A Phase II Study of the PARP Inhibitor Olaparib (AZD2281) Alone and in Combination With AZD1775, AZD5363, or AZD6738 in Advanced Solid Tumors
Overview
- Phase
- Phase 2
- Intervention
- AZD2281
- Conditions
- Cancer
- Sponsor
- Joseph Paul Eder
- Enrollment
- 67
- Locations
- 4
- Primary Endpoint
- Overall Response Rate
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
The primary objective of this phase II trial is to determine tumor overall response rate (ORR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the study.
Detailed Description
This is a phase II signal-searching study in a range of tumor types with the potential to identify novel tumor indications for combination therapy with olaparib that can subsequently be explored in dedicated studies. Patients will be enrolled in this study based on molecular markers from genetic profiling performed on their tumors prior to study entry (outside of protocol). The trial will also identify genetic determinants of response and resistance. Patients with tumors harboring damaging mutations in Homologous - DNA repair (HDR) genes or mutations such as ATM, CHK2, MRN (MRE11/NBS1/RAD50), CDKN2A/B and APOBEC will be treated with olaparib or olaparib and AZD6738. Enrollment to the olaparib monotherapy arm will be completed prior to commencement of enrollment to the olaparib and AZD6738 arm. Patients with tumors harboring IDH1/IDH2 mutations will be treated with olaparib. Patients with tumors harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with AZD1775 plus olaparib. Patients with tumors harboring PTEN, PIK3CA, AKT, or ARID1A mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with AZD5363 plus olaparib.
Investigators
Joseph Paul Eder
Professor of Medicine; Clinical Director, Early Drug Development Program
Yale University
Eligibility Criteria
Inclusion Criteria
- •Histologically documented metastatic cancer (solid tumors, not including hematologic malignancies)
- •Patients who have received standard first-line therapy for metastatic cancer (except for the tumors for which no first-line therapy exists) and in whom a trial of targeted therapy is considered the best available treatment option. Eligible patients should not have available therapies that will convey clinical benefit.
- •Progressive cancer at the time of study entry
- •Measurable disease by RECIST v1.1
- •Age ≥ 18 years
- •Life expectancy ≥ 16 weeks
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 (APPENDIX A: Performance Status Criteria)
- •Able to understand the nature of this trial and provide written informed consent
- •Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- •Molecular testing or appropriate IHC results from CLIA-certified laboratories used for patient eligibility should be obtained from the most recent tumor biopsy (baseline tumor biopsies and on-progression tumor biopsies are optional)
Exclusion Criteria
- •Patients with known germline BRCA mutations in breast cancers will be excluded from the study, however testing is not required for inclusion in the study.
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- •Prior standard of care cancer chemotherapy, immunotherapy, or radiotherapy \<21 days prior to first dose of study agent(s)
- •Patients with hematologic malignancies (includes patients with myelodysplastic syndrome/acute myeloid leukemia).
- •Patients with primary CNS malignancies
- •Patients must not have received allogeneic stem cell transplant
- •Concurrent administration of any other anti-cancer therapy
- •Bisphosphonates and Denosumab for bone metastases are allowed if started at least 4 weeks prior to treatment with study agent(s).
- •Octreotide is allowed if dose is stable for \>3 months with no worsening of carcinoid syndrome
- •Hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate-resistant prostate cancer is permitted
Arms & Interventions
Group 1
Patients with cholangiocarcinoma harboring IDH 1/2 tumors will be treated with olaparib. Patients with tumors harboring mutation in HDR genes will be treated with olaparib.
Intervention: AZD2281
Group 2
Patients with tumors harboring PTEN, PIK3CA, AKT, or ARID1A mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with AZD5363 plus olaparib.
Intervention: AZD2281
Group 2
Patients with tumors harboring PTEN, PIK3CA, AKT, or ARID1A mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with AZD5363 plus olaparib.
Intervention: AZD5363
Group 3
Patients with tumors harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with AZD1775 plus olaparib. TP53 mutations must be found on the TP53 mutation eligibility list.
Intervention: AZD2281
Group 3
Patients with tumors harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with AZD1775 plus olaparib. TP53 mutations must be found on the TP53 mutation eligibility list.
Intervention: AZD1775
Group 4
Patients with tumors harboring mutations in HDR genes, including ATM, CHK2, APOBEC, MRE11 complex, will be treated with AZD6738 and olaparib.
Intervention: AZD2281
Group 4
Patients with tumors harboring mutations in HDR genes, including ATM, CHK2, APOBEC, MRE11 complex, will be treated with AZD6738 and olaparib.
Intervention: AZD6738
Outcomes
Primary Outcomes
Overall Response Rate
Time Frame: Change from baseline to 16 weeks
Tumor overall response rate (ORR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the study (Note: there will be no formal comparison between arms). Complete Response (CR): disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD). Clinical Benefit is defined as the sum of CR, PR, or SD at 16 weeks from the start of treatment.