Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer (MOLTO)
Drug: Platinum-based Chemotherapy
Early Phase 1
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Single Arm Feasibility of Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer|
- To determine the feasibility of administering a second course of maintenance olaparib for more than 6 months (26 weeks) to participants with recurrent platinum-sensitive HGS/EOC who have been previously treated with olaparib. [ Time Frame: 6 months after the last patient has started the second course of olaparib ]The proportion of participants who remain on olaparib for more than 6 months (26 weeks) in the second course of maintenance olaparib.
- Impact of multi-maintenance olaparib treatment on time to first subsequent therapy (TFST) in participants with platinum sensitive recurrent BRCAm HGS/EOC. [ Time Frame: 6 months after the last event ]Secondary endpoints will include time to first subsequent chemotherapy (TFST), which is defined as the interval from the last day of the last cycle of a prior regimen of chemotherapy to the first day of the first cycle of the subsequent regimen for each course of chemotherapy, following the first course of olaparib.
- Impact of multi-maintenance olaparib treatment on time to second subsequent therapy (TSST) in participants with platinum sensitive recurrent BRCAm HGS/EOC. [ Time Frame: 6 months after the last event ]Secondary endpoints will include time to second subsequent chemotherapy (TSST), which is defined as the interval from the last day of the last cycle of a prior regimen of chemotherapy to the first day of the first cycle of the subsequent regimen for each course of chemotherapy, following the second course of olaparib.
- Progression-free survival (PFS) for each course of chemotherapy followed by olaparib [ Time Frame: 6 months after the last event ]Secondary endpoints will include PFS for each course of chemotherapy, which is followed by olaparib.
- To evaluate the feasibility of obtaining fresh tissue biopsies before each course of platinum chemotherapy, where the intention is to maintain platinum-induced clinical benefit with olaparib. [ Time Frame: 6 months after the last patient starts the second course of olaparib. ]The proportion of biopsies received from the total number of patients who begin each course of platinum-based chemotherapy.
|Study Start Date:||November 2016|
|Estimated Study Completion Date:||December 2020|
|Estimated Primary Completion Date:||January 2019 (Final data collection date for primary outcome measure)|
Experimental: Olaparib +/- cediranib
Patients are administered two courses of maintenance olaparib following chemotherapy. It is possible for patients to take cediranib during the second course of olaparib if recommended as per the protocol.
Other Names:Drug: Cediranib
Other Name: AZD2171Drug: Platinum-based Chemotherapy
1 or 2 two courses of platinum-based chemotherapy administered depending on trial entry point.
Epithelial ovarian cancer presents in most participants at an advanced stage when curative surgery is not possible because of extensive pelvic, abdominal or distant metastases. Immediate or delayed surgery combined with platinum-based chemotherapy are the standards of care but even with complete surgical cytoreductive techniques and the prescription of combination platinum-based chemotherapy, the 5 year survival rate remains approximately 35%.
Approximately 50% of ovarian cancers harbour defects in HR. Defects in the pathway can arise as a result of genomic or epigenetic events in any one of up to 33 genes.
Phase I and II clinical trials with the PARPi, olaparib, have shown promising results in BRCA mutated (BRCAm) recurrent EOC and in a proportion of HGSOC participants with wild type germline BRCA (BRCA wt). Additionally the favourable toxicity profile of olaparib has prompted the long-term use of PARPi as a maintenance strategy. The results of a randomized placebo-controlled phase II clinical trial of olaparib maintenance therapy showed an improvement in progression free survival (PFS) and time to progression in participants with recurrent platinum-sensitive HGSOC6. Recent data have confirmed that the increase in median PFS is most marked in BRCAm participants who received olaparib as maintenance treatment compared with the BRCAm participants who received placebo treatment (11.2 vs 4.3 months respectively; HR, 0.18; 95% CI, 0.11-0.31; p<0.00001). These studies were performed with the original capsule formulation of olaparib at a dose of 400mg bd.
Rationale for this study The improvement in PFS with maintenance olaparib in participants with germline BRCA-mutation (g-BRCAm), although particularly striking, has not translated into improved overall survival, presumably because subsequent salvage therapy obscures this effect. Emerging data indicate that a significant proportion of BRCAm HGSOC participants retain sensitivity to platinum agents or other chemotherapies following progression on olaparib. Thus it is appropriate to offer further platinum-containing therapy to participants whose disease progresses more than 6 months after previous platinum therapy. In those whose disease benefits from further platinum chemotherapy, a further course of olaparib might consolidate the gains from the first course of olaparib, improving PFS to the point that OS is increased as well. However, to date no trial has tested the feasibility of successive treatments with 2 or more courses of maintenance olaparib and this issue will be addressed here, in participant who harbour a germline BRCA defect and whose disease has recurred and which is at least stabilised by subsequent platinum-based chemotherapy.
Functional testing remains the gold standard test for HR status and has greater predictive accuracy than non-functional tests. The Rad51 functional assay involves the recognition of completion of HR by the formation of Rad51 foci in viable cells that have undergone DNA damage, recognised by γH2AX focus formation. The assay is robust and reproducible but requires viable cells derived from either participant ascites or solid tumour deposits.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02855697
|Contact: Anna Thomason, BSc||0161 918 email@example.com|
|Contact: Heather Driscoll, PhD||0161 918 firstname.lastname@example.org|
|The Christie NHS Foundation Trust||Not yet recruiting|
|Manchester, United Kingdom, M20 4BX|
|Principal Investigator: Andrew Clamp|
|Study Chair:||Gordon Jayson||The Christie National Health Service (NHS) Foundation Trust|