L, platelet count ≥ 100 × 10 9/L.
7. Subject must have adequate renal and hepatic function: Serum creatinine ≤ 1.5 × ULN and 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 tumour 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 tumour
10. Ability to understand and the willingness to sign a written informed consent document.
Part B:
Inclusion criterion 2/3/4/6/8/9/10/12 from part A
1. Subjects must have metastatic or unresectable malignant tumour, histologically or cytological confirmed and progressing to current therapy. Tumours must be refractory to standard therapy or tumours for which standard therapy does not exist, or subjects may be unable to receive standard therapy.
2. Subjects must have adequate renal and hepatic function as described in the module protocol::
• 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
3. Subjects receiving therapeutic anticoagulation (such as low−molecular weight heparin or warfarin) should be on a stable dose
4.For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and refrain from donating eggs, as described in the module protocol.
5.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
(Please refer to section 3.1 Inclusion Criteria of iProfiler, Module 1, 2 & 3 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 tumours.
•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, uncontrolled diabetes, active bleeding diathesis, impaired oxygenation requiring continuous oxygen supplementation, ophthalmologic condition that is clinically unstable, 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.History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, fusion proteins or any excipient of the experimental product.
11.Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
13. 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 (example: approximately October to March in the Northern Hemisphere), but subjects must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.
14. History of active tuberculosis.
15. Contraindications included in the product information of the drugs used in the study.
Please refer to section 3.2 Exclusion Criteria for full list of iProfiler and module protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Module 1, 2 & 3:
• Overall response rate (ORR) or complete response (CR) by RECIST 1.1 of different targeted agents in molecularly selected small patient populations.
Specific to Module 1:
* For patients with prostate cancer in arm 1G: ORR at 12 weeks of atezolizumab by a composite of biochemical and/or objective radiographic responses according to Prostate Cancer Working Group 3 (PCWG3) and RECIST 1.1.
No specific primary endpoint in iProfiler (Part A) protocol. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At Week 12 (Module 1 & 3)
At Week 16 (Module 2)
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| E.5.2 | Secondary end point(s) |
Specific Secondary Endpoints for iProfiler (Part A):
•To determine the prevalence of genetic alterations in the iPROFILER screened population.
• Progression free survival (PFS by RECIST 1.1) of the patients treated with each investigational agent evaluated at the end of the module.
*(M1) For patients with prostate cancer in arm 1G: PFS will be assessed by a composite of biochemical and/or objective radiographic progression according to PCWG3 and RECIST 1.1 for patients with prostate cancer.
• Progression Free Survival (PFS by RECIST 1.1) at 6 months of subjects treated with each investigational agent.
(M1)* For patients with prostate cancer in arm 1G: PFS at 6 months will be assessed by a composite of biochemical and/or objective radiographic progression according to PCWG3 and RECIST 1.1 for patients with prostate cancer.
• Overall survival (OS) of subjects treated with each investigational agent evaluated at the end of each module.
• Incidence and severity of adverse events (AEs) in subjects receiving each investigational agent.
Specific Secondary Endpoints for Module 2 &3:
• Duration of response (CR or PR), calculated from the date of initial documentation of a response to the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death. Data from subjects who are progression-free and alive or have unknown status will be censored at the last tumour assessment.
• Health-related quality of life (HRQoL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 items (EORTC-C30) and the 36-item Short Form health survey version 1 (SF36-v1).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Progression free survival at the end of the module.
- Progression Free Survival at 6 months (Module 1&2) & 3 months (Module 3)
- Overall survival at the end of the module
- Safety, continued evaluation during the trial
Specific Secondary Endpoints for Module 2 &3:
- at the last tumour assessment.
- throughout the study course
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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 | 2 |
| 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 | 7 |
| 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 | Yes |
| 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
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| End of the each 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 | 5 |
| 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 | 5 |
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