Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer (MOLTO)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02855697|
Recruitment Status : Recruiting
First Posted : August 4, 2016
Last Update Posted : October 23, 2017
|Condition or disease||Intervention/treatment||Phase|
|Ovarian Cancer||Drug: Olaparib Drug: Cediranib Drug: Platinum-based Chemotherapy||Early Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||26 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Single Arm Feasibility of Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer|
|Actual Study Start Date :||May 26, 2017|
|Estimated Primary Completion Date :||January 31, 2019|
|Estimated Study Completion Date :||December 2020|
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.
300 mg taken twice daily, equivalent to a total daily dose of 600 mg
Other Names:Drug: Cediranib
20mg dose of cediranib was selected for this study
Other Name: AZD2171Drug: Platinum-based Chemotherapy
1 or 2 two courses of platinum-based chemotherapy administered depending on trial entry point.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02855697
|Contact: Rosie Lubiatowska, MSc||0161 918 7771||Rozalia.Lubiatowska@christie.nhs.uk|
|Contact: Anna Thomason, BSc||0161 918 email@example.com|
|The Christie NHS Foundation Trust||Recruiting|
|Manchester, United Kingdom, M20 4BX|
|Contact: Andrew Clamp, MD, PhD 0161 446 3606 Andrew.Clamp@christie.nhs.uk|
|Contact: Catherine Rogers, Nurse 0161 918 7689 firstname.lastname@example.org|
|Principal Investigator: Andrew Clamp|
|Study Chair:||Gordon Jayson, MD, Prof.||The Christie National Health Service (NHS) Foundation Trust|