| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
•Molecularly selected cohorts that harbor DNA repair deficiency:
–Non-Small Cell Lung Cancer
–Urothelial Bladder Cancer
–Metastatic Castration Resistant Prostate Cancer
–Others: any histology, excepted breast cancer or serous ovarian cancer
•Platinum-sensitive disease:
-Non-Small Cell Lung Cancer
-Urothelial Bladder Cancer
-Gastric or gastro-esophageal junction adenocarcinoma
•Metastatic Castration Resistant Prostate Cancer (mCRPC)
•Clear Cell Renal Cell Carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
Non-Small Cell Lung Cancer,Urothelial Bladder Cancer,Metastatic Castration Resistant Prostate Cancer,Gastro-esophageal junction adenocarcinoma,Clear Cell Renal Cell Carcinoma...
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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 | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10005003 |
| E.1.2 | Term | Bladder cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073251 |
| E.1.2 | Term | Clear cell renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10066350 |
| E.1.2 | Term | Adenocarcinoma of the gastrooesophageal junction |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 of the trial is to evaluate the antitumor activity of atezolizumab and rucaparib in patients with selected advanced solid tumors as measured by the Overall Response Rate at 12 weeks according to RECIST v1.1 (or PSAWG-criteria for prostate cancer patients). |
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| E.2.2 | Secondary objectives of the trial |
To describe :
-Disease Control Rate, Overall Response Rate, Duration Of Response, Best Overall Response Rate, Progression-Free Survival, Time To Progression, percentage of change from baseline in tumor size
-DCR, ORR, DOR, BORR, PFS, TTP, and percentage of change from baseline in tumor size
To evaluate :
-Overall Survival
-safety and tolerability of atezolizumab and rucaparib in combination in patients with selected advanced solid tumors
To explore relationship between:
- tumor DNA repair deficiency and measures of efficacy
- immune-related biomarkers and measures of efficacy
To evaluate the relationship between DDR status and measures of efficacy.
To explore:
-relationship between immune-related biomarkers and DNA repair-related biomarkers
-modification of immune-related and DNA repair-related biomarkers on treatment
To assess whether the identified biomarkers of interest are private to each tumor type or shared across histologies
To evaluate quality of life |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent form.
2. Age ≥ 18 years.
3. Patients must have histologically or cytologically confirmed progressive metastatic or recurrent solid tumor (as defined below for each tumor type). Diagnosis must be stated in a pathology report and confirmed by the investigator.
4. To be enrolled in this study, only the tumor types and settings described below are allowed:
4.1 - Cohorts 1 A-D: DNA repair deficiency, defined as bi-allelic loss-of-function alteration (mutation and/or deletion) in at least one of the following genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, PALB2, RAD51C, RAD51D, FANCA, NBN, RAD51, RAD54L.
4.2 - Cohorts 2A-C: Platinum-sensitive disease defined as disease which reached at least partial response after the last platinum chemotherapy line and progressed at least 3 months after the last cycle of chemotherapy
4.3 - Cohort 3: Metastatic Castration Resistant Prostate Cancer (mCRPC)
4.4 - Cohort 4: Clear cell Renal Cell Carcinoma
5. Representative archival formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or 20 freshly cut and unstained slides, with an associated pathology report, for ancillary studies and central testing, is mandatory for all cohorts. In all cases, recovery of the most recent tumor block or biopsy is encouraged and tumor tissue has to date back from less than 3 years ago. If tumor tissue is more than 3 years old, a fresh tumor biopsy is mandatory for cohorts 1, 2 and 4.
6. Measurable disease, defined as:
-For the non-prostate cohorts: At least one lesion, not previously irradiated, measurable according to RECIST v1.1 as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and suitable for repeated assessment.
-For prostate cohorts: At least one lesion, not previously irradiated, measurable according to RECIST v1.1 and / or bone scan measurable disease (Cf inclusion criteria 4) and / or measurable disease according to Prostate Cancer Working Group Criteria 3 (PCWG3)
7. Agreement of the patient to sign the genetic analysis consent form for access to plasma samples for ctDNA analysis.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration from registration date.
