Olaparib for Advanced/metastatic solid tumors

Inclusion criteria

• {"criterion_text":"- Patient ≥ 18 years of age\n- The recommended study treatment must have been approved by the medical staff of the steering committee.\n- ECOG performance status 0, 1 or 2.\n- For immunotherapy cohort only: o Availability of a pre-treatment tumor sample (only FFPE block with sufficient material) or presence of at least one biopsable tumor lesion, o Patient with a maximum of 2 prior lines of treatment at time of C1D1 for their metastatic or locally advanced cancer.\n- Specific toxicities related to any prior anti-cancer therapy must have resolved to grade ≤1 (defined by the NCI-CTCAE v4.03), except for alopecia and fatigue. Grade 2 neutropenia or anemia is accepted (as defined in the criteria for minimal laboratory requirements).\n- Informed consent signed.\n- Adequate organ system function as assessed by the following minimal laboratory requirements (within 7 days prior to C1D1): o Absolute Neutrophil Count (ANC) ≥ 1 x 109 /L (for pazopanib and olaparib: ≥ 1.5 x 109 /L) o Platelets ≥ 100 x 109 /L o Hemoglobin ≥ 9 g/dL (5.6 mmol/L). Transfusion is not allowed within 7 days of screening assessment. (for olaparib: ≥ 10 g/dL, transfusion within 28 days is not allowed, no features suggestive of MDS/AML on peripheral blood smear within the 28 days). o For pazopanib: aPTT ≤ 1.2x ULN (Upper Limit of Normal) and PT or INR ≤ 1.2x ULN; Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation. o AST(SGOT) and ALT(SGPT) ≤ 3x ULN (Upper Limit of Normal) in the absence of liver metastases (≤ 5x ULN for patients with liver involvement of their cancer) and total bilirubin ≤ 1.5x ULN. (for olaparib, IT, nilotinib and pazopanib: AST and ALT ≤ 2.5x ULN; for pazopanib and nilotinib concomitant elevations in bilirubin and AST or ALT above 1x ULN and 1,5xULN respectively are not permitted) o Serum creatinine ≤ 1.5x ULN or creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula, or MDRD formula for patients older than 65 years) (for pazopanib: creatinine clearance ≥ 30 mL/min; for Olaparib: creatinine clearance calculated by Cockcroft-Gault formula ≥ 51 mL/min; for IT creatinine clearance > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance o For pazopanib: Urine Protein to Creatinine ratio (UPC) <1; if UPC ≥1, 24-hour urine protein must be <1g (use of urine dipstick for renal function assessment is not acceptable). o Corrected QT interval (QTcB) ≤ 450 msecs from 3 electrocardiograms (≤ 480 msecs if recommended MTT has no known effect on QT interval) on screening ECG, within 14 days prior to C1D1. For olaparib, resting ECG with QTc < 470 msec on 2 or more time points within a 24 hour period.\n- Life expectancy of at least 4 months\n- Histologically or cytologically confirmed diagnosis of metastatic or locally advanced and unresectable solid tumor of any type-except for Nilotinib cohort: only pigmented villonodular synovitis are eligible -, not amenable to curative treatment. Concerning primitive tumors of the central nervous system (CNS), all histological types of malignant tumors (including parenchymal and meningeal tumors) are eligible (CNS tumor are not eligible for the IT group)\n- Documented disease progression at the time of study entry.\n- At least one prior systemic treatment regimen for locally advanced or metastatic disease (chemotherapy, immunotherapy, targeted therapy, hormonotherapy; systemic treatment regimens given in the neoadjuvant or adjuvant setting and maintenance therapies will not be considered) - except for Nilotinib cohort (No previous treatment by immunotherapy is allowed for IT group). Patients who are candidates for a validated second line treatment regimen are not eligible for the study. For patients with a primitive CNS tumor, the absence of other therapeutic options must be validated by the reference committee for the patient’s pathology.\n- Measurable disease, defined as at least one lesion that can be accurately measured on CT-scan or MRI (performed within 28 days prior to C1D1) according to RECIST 1.1. As there is no prior systemic treatment regimen available for locally advanced or metastatic PEComa, these tumors are eligible for a MTT treatment in first line of their advanced or metastatic disease.\n- A multidisciplinary molecular board must have recommended one of the investigational MTT available in the study after review of a tumor or blood molecular profiling previously established from a biopsied lesion (preferably on a sample of the most recent progression) and/or primitive tumor (by NGS, Sanger sequencing, CGH or any other valuable technique) or from a liquid biopsy, respectively\n- The MTT recommended by the multidisciplinary molecular board after the review of molecular profile is not approved and reimbursed in France for the disease affecting the patient in the same label."}

