A Phase I/II Study of MEDI4736 in Combination with Olaparib in Patients with Advanced Solid Tumors

Phase 1

Conditions: Initial stage cohort:SCLC germline BRCA mutated (gBRCAm) metastatic human epidermal growthfactor receptor 2 (HER2) negative breast cancer (BC) gBRCAm platinum sensitive relapsed ovarian cancer (OvC) gastric cancerSecond stage cohort:BRCAm platinum sensitive relapsed OvC non BRCAm platinum sensitive relapsed OvC Third stage cohort:HER2-negative, BRCAm BCHER2 negative, non BRCAm, Homologous Recombination Repair gene mutated (HRRm) BC non BRCAm, non HRRm triple negative BC
MedDRA version: 20.0Level: LLTClassification code 10033130Term: Ovarian cancer NOSSystem Organ Class: 100000004864
MedDRA version: 21.1Level: LLTClassification code 10071114Term: Metastatic gastric adenocarcinomaSystem Organ Class: 100000004864
MedDRA version: 20.0Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 100000004864
MedDRA version: 21.1Level: LLTClassification code 10041071Term: Small cell lung cancer stage unspecifiedSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2015-004005-16-NL

Lead Sponsor: Astra Zeneca AB

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 262

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 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

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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