9. Estimated life expectancy of greater than 12 weeks.
10. Adequate hematologic and organ function, defined by the following laboratory results obtained within 3 days prior to the first study treatment (Cycle 0 Day 1):
o Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks before cycle 0 day 1).
o Platelet count ≥ 100.000/μL (without transfusion within 2 weeks before Cycle 0 Day 1).
o Hemoglobin ≥ 9g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion).
o Total bilirubin ≤ 1.5 ULN (subjects with documented/suspected Gilbert’s disease or liver metastases may be enrolled with bilirubin ≤ 3 × ULN).
o Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit (ULN) or ≤ 5 × ULN in case of liver metastases.
o Albumin ≥ 28g/L.
o Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40mL/min (according to Cockroft and Gault formula).
o International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular weight heparin or warfarin) should be on stable dose.
11. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior to the administration of the first study treatment
12. Sexually active women of childbearing potential must agree to use a highly effective method of contraception << supplemented by a barrier method >>, or to abstain from sexual activity during the study and for at least 6 months after the last study treatment administration.
13. Sexually active males patients must agree to use condom during the study and for at least 6 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception.
14. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
15. Patient should be able and willing to comply with study visits and procedures as per protocol.
16. Patients must be affiliated to a social security system or beneficiary of an equivalent system.
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| E.4 | Principal exclusion criteria |
1. Participation in another clinical study with an investigational product during the last 4 weeks (excepting observational or non-interventional clinical studies) and while on study treatment.
2. Receipt of the last dose of anti-cancer therapy 28 days prior to the first dose of study drug, or five half lives of the previous agent, whichever is the shorter.
3. Prior radiation therapy within 2 weeks prior to Cycle 0 Day 1.
4. History of another primary malignancy within 5 years prior to Cycle 0 Day 1 except for:
. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence.
. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
. Adequately treated carcinoma in situ without evidence of disease (eg, carcinoma in situ of the cervix, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
5. Treatment with systemic corticosteroids or other immunosuppressive medications within 2 weeks prior to Cycle 0 Day 1, or anticipated requirements for systemic immunosuppressive medications during the trial
6. Acute toxicities from previous therapies that have not resolved to Grade ≤ 1, with the exception of alopecia.
7. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
8. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
9. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation.
10. History of autoimmune/immune mediated inflammatory disease excepted stable hypothyroidism or stable Type 1 diabetes mellitus.
11. Active or prior documented inflammatory bowel disease
12. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan – History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
13. History of allogeneic organ transplant or prior bone marrow transplantation of double umbilical cord blood transplantation.
14. Uncontrolled intercurrent illness
15. Patients with known left ventricular ejection fraction (LVEF) < 40%; patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable cardiologic treatment.
16. Known positive test for HIV.
17. Patients with active hepatitis B (defined as positive HBsAg test at screening) or hepatitis C (HCV). Patients 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) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
18. Active tuberculosis.
19. 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 should be given during influenza season only (example: approximately October to March in the Northern Hemisphere). Patients 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 treatment or within 5 months after the last dose of atezolizumab.
20. Major surgical procedure within 28 days prior to Cycle 0 Day 1 or anticipation of need for a major surgical procedure during the course of the study.
21. Uncontrolled tumor-related pain: patients requiring pain medication must be on a stable regimen at study entry and symptomatic lesions amenable to palliative radiotherapy should be treated prior to enrollment.
22. Uncontrolled effusion (pleural, pericardial or ascites) requiring recurrent drainage procedures (once a month or more frequently); patients with indwelling catheters (e.g. PleurX) are allowed.
23. 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.
24. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history or clinically significant hypercalcemia are eligible
25. History of leptomeningeal disease
26. Previous treatment with PARP inhibitors.
27. Concomitant use of strong inhibitors or inducers of CYP3A4
28. Treatment with systemic immunostimulatory agents within 4 weeks prior to Cycle 0 Day 1.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Response Rate (ORR) at 12 weeks according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) or Prostate Cancer Clinical Trials Working Group 3 (PCWG3) for prostate cancer. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Overall Response Rate (ORR) at 18 and 24 weeks according to RECIST v1.1.
