Ovarian CancerEarly Phase 1MOLTONCT02855697
Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer
A Early Phase 1 study testing Olaparib, Cediranib and Platinum-based Chemotherapy in people with Ovarian Cancer, run by The Christie NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
PARP inhibitors, such as olaparib, significantly improve progression free survival (PFS) in participants with recurrent, platinum-sensitive high-grade serous/endometrioid ovarian cancer (HGS/EOC), who harbour a germline mutation in BRCA 1 or 2 genes. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Ovarian Cancer
- What is being tested?
- Olaparib, Cediranib and Platinum-based Chemotherapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 26 May 2017to 31 Dec 2021
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Progressive, measureable high grade serous or endometrioid ovarian cancer, fallopian tube or primary peritoneal cancer
- Participants who have not been treated with PARP inhibitor previously will be treated with two maintenance courses of olaparib.
- Participants, who have received one course of maintenance olaparib before entry to the trial, will only receive one further course of treatment.
- Aged 18 or over
- Measureable disease by RECIST 1.1
- ECOG performance status 0-2 and life expectancy of over 12 weeks
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- Adequate haematological function: Hb ≥ 10.0 g/l, Neutrophils ≥ 1.5 x 109/l, Platelets ≥ 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and/or APPT ratio <1.4
- Adequate liver function: bilirubin ≤1.5 x ULN, Transaminases (ALT and AST) ≤2.5x ULN unless liver metastases are present in which case they must be ≤ 5x ULN
- Adequate renal function defined as GFR ≥ 51ml/min
- Written, informed consent that includes genetic research on tissue derived from biopsies.
- Pathogenic germline BRCA-1 or -2 gene mutation
- Ability to swallow oral medication (tablets).
Who cannot join
- Concurrent medical illness that would impact on compliance with the protocol including MDS/ AML
- Uncontrolled brain metastases or seizures. A scan to confirm the absence of brain metastases is not required.
- Known positivity for Hep B, Hep C or HIV.
- Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
- Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
- Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
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- Another cancer, which has been active within the previous 5 years, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin and no evidence of recurrence of other malignancy.
- Female participants who are able to become pregnant (or are already pregnant or lactating) unless the following apply: Those who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for one month afterwards are considered eligible. Alternatively if the participant can abstain from sexual intercourse for the same interval, then they are eligible to participate.
- Participants who are planning to receive maintenance bevacizumab.
- Participants will be excluded if the side effects of previous treatments have not resolved to grade I or less, with the exception of alopecia or grade 2 neurotoxicity that is considered related to cytotoxic chemotherapy.
- Radiotherapy, surgery or tumour embolization within 28 days before the cycle 1 day 1 of the platinum-containing chemotherapy.
- Additional concurrent anti-cancer therapy.
- Causes of malabsorption e.g. uncontrolled diarrhoea or poorly controlled stoma is not permitted.
- Participants who have contra-indications to VEGF inhibitors will not be eligible to receive cediranib (second treatment). These contra-indications include concurrent or past history of malignant fistula, uncontrolled hypertension, recent arterial thrombosis (cerebrovascular accident or myocardial infarction) within the past 6 months, participants who are at risk of bowel perforation, proteinuria greater than 2g/24 hours or a past history of VEGF inhibitor-associated reversible posterior leukoencephalopathy.
- Any participant that is participating in another interventional clinical trial within 30 days or 5-lives prior to signing of consent. Participation in an observational trial would be acceptable.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
The Christie NHS Foundation Trust
Manchester, M20 4BX
About this study
Official title: Single Arm Feasibility of Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer
PARP inhibitors, such as olaparib, significantly improve progression free survival (PFS) in participants with recurrent, platinum-sensitive high-grade serous/endometrioid ovarian cancer (HGS/EOC), who harbour a germline mutation in BRCA 1 or 2 genes. Despite some of the most impressive hazard ratios seen in ovarian oncology, such improvements in PFS have not translated into improved overall survival (OS) advantage potentially because maintenance poly ADP ribose polymerase inhibitors (PARPi) are only being administered during a single remission. Here the investigators will test the feasibility of administering a second course of olaparib in participants who have recurrent platinum-sensitive HGS/EOC.
Read the detailed description
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.
