A multicenter, open label, phase II trial exploring the efficacy and safety of the combination of rucaparib and atezolizumab in patients with DNA repair-deficient or platinum-sensitive solid tumors

Phase 1

• Conditions: •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; MedDRA version: 20.0Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10005003Term: Bladder cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10036909Term: Prostate cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10076506Term: Castration-resistant prostate cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.1Level: PTClassification code 10073251Term: Clear cell renal cell carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10066350Term: Adenocarcinoma of the gastrooesophageal junctionSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-001744-62-FR
• Lead Sponsor: Gustave Roussy

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-08-28
• Last Update Posted: 4 December 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 1000

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):
oAbsolute neutrophil count (ANC) = 1500 cells/µL (without granulocyte colony-stimulating factor support within 2 weeks before cycle 0 day 1).
oPlatelet count = 100.000/µL (without transfusion within 2 weeks before Cycle 0 Day 1).
oHemoglobin = 9g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion).
oTotal bilirubin = 1.5 ULN (subjects with documented/suspected Gilbert’s disease or liver metastases may be enrolled with bilirubin = 3 × ULN).
oAspartate aminotransferase (AST) or Alanine aminotransferase (ALT) = 2.5 x upper normal limit (ULN) or = 5 × ULN in case of liver metastases.
oAlbumin = 28g/L.
oSerum creatinine = 1.5 x ULN or creatinine clearance = 40mL/min (according to Cockroft and Gault formula).
oInternational 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

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified