Ovarian CancerNCT02681237
A Study of Cediranib and Olaparib at Disease Worsening in Ovarian Cancer
A study testing Cediranib and Olaparib in people with Ovarian Cancer, run by University Health Network, Toronto at 1 site in Canada.
Trial summary
This is a proof of concept study (a study to initially assess the benefit a new drug indication) of the combination of two investigational drugs cediranib and olaparib in patients with ovarian cancer whose cancer worsened despite previously receiving a poly (ADP-ribose) polymerase (PARP) inhibitor (such as olaparib). 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?
- Cediranib and Olaparib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteCanada
- Study dates
- 29 Apr 2016to 25 Mar 2022
- Phase
- Interventional
- 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
- Age >= 18 years.
- Performance status <= 2.
- Histologically confirmed ovarian cancer, high grade serous or high grade endometrioid histology subtype.
- Radiographically documented disease progression within 28 days of registration and evaluable.
- Radiological progression on any PARP inhibitor therapy (example: olaparib):
- a cohort of platinum sensitive recurrence and response for at least 6 months on PARP inhibitor treatment
Show all 17Show fewer
- a cohort of platinum resistance with disease progression within 6 months after the last dose of a platinum based chemotherapy
- Patients who discontinue PARP therapy will be eligible after a break in therapy or intervening therapy.
- Patients must have adequate bone marrow, renal and hepatic function per local laboratory reference range.
- Ongoing prior toxicities related to previous treatments must be recovered to <= grade 2 at the time of registration.
- Left ventricular ejection fraction (LVEF) >= 50% by echocardiograms or multigated acquisition (MUGA) scan within 28 days of registration.
- Acceptable urine dipstick/urine analysis for proteinuria.
- Patients are willing to undergo tumour biopsy pre-treatment if a biopsy at the time of progression on olaparib is not available.
- Life expectancy of greater than 3 months.
- Ability to understand and the willingness to sign a written informed consent document.
- Patient's willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
- Patients of child bearing potential and their partners who are sexually active must agree to the use of 2 highly effective forms of contraception throughout their participation during the study treatment and for 3 months after last dose of study treatment(s).
Who cannot join
- Patients with current bowel obstruction.
- Patients with known brain metastases.
- Unacceptable mean corrected QT (QTc) in screening electrocardiograms within 7 days of registration or history of familial long QT syndrome.
- Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- A New York Heart Association classification of III or IV.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or cediranib.
Show all 15Show fewer
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
- Patients with myelodysplastic syndrome/acute myeloid leukaemia.
- Immuno-compromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV), patients with known active hepatitis (i.e., hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids.
- Patients who require maximal doses of calcium channel blockers to stabilize blood pressure.
- Patients with significant hemorrhage or haemoptysis.
- Patients who have had recent (within 2 weeks of registration, or until any wound has completely healed) major thoracic or abdominal surgery prior to study start, or a surgical incision that is not fully healed.
- History of stroke or transient ischemic attack within six months.
- Patients that are receiving and cannot stop the following prohibited medications prior to Cycle 1, Day 1.
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Proof of Concept, Multi-centre, Clinical Trial of the Combination Cediranib-Olaparib at the Time of Disease Progression on PARP Inhibitor in Ovarian Cancer
This is a proof of concept study (a study to initially assess the benefit a new drug indication) of the combination of two investigational drugs cediranib and olaparib in patients with ovarian cancer whose cancer worsened despite previously receiving a poly (ADP-ribose) polymerase (PARP) inhibitor (such as olaparib).
The purpose of this study is to find out whether taking cediranib and olaparib at the same time will be able to stop tumors from growing further or shrink it.
Read more
Cediranib works by blocking (inhibiting) several specific proteins in cancer cells called the vascular endothelial growth factor (VEGF) receptors. These proteins are important in the formation of blood vessels to the tumor. It is believed that many tumors survive because the blood vessels on the tumors bring oxygen and nutrients to the cancer cells which enable them to grow. If the formation of the blood vessels is blocked, the tumor cells may die.
Olaparib, works by blocking a protein called poly [adenosine diphosphate-ribose] polymerase (PARP). PARP is an important protein which tries to fix damaged deoxyribonucleic acid (DNA, molecules that contain important instructions for the development of cells). Many cancers are thought to develop from damaged DNA. By blocking PARP from fixing damaged DNA, the tumor cells may die.
Adding cediranib to olaparib, and therefore blocking several different mechanisms for cancer growth, may stop tumor growth.
Read the detailed description
The recent changes in OC treatment with maintenance therapy raise the question of drug strategy at progression. It remains unclear what the best option for a patient relapsing during PARP inhibitor treatment would be. Findings from a retrospective study-and the first data available for treatment after a PARP inhibitor-have provided support for a lack of significant clinical cross-resistance between PARP inhibitor and platinum-based chemotherapy. However, based on a recent clinical trial, the addition of an anti-angiogenic to olaparib adds significant benefit. In a randomized phase II trial, cediranib with olaparib showed an objective response rate markedly higher in the combination arm (80%) than the olaparib single agent arm (48%) with a median PFS of 9.0 months for olaparib and 17.7 months for cediranib/olaparib (p=0.001). The overall rate of grade 3/4 toxicity was higher on the combination (70%) than on olaparib (7%). The main toxicities occurring were fatigue (27% cediranib/olaparib vs 7% olaparib), diarrhea (23% vs 0%), and hypertension (39% vs 0%). This is the first oral, non-chemotherapy-based combination treatment in the platinum-sensitive recurrent OC. Preclinically, PARP-inhibition has reported anti-angiogenic effects, where GPI 15427 (a potent PARP-1/2 inhibitor) inhibits in vivo angiogenesis in a matrigel plug assay. PARP-1 knockout mice also demonstrate decreased in vivo angiogenesis compared to control mice with wild-type PARP-1, supporting the notion that the observed anti-angiogenic effects are specific to anti-PARP activity. More recent work has demonstrated that HR can be suppressed by hypoxia through downregulation of HR repair proteins such as BRCA1 and RAD51 and that PARP inhibitor sensitivity is enhanced in hypoxic states. This information raises the hypothesis that PARP-inhibitors and anti-angiogenics may have synergistic effects. Furthermore, preclinical data demonstrated that hypoxia-mediated defects in DNA repair can lead to genetic instability and drive oncogenesis. Some patients with tumor expressing a 'mutator' phenotype due to the acquisition of repair-deficient cancer cells from an unfavourable tumour microenvironment could benefit from this combined approach. Based on evidence for targeting HRR and angiogenesis (two potential Achilles Heels in OC), we will evaluate the interest in adding cediranib to olaparib in patients relapsing after initial good response to olaparib treatment. This is a proof of concept study as we will assess the benefit of adding cediranib to olaparib at the time of disease progression under olaparib. As other PARP inhibitor are currently under investigations such as Rucaparib and ABT-888, with no data available regarding a rechallenge of PARP inhibitor beyond progression, we propose the combination cediranib and olaparib in the setting of disease progression under treatment with a PARP inhibitor such as olaparib.
- Conditions
- Ovarian Cancer
- Being tested
- Cediranib, Olaparib
- Medical subject headings
- Ovarian Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CediranibDrug
Small-molecule inhibitor of several tyrosine kinases including VEGFR-1, VEGFR-2, VEGFR-3 and c-kit.
OlaparibDrug
Poly (ADP-ribose) polymerase (PARP) inhibitor.
| Study group | Role | What they receive |
|---|---|---|
| Cediranib and Olaparib | Experimental | Cediranib will be given by mouth, at a dose of 20 mg, once a day, everyday.
Olaparib will given by mouth, at a dose of 300 mg, twice a day, every day. Receives: Drug: Cediranib; Drug: Olaparib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate
objective response rate by RECIST 1.1
Measured: 8 weeks
Progression-Free Survival Rate
objective response rate by RECIST 1.1 or death
Measured: 16 weeks
Secondary outcomes (4)
CA125 response rate
objective response rate by GCIG criteria
Measured: 2 years
Disease control rate
Measured: 2 years
Overall survival rate
Measured: 2 years
Number of Adverse Events Experienced
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2016 (estimated)
- Study start29 Apr 2016
- Primary completion10 Jan 2022
- Study completion25 Mar 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Ovarian CancerStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- 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
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
- Investigators
- Amit Oza, M.D., Principal investigator, Princess Margaret Cancer Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02681237
- Sponsor's protocol ID
- e-Volve 1
- Status last verified
- May 2022
- First submitted
- 10 Feb 2016
- Last updated
- 9 May 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Lheureux S, Oaknin A, Garg S, Bruce JP, Madariaga A, Dhani NC, Bowering V, White J, Accardi S, Tan Q, Braunstein M, Karakasis K, Cirlan I, Pedersen S, Li T, Farinas-Madrid L, Lee YC, Liu ZA, Pugh TJ, Oza AM. EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression. Clin Cancer Res. 2020 Aug 15;26(16):4206-4215. doi: 10.1158/1078-0432.CCR-19-4121. Epub 2020 May 22.
