Initial stage cohort: SCLC germline BRCA mutated (gBRCAm) metastatic human epidermal growth factor receptor 2 (HER2) negative breast cancer (BC) gBRCAm platinum sensitive relapsed ovarian cancer (OvC) gastric cancer Second stage cohort: BRCAm platinum sensitive relapsed OvC non BRCAm platinum sensitive relapsed OvC Third stage cohort: HER2-negative, BRCAm BC HER2 negative, non BRCAm, Homologous Recombination Repair gene mutated (HRRm) BC non BRCAm, non HRRm triple negative BC MedDRA version: 2
Conditions
Sponsors
Astra Zeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria are presented separately for each cohort of Modules 1 to 7 Small cell lung cancer cohort: Patients must have histologically or cytologically confirmed progressive metastatic or recurrent solid tumor (as defined below for each tumor type). To be enrolled in the SCLC cohort, only the tumor types and settings described below are allowed (see in the Protocol) At least 1 measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (or magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1. The baseline scan must be obtained within 28 days prior to the first dose of olaparib. Biomarker-only disease is not considered evaluable. Breast cancer cohort: Patients must have histologically or cytologically confirmed progressive metastatic or recurrent solid tumor (as defined below for each tumor type). To be enrolled in the gBRCAm breast cancer cohort, only the tumor types and settings described below are allowed (see in the Protocol). At least 1 measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (or magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1. The baseline scan must be obtained within 28 days prior to the first dose of olaparib. Biomarker-only disease is not considered evaluable. gBRCAm human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with metastatic or locally advanced disease, which is unresectable (or the patient is not a candidate for resection), may be first, second or third line but all patients must meet the following specific criteria: Must have confirmation of a germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). Must have previously received treatment with an anthracycline (eg, doxorubicin, epirubicin) unless contraindicated and/or a taxane (eg, paclitaxel, docetaxel) in either a neo-adjuvant/adjuvant or metastatic setting. For all ovarian cancer (OC) cohorts: Patients must have histologically confirmed recurrent ovarian cancer. Patients must be naïve to prior PARP inhibitor treatment and immunotherapy naïve Patients must have had at least 1 prior line of platinum-based therapy and be platinum sensitive (relapsed = 24 weeks after administration of last platinum treatment). For 1st stage gBRCAm OC and 2nd stage expansion OC cohorts: Patients must have a gBRCA mutation. For 2nd stage doublet and triplet non-gBRCAm OC cohorts: Patients must not have a gBRCA mutation. Gastric cancer cohort: Patients must have histologically or cytologically confirmed progressive metastatic or recurrent solid tumor (as defined below for each tumor type). To be enrolled in the gastric cancer cohort, only the tumor types and settings described below are allowed (see in the Protocol). At least 1 measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (or magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1. The baseline scan must be obtained within 28 days prior to the first dose of olaparib. Biomarker-only disease is not considered evaluable. Metastatic or recurrent gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) that has progressed following first-line therapy, confirmed b
Exclusion criteria
Exclusion criteria: Exclusion criteria are presented separately for each cohort in Modules 1 to 7 Small cell lung cancer cohort: Prior chemotherapy or other systemic anticancer therapy (eg, targeted biotherapy or hormonal agents) within 4 weeks prior to start of olaparib treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and treatments of particular importance are noted below (see Protocol) Radiation therapy within 4 weeks prior to start of olaparib treatment (includes radiation targeting bone metastases) or radionuclide treatment within 6 weeks of treatment start. Patients with mixed small cell and non-small cell lung cancer histology. Breast cancer cohort: Prior chemotherapy or other systemic anticancer therapy (eg, targeted biotherapy or hormonal agents) within 4 weeks prior to start of olaparib treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and treatments of particular importance are noted below (see the Protocol). Radiation therapy within 4 weeks prior to start of olaparib treatment (includes radiation targeting bone metastases) or radionuclide treatment within 6 weeks of treatment start. Patients with HER2-positive disease (3+ by immunohistochemistry [IHC] or in situ hybridization amplified =2.0). Patients cannot have received more than 2 prior lines of cytotoxic chemotherapy for metastatic disease. Prior treatments with hormonal therapy and non-hormonal targeted therapy are allowed and not counted as a prior line of cytotoxic chemotherapy. For the purposes of this protocol, the combination of an aromatase inhibitor and everolimus or palbociclib, are not considered cytotoxic chemotherapy. BRCA1 and/or BRCA2 variants that are considered to be non-detrimental (eg, "Variants of uncertain clinical significance" or "Variant of unknown significance" or "Variant, favor polymorphism" or "benign polymorphism" etc). 