Olaparib in gBRCA Mutated Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum-Based Chemotherapy (POLO)

• ClinicalTrials.gov Identifier: NCT02184195
• Recruitment Status: Completed
• First Posted: July 9, 2014
• Results First Posted: January 27, 2020
• Last Update Posted: September 13, 2023
• Sponsor: AstraZeneca
• Collaborators: Myriad Genetic Laboratories, Inc.; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: June 6, 2014
• First Posted Date: July 9, 2014
• Results First Submitted Date: January 14, 2020
• Results First Posted Date: January 27, 2020
• Last Update Posted Date: September 13, 2023
• Actual Study Start Date: December 16, 2014
• Actual Primary Completion Date: January 15, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 14, 2020)

Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Using Modified Response Evaluation Criteria in Solid Tumours. This Study Used Modified RECIST Version (v) 1.1 (RECIST v1.1) [ Time Frame: Up to 4 years ]

To determine the efficacy of olaparib maintenance monotherapy compared to placebo by PFS. The PFS was defined as the time from randomisation until the date of objective radiological disease progression according to modified RECIST v1.1 or death (by any cause in the absence of disease progression) regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to disease progression.

Original Primary Outcome Measures (submitted: July 3, 2014)

Progression free survival (PFS) by central review of modified RECIST 1.1 [ Time Frame: Up to 4 years ]

Efficacy by assessment of PFS (time from randomisation to objective disease progression according to modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1) or death) of olaparib maintenance monotherapy compared to placebo, using blinded independent central review (BICR) of radiological scans.

Current Secondary Outcome Measures (submitted: January 14, 2020)

• Overall Survival (OS) [ Time Frame: Upto 4 years ]
  To determine the efficacy by assessment of OS of olaparib maintenance monotherapy compared to placebo. The OS was defined as the time from the date of randomization until death due to any cause.
• Time From Randomisation to Second Progression (PFS2) [ Time Frame: Up to 4 years ]
  To determine efficacy by assessment of PFS2 of olaparib maintenance monotherapy compared to placebo. The PFS2 was defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or death.
• Time From Randomisation to Second Subsequent Therapy or Death (TSST) [ Time Frame: Up to 4 years ]
  To determine the efficacy by assessment of TSST of olaparib maintenance monotherapy compared to placebo. The TSST was defined as time to second subsequent therapy or death.
• Time From Randomisation to First Subsequent Therapy or Death (TFST) [ Time Frame: Up to 4 years ]
  To determine the efficacy by assessment of TFST of olaparib maintenance monotherapy compared to placebo. The TFST was defined as time to first subsequent therapy or death.
• Time From Randomisation to Study Treatment Discontinuation or Death (TDT) [ Time Frame: Up to 4 years ]
  To determine the efficacy by assessment of TDT compared to placebo. compared to placebo. The TDT was defined as time to study treatment discontinuation or death.
• Number of Participants With Objective Response Rate (ORR) by BICR Using Modified RECIST 1.1 [ Time Frame: Up to 4 years ]
  To determine efficacy by assessment of objective response rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo. The ORR is defined as the number of with a BoR of CR and PR according to the BICR data divided by the number of patients in the treatment group with measurable disease at baseline.
• Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1 [ Time Frame: At 16 weeks ]
  Efficacy by assessment of disease control rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo.
• Adjusted Mean Change From Baseline up to 6 Months in Global Quality of Life (QoL) Score From the EORTC-QLQ-C30 Questionnaire [ Time Frame: From baseline up to 6 months ]
  To assess the effect of olaparib on health-related quality of life (QoL) as measured by the EORTC-QLQ-C30 global QoL scale. The EORTC-QLQ-C30 is defined as EORTC QLQ-C30: a questionnaire (30 questions) used to evaluate disease symptoms, functional impacts (eg, physical functioning), and HRQoL and to characterize clinical benefit from the patient perspective. The HRQoL score ranges from 0 to 100. A higher score indicates better QoL. A score change of 10 points was pre-defined as clinically meaningful. bd twice daily.
• Number of Participants With Adverse Events (AEs) [ Time Frame: Up to 4 years ]
  To assess the safety and tolerability of olaparib maintenance monotherapy. SAE: serious adverse events CTCAE: Common Terminology Criteria for Adverse Events

Original Secondary Outcome Measures (submitted: July 3, 2014)

• Overall survival (OS) [ Time Frame: Up to 4 years ]
  Efficacy by assessment of OS (time from randomisation to death by any cause) of olaparib maintenance monotherapy compared to placebo
• Time from randomisation to second progression or death (PFS2) [ Time Frame: Up to 4 years ]
  Efficacy by assessment of PFS2 (time from randomisation to second progression, defined as objective radiological or symptomatic progression, or death) of olaparib maintenance monotherapy compared to placebo.
• Time from randomisation to first subsequent therapy or death (TFST) [ Time Frame: Up to 4 years ]
  Efficacy by assessment of TFST (time from randomisation to the earlier of first subsequent therapy following study treatment discontinuation, or death) of olaparib maintenance monotherapy compared to placebo.
• Time from randomisation to second subsequent therapy or death (TSST) [ Time Frame: Up to 4 years ]
  Efficacy by assessment of TSST (time from randomisation to the earlier of second subsequent therapy following study treatment discontinuation, or death) of olaparib maintenance monotherapy compared to placebo.
• Time from randomisation to study treatment discontinuation or death (TDT) [ Time Frame: Up to 4 years ]
  Efficacy by assessment of TDT (time from randomisation to the earlier of study treatment discontinuation or death) of olaparib maintenance monotherapy compared to placebo. compared to placebo.
• Objective response rate by BICR using modified RECIST 1.1 [ Time Frame: Up to 4 years. ]
  Efficacy by assessment of objective response rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo
• Disease control rate by BICR using modified RECIST 1.1 [ Time Frame: Up to 4 years ]
  Efficacy by assessment of disease control rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo.
• Adjusted mean change from baseline in global quality of life (QoL) score from the EORTC-QLQ-C30 questionnaire [ Time Frame: Up to 4 years ]
  Assessment of the effect of olaparib on health-related quality of life (QoL) as measured by the EORTC-QLQ-C30 global QoL scale
• Safety and tolerability of olaparib [ Time Frame: Up to 4 years ]
  Assessment of adverse events (AEs), physical examination, vital signs including blood pressure (BP), pulse, electrocardiogram (ECG) and laboratory findings including clinical chemistry and haematology.
• Time to deterioration of global quality of life (QoL) [ Time Frame: Up to 4 years. ]
  Assessment of the effect of olaparib on time to deterioration of global health status/QoL and pancreatic pain as measured by the EORTC-QLQ-C30 global QoL scale and the PAN-26 pancreatic pain scale.
• Improvement rate of global quality of life (QoL) [ Time Frame: Up to 4 years ]
  Assessment of the effect of olaparib on improvement rate of global health status/QoL and pancreatic pain as measured by the EORTC-QLQ-C30 global QoL scale and the PAN-26 pancreatic pain scale.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Olaparib in gBRCA Mutated Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum-Based Chemotherapy
• Official Title: A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Maintenance Olaparib Monotherapy in Patients With gBRCA Mutated Metastatic Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy
• Brief Summary: A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Maintenance Olaparib Monotherapy in Patients with gBRCA Mutated Metastatic Pancreatic Cancer whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy

Detailed Description

Approximately 145 patients will be randomised using an Interactive Voice Response System /Interactive Web Response System (IVR/IWR system) in a 3:2 ratio (Olaparib:placebo) to the treatments as specified below:

• Olaparib tablets p.o. 300 mg twice daily
• Matching placebo tablets p.o. twice daily Eligible patients will be those patients with pancreas cancer previously treated for metastatic disease who have not progressed following completion of at least 16 weeks (can be more) of first line platinum-based chemotherapy. All patients must have a known deleterious or suspected deleterious germline BRCA mutation to be randomised; this may have been determined prior to enrolment into the study or may be assessed as part of the enrolment procedure for the study (via centrally provided MyriadIntegrated BRAC.

Patients will be randomised within 6 weeks after their last dose of chemotherapy (last dose is the day of the last infusion) and treatment started as soon as possible but no less than 4 and no more than 8 weeks of the last chemotherapy dose. At the time of starting protocol treatment, all previous chemotherapy treatment should be discontinued.

Following randomisation, patients will attend clinic visits weekly for the first 4 weeks of treatment (Days 8, 15, 22 and 29). Patients will then attend clinic visits every 4 weeks whilst on study treatment. Patients should continue to receive study treatment until objective radiological disease progression as per RECIST as assessed by the investigator and as long as in the investigator's opinion they are benefiting from treatment and they do not meet any other discontinuation criteria.

Once a patient has progressed the patient will be followed for second progression (PFS2) every 8 weeks and then survival until the final analysis.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Germline BRCA1/2 Mutations and
• Metastatic Adenocarcinoma of the Pancreas

Intervention

• Drug: Olaparib
  Tablet -100mg
• Drug: Olaparib
  Tablet-150mg
• Drug: Placebo
  Match Olaparib 100mg placebo
• Drug: Placebo
  Match Olaparib 150mg placebo

Study Arms

• Experimental: Olaparib
  Olaparib tablets po. 300 mg twice daily
  Interventions:

  • Drug: Olaparib
  • Drug: Olaparib
• Placebo Comparator: Placebo
  Placebo tablets twice daily
  Interventions:

  • Drug: Placebo
  • Drug: Placebo

Publications *

• Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algul H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. doi: 10.1056/NEJMoa1903387. Epub 2019 Jun 2.
• Amin S, Joo S, Nolte S, Yoo HK, Patel N, Byrnes HF, Costa-Cabral S, Johnson CD. Health-related quality of life scores of metastatic pancreatic cancer patients responsive to first line chemotherapy compared to newly derived EORTC QLQ-C30 reference values. BMC Cancer. 2022 May 20;22(1):563. doi: 10.1186/s12885-022-09661-7.
• Li N, Zheng H, Huang Y, Zheng B, Cai H, Liu M. Cost-Effectiveness Analysis of Olaparib Maintenance Treatment for Germline BRCA-Mutated Metastatic Pancreatic Cancer. Front Pharmacol. 2021 Apr 20;12:632818. doi: 10.3389/fphar.2021.632818. eCollection 2021.
• Zhan M, Zheng H, Yang Y, He Z, Xu T, Li Q. Cost-Effectiveness Analysis of Maintenance Olaparib in Patients with Metastatic Pancreatic Cancer and a Germline BRCA1/2 Mutation Based on the POLO Trial. Cancer Manag Res. 2020 Dec 16;12:12919-12926. doi: 10.2147/CMAR.S283169. eCollection 2020.
• Golan T, Kindler HL, Park JO, Reni M, Macarulla T, Hammel P, Van Cutsem E, Arnold D, Hochhauser D, McGuinness D, Locker GY, Goranova T, Schatz P, Liu YZ, Hall MJ. Geographic and Ethnic Heterogeneity of Germline BRCA1 or BRCA2 Mutation Prevalence Among Patients With Metastatic Pancreatic Cancer Screened for Entry Into the POLO Trial. J Clin Oncol. 2020 May 1;38(13):1442-1454. doi: 10.1200/JCO.19.01890. Epub 2020 Feb 19.
• Hammel P, Kindler HL, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algul H, O'Reilly EM, McGuinness D, Cui KY, Joo S, Yoo HK, Patel N, Golan T; POLO Investigators. Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib. Ann Oncol. 2019 Dec 1;30(12):1959-1968. doi: 10.1093/annonc/mdz406.
• Lowery MA, Kelsen DP, Capanu M, Smith SC, Lee JW, Stadler ZK, Moore MJ, Kindler HL, Golan T, Segal A, Maynard H, Hollywood E, Moynahan M, Salo-Mullen EE, Do RKG, Chen AP, Yu KH, Tang LH, O'Reilly EM. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018 Jan;89:19-26. doi: 10.1016/j.ejca.2017.11.004. Epub 2017 Dec 8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 14, 2020): 154
• Original Estimated Enrollment (submitted: July 3, 2014): 145
• Actual Study Completion Date: January 27, 2023
• Actual Primary Completion Date: January 15, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria

• Histologically or cytologically confirmed pancreas adenocarcinoma receiving initial chemotherapy for metastatic disease and without evidence of disease progression on treatment
• Patients with measurable disease and/or non-measurable or no evidence of disease assessed at baseline by CT (or MRI where CT is contraindicated) will be entered in this study.
• Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious
• Patients are on treatment with a first line platinum-based (cisplatin, carboplatin or oxaliplatin) regimen for metastatic pancreas cancer, have received a minimum of 16 weeks of continuous platinum treatment and have no evidence of progression based on investigator's opinion.
• Patients who have received platinum as potentially curative treatment for a prior cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for pancreas cancer are eligible provided at least 12 months have elapsed between the last dose of platinum-based treatment and initiation of the platinum-based chemotherapy for metastatic pancreas cancer.

Major Exclusion Criteria:

• gBRCA1 and/or gBRCA2 mutations that are considered to be non detrimental (eg, "Variants of uncertain clinical significance" or "Variant of unknown significance" or "Variant, favour polymorphism" or "benign polymorphism" etc.)
• Progression of tumour between start of first line platinum based chemotherapy for metastatic pancreas cancer and randomisation.

• Cytotoxic chemotherapy or non-hormonal targeted therapy within 28 days of Cycle

  1 Day 1 is not permitted.

• Exposure to an investigational product within 30 days or 5 half lives (whichever is longer) prior to randomisation
• Any previous treatment with a PARP inhibitor, including Olaparib

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, France, Germany, Israel, Italy, Korea, Republic of, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02184195
• Other Study ID Numbers: D081FC00001; 2014-001589-85 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current

Collaborators

• Myriad Genetic Laboratories, Inc.
• Merck Sharp & Dohme LLC

• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: June 2023