Exclusion criteria

• {"criterion_text":"- Previous treatment in advanced phase with a investigational therapy inhibiting the same target proteins as this recommended for the study.\n- Patient unable or unwilling to discontinue use of prohibited medications (as indicated in the corresponding section of the SPC of each investigational product, see also Appendix 6 for pazopanib), for at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.\n- Pregnant or breastfeeding women.\n- Any contra-indication to receive the recommended investigational therapy (refer to the contraindications and special warnings and precautions for use in the SPC of each investigational product, or the corresponding IB if applicable), including known or suspected hypersensitivity to compounds of similar chemical or biologic composition as the active substance, or to any of the excipients. (for Durvalumab + Tremelimumab: this includes hypersensitivity to other humanized monoclonal antibody).\n- For nilotinib, sorafenib, pazopanib and olaparib: Patient with hypokalemia (< Lower Limit of Normal) or known history of congenital long QT syndrome (QT interval prolongation).\n- Presence of any other active malignancy.\n- Patient who have had major surgery or trauma within 28 days prior to first dose of investigational product. Patient must have recovered from any effects of any major surgery.\n- Patient with symptomatic or uncontrolled central nervous system (CNS) metastatic involvement of his/her cancer, unless the patient have stable neurological function without evidence of CNS progression within 12 weeks prior to study entry and does not require treatment with enzymeinducing anticonvulsants or steroids (within 4 weeks prior to study inclusion and during study participation). Patients with a primitive tumor of the CNS are not eligible if one of the following conditions is fulfilled: o Alteration of cognitive functions impeding the patient’s comprehension of study and the provision of informed consent by the patient himself/herself. o Need for supportive care treatment(s) (anticonvulsant, steroids…) interfering with study treatment (see concomitant treatments to avoid in the drug interaction section of the SPC of each investigational product (Appendix 9) or the corresponding IB if applicable, or as listed in Appendix 6 for pazopanib, Appendix 7 for olaparib). o Patients enrolled in the IT cohort\n- Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment: radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of study treatment OR immunotherapy within 28 days OR chemotherapy, biologic therapy (i.e. targeted therapy), investigational therapy or hormonal therapy within 14 days or 5 half-lives of a drug (whichever is longer). Palliative radiotherapy (for analgesia) is authorized only if the irradiated field does not include target lesions. (For olaparib: Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks or 5 half-lives of a drug (whichever is longer) prior to study treatment)\n- Administration of any non-oncologic investigational agent within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment.\n- Any clinically significant and/or uncontrolled medical disease that could compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results."}

Primary endpoints

• {"endpoint_text":"- Induction period: The 12-week Progression-Free Rate (PFR) or 52-week PFR for IT","definition_or_measurement_approach":"PFR measured at 12 weeks for induction period (or at 52 weeks for IT cohort) after induction treatment; this is described as the induction-Progression-Free Rate after induction treatment."}
• {"endpoint_text":"- Maintenance period Progression-Free Survival (PFS)","definition_or_measurement_approach":"PFS compared between maintenance versus interruption of study treatment in the maintenance period for patients with stable disease (MTT cohorts) or objective response (IT cohort) after the induction period."}

Secondary endpoints

• {"endpoint_text":"- Induction period The Objective Response Rate (ORR)","definition_or_measurement_approach":"ORR evaluated over the induction period."}
• {"endpoint_text":"- Maintenance period Secondary endpoints of the maintenance period will be analyzed on the ITT population. Overall survival (OS) and EORTC QLQ-C30 scores","definition_or_measurement_approach":"OS and quality of life measured by EORTC QLQ-C30 in the ITT population during the maintenance period."}
• {"endpoint_text":"- Whole study period Progression-Free Survival","definition_or_measurement_approach":"PFS evaluated over the whole study period."}
• {"endpoint_text":"- Whole study period: The duration of response","definition_or_measurement_approach":"Duration of response measured over the whole study period."}
• {"endpoint_text":"- Whole study period: Safety assessment","definition_or_measurement_approach":"Safety assessment (toxicity profiles) of the different targeted agents over the whole study period."}

Other endpoints

• {"endpoint_text":"- Exploratory secondary objectives (over the whole study period) - To evaluate the PFS of the whole cohort - To identify long-term responders and long-term survivors - To evaluate the duration of response - To evaluate the medico-economic impact of both strategies (maintenance treatment versus interruption of treatment after an induction period (i.e 12 weeks for MTT and 52 weeks for IT) and reintroduction at disease progression) - To identify clinical, histological, imaging, immunological or molecular factors with potential prognostic or predictive value for patient’s survival and/or response or resistance to treatment. - To monitor by ctDNA analysis, the molecular evolution of tumor at progression (only for olaparib and Immunotherapy groups)","definition_or_measurement_approach":"Exploratory evaluations include cohort-wide PFS, identification of long-term responders/survivors, duration of response, medico-economic impact of maintenance vs interruption strategies, identification of prognostic/predictive clinical/histological/imaging/immunological/molecular factors, and monitoring tumor molecular evolution by ctDNA at progression (specified for olaparib and immunotherapy groups)."}

France

Earliest CTIS Part Ii Submission Date

12-09-2024

Latest Decision Or Authorization Date

12-12-2025

Processing Time Days

456

Number Of Sites

8

Number Of Participants

900

Primary sponsor

Full Name

Centre Leon Berard

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France

Third parties

• {"country":"United Kingdom","full_name":"Almac Clinical Service Limited","duties_or_roles":"sponsorDuties codes: 14; 15: QP GMP certification and as manufacturer and importer; 15: Manufacturer and distributor","organisation_type":"Industry"}