1st stage OC cohort: Prior chemotherapy or other systemic anticancer therapy within 4 weeks prior to start of study treatment. Radiation therapy within 4 weeks prior to start of olaparib treatment. Other malignancy within 5 years. 2nd stage cohorts (expansion OC, doublet OC and triplet cohorts) Same as 1st stage gBRCAm OC cohort Patients who received more than 3 prior lines of chemotherapy. Gastric cancer cohort: Prior chemotherapy or other systemic anticancer therapy (eg, targeted biotherapy or hormonal agents) within 4 weeks prior to start of olaparib treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and treatments of particular importance are noted below (see in the Protocol). Radiation therapy within 4 weeks prior to start of olaparib treatment (includes radiation targeting bone metastases) or radionuclide treatment within 6 weeks of treatment start For HER2-negative patients: More than 1 prior chemotherapy regimen (except for adjuvant/neoadjuvant chemotherapy with more than 6 months wash-out period) for the treatment of gastric cancer in the metastatic or recurrent setting. For HER2-positive patients: More than 2 prior chemotherapy regimens (except for adjuvant/neoadjuvant with more than 6 months wash-out period) for the treatment of gastric cancer in the metastatic or recurrent setting. Intestinal obstruction or CTCAE grade 3 or grade 4 upper gastrointestinal bleeding within 4 weeks before the study entry
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: To investigate the preliminary antitumor activity of MEDI4736 in comb with olaparib±bevacizumab in patients with selected advanced solid tumors. To determine plasma conc of olaparib after single and multiple dosing when given orally to patients alone and in combination with MEDI4736±bevacizumab. To characterize the PK, immunogenicity and pharmacodynamics of MEDI4736 after single dosing and multiple dosing when given intravenously to patients in combination with olaparib±bevacizumab. To characterize the PK and pharmacodynamics of bevacizumab after single dosing and multiple dosing when given i.v. to patients in combination with MEDI4736 and olaparib. To evaluate candidate predictive biomarkers of treatment effect such as, but not limited to, PD-L1 expression Exploratory: To evaluate baseline measures and changes induced by olaparib alone and in combination with MEDI4736±bevacizumab, in peripheral blood, archival tumor, and tumor biopsies (frozen and fixed cores);Main Objective: To assess the effect of MEDI4736 in combination with olaparib±bevacizumab in patients with selected advanced solid tumors. To assess the safety and tolerability of MEDI4736 in combination with olaparib (±bevacizumab) in patients with selected advanced solid tumors.;Primary end point(s): Initial Stage Cohorts: Disease Control Rate (CR+PR+SD) based on modified RECIST 1.1 at 12 weeks Secondary Stage Cohorts: BRCAm cancer expansion cohort: ORR (CR+PR) based on modified RECIST 1.1 assessed by Inv. Ovarian cancer triplet and doublet cohorts: DCR (CR+PR+SD) based on modified RECIST 1.1 at 24 weeks Third stage cohorts: BRCAm breast cancer expansion cohort: ORR (CR+PR) based on RECIST 1.1 assessed by Inv. HRRm breast cancer and TNBC triplet cohorts: DCR (CR+PR+SD) based on RECIST at 16 weeks All cohorts: AEs vital signs, including blood pressure, pulse, ECG and laboratory findings (including clinical chemistry and hematology) irAEs: given the intended mechanisms of action of MEDI4 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Initial Stage Cohorts: DCR at 28 weeks* ORR (CR+PR) based on modified RECIST 1.1* DoR based on modified RECIST 1.1* PFS based on modified RECIST 1.1* *Assessed by the investigator in all Initial Stage Cohorts. Also assessed by BICR in the gBRCAm ovarian cancer cohort Percentage change from baseline in tumor size at 12 weeks and 28 weeks Best percentage change from baseline in tumor size Time to study treatment discontinuation Overall survival BRCAm ovarian cancer expansion cohort: DCR at 24 weeks and 56 weeks** DoR based on modified RECIST 1.1** PFS based on modified RECIST 1.1** **Assessed by the investigator and assessed by BICR ORR (CR+PR) based on modified RECIST 1.1 assessed by BICR Percentage change from baseline in tumor size at 24 weeks and 56 weeks Best percentage change from baseline in tumor size TDT Overall survival Ovarian cancer triplet and doublet cohorts: DCR at 56 weeks DoR based on modified RECIST 1.1 PFS based on modified RECIST 1.1 ORR (CR+PR) based on modified RECIST 1.1 assessed by the Inv. Percentage change from baseline in tumor size at 24 and 56 weeks Best percentage change from baseline in tumor size TDT Overall survival Third Stage Cohorts: BRCAm breast cancer expansion cohort DCR and 16 and 24 weeks** DoR based on modified RECIST 1.1** PFS based on modified RECIST 1.1** **assessed by the Inv. and by BICR ORR (CR+PR) based on RECIST 1.1 assessed by BICR Percentage change from baseline in tumor size at 24 and 56 weeks Best percentage change from baseline in tumor size TDT Overall survival HRRm breast cancer and TNBC triplet cohorts: DCR at 24 weeks DoR based on RECIST 1.1 PFS based on RECIST 1.1 ORR (CR+PR) based on RECIST 1.1 assessed by the Inv. Percentage change from baseline in tumor size at weeks 24 and 56 Best percentage change from baseline in tumor size TDT Overall survival;Timepoint(s) of evaluation of this end point: Initial Stg Coh:DCR at 28weeks(w),DoR,PFS,ORR,OS* ,TDT** ,Percentage change(PC) from baseli | — |
Countries
France, Israel, Korea, Republic of, Netherlands, Switzerland, United Kingdom, United States
Contacts
Public ContactInformation Centre
Astra Zeneca AB
Outcome results
None listed