- Conditions
- Ovarian Cancer
- Being tested
- Olaparib, Cediranib, Platinum-based Chemotherapy
- Medical subject headings
- Ovarian Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OlaparibDrug
Also called Lynparza, AZD2281, KU-0059436
300 mg taken twice daily, equivalent to a total daily dose of 600 mg
CediranibDrug
Also called AZD2171
20mg dose of cediranib was selected for this study
Platinum-based ChemotherapyDrug
1 or 2 two courses of platinum-based chemotherapy administered depending on trial entry point.
| Study group | Role | What they receive |
|---|---|---|
| Olaparib +/- cediranib | Experimental | 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. Receives: Drug: Olaparib; Drug: Cediranib; Drug: Platinum-based Chemotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
The proportion of participants who remain on olaparib for more than 6 months (26 weeks) in the second course of maintenance olaparib.
Measured: 6 months after the last patient has started the second course of olaparib
Secondary outcomes (3)
Impact of multi-maintenance olaparib treatment on time to first subsequent therapy (TFST) in participants with platinum sensitive recurrent BRCAm HGS/EOC.
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.
Measured: 6 months after the last event
Impact of multi-maintenance olaparib treatment on time to second subsequent therapy (TSST) in participants with platinum sensitive recurrent BRCAm HGS/EOC.
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.
Measured: 6 months after the last event
Progression-free survival (PFS) for each course of chemotherapy followed by olaparib
Secondary endpoints will include PFS for each course of chemotherapy, which is followed by olaparib.
Measured: 6 months after the last event
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Aug 2016 (estimated)
- Study start26 May 2017
- Primary completion31 Dec 2021
- Study completion31 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Ovarian CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Christie NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Trials Unit, Manchester
- Responsible party
- Sponsor
- Investigators
- Gordon Jayson, MD, Prof., Study chair, The Christie National Health Service (NHS) Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02855697
- Sponsor's protocol ID
- 15_DOG01_142
- Acronym
- MOLTO
- Status last verified
- Feb 2022
- First submitted
- 25 Jul 2016
- Last updated
- 22 Feb 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Single Arm Feasibility of Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer
- ClinicalTrials.gov ID
- NCT02855697
- Acronym / sponsor ID
- MOLTO / 15_DOG01_142
- Conditions
- Ovarian Cancer
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- The Christie NHS Foundation TrustUniversity, hospital or other
- Collaborators
- Clinical Trials Unit, Manchester
- Study start
- 26 May 2017 (actual)
- Primary completion
- 31 Dec 2021 (actual)
- Study completion
- 31 Dec 2021 (actual)
- First posted
- 4 Aug 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
PARP inhibitors, such as olaparib, significantly improve progression free survival (PFS) in participants with recurrent, platinum-sensitive high-grade serous/endometrioid ovarian cancer (HGS/EOC), who harbour a germline mutation in BRCA 1 or 2 genes. Despite some of the most impressive hazard ratios seen in ovarian oncology, such improvements in PFS have not translated into improved overall survival (OS) advantage potentially because maintenance poly ADP ribose polymerase inhibitors (PARPi) are only being administered during a single remission. Here the investigators will test the feasibility of administering a second course of olaparib in participants who have recurrent platinum-sensitive HGS/EOC.
Detailed description
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Olaparib +/- cediranib | Experimental | Drug: Olaparib, Drug: Cediranib, Drug: Platinum-based ChemotherapyPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Progressive, measureable high grade serous or endometrioid ovarian cancer, fallopian tube or primary peritoneal cancer
- Aged 18 or over
- Measureable disease by RECIST 1.1
- ECOG performance status 0-2 and life expectancy of over 12 weeks
- Adequate haematological function: Hb ≥ 10.0 g/l, Neutrophils ≥ 1.5 x 109/l, Platelets ≥ 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and/or APPT ratio <1.4
Key exclusion criteria (15 listed)
- Concurrent medical illness that would impact on compliance with the protocol including MDS/ AML
- Uncontrolled brain metastases or seizures. A scan to confirm the absence of brain metastases is not required.
- Known positivity for Hep B, Hep C or HIV.
- Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
- Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OlaparibAlso: Lynparza, AZD2281, KU-0059436300 mg taken twice daily, equivalent to a total daily dose of 600 mg | Drug | Olaparib +/- cediranib |
| CediranibAlso: AZD217120mg dose of cediranib was selected for this study | Drug | Olaparib +/- cediranib |
| Platinum-based Chemotherapy1 or 2 two courses of platinum-based chemotherapy administered depending on trial entry point. | Drug | Olaparib +/- cediranib |
Primary outcome
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.
3 secondary outcomes
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
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
Progression-free survival (PFS) for each course of chemotherapy followed by olaparib
Time frame: 6 months after the last event
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Feb 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gordon Jayson, MD, Prof. study chair
The Christie National Health Service (NHS) Foundation Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Olaparib, Cediranib and Platinum-based Chemotherapy in people with Ovarian Cancer, run by The Christie NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Feb 2022.