• Overall Response Rate (ORR) at 12, 18 and 24 weeks according to iRECIST.
• Best Overall Response (BOR) according to RECIST v1.1 (or PCWG3-criteria for prostate cancer patients).
• Duration Of Response (DOR) according to RECIST v1.1 (or PCWG3-criteria for prostate cancer patients).
• Progression-Free Survival (PFS) according to RECIST v1.1 (or PCWG3-criteria for prostate cancer patients).
• Time To Progression (TTP) according to RECIST v1.1 (or PCWG3-criteria for prostate cancer patients).
• Immune related (i)TTP according to iRECIST.
• iPFS according to iRECIST.
• Best overall response (iBOR) according to iRECIST.
• Duration of response (iDOR) according to iRECIST.
• Maximum percentage of change from baseline in the sum of the reference diameters of the target lesions (selected according to RECIST) – non-prostate cohorts only.
• Percentage of PSA decline from baseline according to PCWG3-criteria – prostate cancer cohort only.
• Radiologic-PFS according to PCWG3- modified RECIST 1.1 criteria – prostate cancer cohort only.
• Overall Survival.
• Safety according to CTCAE v.5.0.
Objective tumor response and time to progression will be measured according to RECIST (version 1.1, Eisenhauer E, 2009), Prostate Cancer Working Group Criteria 3 (PCWG3) for prostate cancer (Sher HI, J Clin Oncol. 2016) and iRECIST (Seymour L et al; Lancet Oncol 2017).
ORR at 12 weeks is defined as the rate of patients with at least a Complete Response (CR) or Partial Response (PR) by the 12 weeks assessment (from the start of treatment). For the primary endpoint response is defined according to RECIST v1.1 or PCWG3. For the secondary endpoint, response assessment according to iRECIST will be considered.
Best Overall Response (BOR; CR + PR) is based on the best response recorded from the start of treatment until treatment discontinuation. BOR will be determined based on RECIST v1.1 or PCWG3. iBOR will be determined based on iRECIST.
Duration Of Response (DOR, iDOR respectively) will be measured from the time measurement criteria for CR/PR (whichever is first recorded; based on either RECIST v1.1, PCWG3, iRECIST) are first met until the first date that recurrent or progressive disease is objectively documented.
PFS will be measured from the date of start of treatment until the date of first documented progression or death, whichever occurs first. Patients who are alive without evidence of progression at their last radiological assessment will be censored at that date. Patients with no tumor assessment after the baseline visit will be censored at the time of the first day of study treatment plus 1 day. Progression will be assessed according to PCGW3 and iRECIST (iPFS).
TTP is defined as time from the first day of study treatment to the first occurrence of progressive disease or death due to reason of disease progression, whichever occurs first. Patients who have not progressed or died due to disease progression at the time of study completion or who are lost to follow-up will be censored at the date of the last evaluable tumor assessment. Patients with no tumor assessment after the baseline visit will be censored at the time of the first day of study treatment plus 1 day.
OS will be measured from the date of randomization to the date of death, whatever the cause of death. Patients who are alive will be censored at the date of last follow-up.
Best percentage change from baseline is defined as the largest percentage of shrinkage in the sum of the longest diameter of target lesions observed from baseline.
Radiological PFS is defined according to the recommendations of the "Prostate-Cancer clinical trials Working Group" version 3 and referred to as the "PCWG3" (Sher HI, J Clin Oncol. 2016); for the setting "delay/prevent" progression and defined from the day of randomization to the day the first event of progression or death is recorded. Patients who are alive without evidence of radiological progression at their last imaging assessment will be censored at that date.
Quality of life: C0D1, C1D1, Day 1 of each 21-day cycle from C4D1 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| 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.8.3 |
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 | 5 |
| 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
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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