PubMed 32444417
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Proof of Concept, Multi-centre, Clinical Trial of the Combination Cediranib-Olaparib at the Time of Disease Progression on PARP Inhibitor in Ovarian Cancer
- ClinicalTrials.gov ID
- NCT02681237
- Acronym / sponsor ID
- e-Volve 1
- Conditions
- Ovarian Cancer
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 29 Apr 2016 (actual)
- Primary completion
- 10 Jan 2022 (actual)
- Study completion
- 25 Mar 2022 (actual)
- First posted
- 12 Feb 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.
This is a proof of concept study (a study to initially assess the benefit a new drug indication) of the combination of two investigational drugs cediranib and olaparib in patients with ovarian cancer whose cancer worsened despite previously receiving a poly (ADP-ribose) polymerase (PARP) inhibitor (such as olaparib).
The purpose of this study is to find out whether taking cediranib and olaparib at the same time will be able to stop tumors from growing further or shrink it.
Cediranib works by blocking (inhibiting) several specific proteins in cancer cells called the vascular endothelial growth factor (VEGF) receptors. These proteins are important in the formation of blood vessels to the tumor. It is believed that many tumors survive because the blood vessels on the tumors bring oxygen and nutrients to the cancer cells which enable them to grow. If the formation of the blood vessels is blocked, the tumor cells may die.
Olaparib, works by blocking a protein called poly [adenosine diphosphate-ribose] polymerase (PARP). PARP is an important protein which tries to fix damaged deoxyribonucleic acid (DNA, molecules that contain important instructions for the development of cells). Many cancers are thought to develop from damaged DNA. By blocking PARP from fixing damaged DNA, the tumor cells may die.
Adding cediranib to olaparib, and therefore blocking several different mechanisms for cancer growth, may stop tumor growth.
Detailed description
The recent changes in OC treatment with maintenance therapy raise the question of drug strategy at progression. It remains unclear what the best option for a patient relapsing during PARP inhibitor treatment would be. Findings from a retrospective study-and the first data available for treatment after a PARP inhibitor-have provided support for a lack of significant clinical cross-resistance between PARP inhibitor and platinum-based chemotherapy. However, based on a recent clinical trial, the addition of an anti-angiogenic to olaparib adds significant benefit. In a randomized phase II trial, cediranib with olaparib showed an objective response rate markedly higher in the combination arm (80%) than the olaparib single agent arm (48%) with a median PFS of 9.0 months for olaparib and 17.7 months for cediranib/olaparib (p=0.001). The overall rate of grade 3/4 toxicity was higher on the combination (70%) than on olaparib (7%). The main toxicities occurring were fatigue (27% cediranib/olaparib vs 7% olaparib), diarrhea (23% vs 0%), and hypertension (39% vs 0%). This is the first oral, non-chemotherapy-based combination treatment in the platinum-sensitive recurrent OC. Preclinically, PARP-inhibition has reported anti-angiogenic effects, where GPI 15427 (a potent PARP-1/2 inhibitor) inhibits in vivo angiogenesis in a matrigel plug assay. PARP-1 knockout mice also demonstrate decreased in vivo angiogenesis compared to control mice with wild-type PARP-1, supporting the notion that the observed anti-angiogenic effects are specific to anti-PARP activity. More recent work has demonstrated that HR can be suppressed by hypoxia through downregulation of HR repair proteins such as BRCA1 and RAD51 and that PARP inhibitor sensitivity is enhanced in hypoxic states. This information raises the hypothesis that PARP-inhibitors and anti-angiogenics may have synergistic effects. Furthermore, preclinical data demonstrated that hypoxia-mediated defects in DNA repair can lead to genetic instability and drive oncogenesis. Some patients with tumor expressing a 'mutator' phenotype due to the acquisition of repair-deficient cancer cells from an unfavourable tumour microenvironment could benefit from this combined approach. Based on evidence for targeting HRR and angiogenesis (two potential Achilles Heels in OC), we will evaluate the interest in adding cediranib to olaparib in patients relapsing after initial good response to olaparib treatment. This is a proof of concept study as we will assess the benefit of adding cediranib to olaparib at the time of disease progression under olaparib. As other PARP inhibitor are currently under investigations such as Rucaparib and ABT-888, with no data available regarding a rechallenge of PARP inhibitor beyond progression, we propose the combination cediranib and olaparib in the setting of disease progression under treatment with a PARP inhibitor such as olaparib.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Cediranib and Olaparib | Experimental | Drug: Cediranib, Drug: OlaparibCediranib will be given by mouth, at a dose of 20 mg, once a day, everyday. Olaparib will given by mouth, at a dose of 300 mg, twice a day, every day. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Age >= 18 years.
- Performance status <= 2.
- Histologically confirmed ovarian cancer, high grade serous or high grade endometrioid histology subtype.
- Radiographically documented disease progression within 28 days of registration and evaluable.
- Radiological progression on any PARP inhibitor therapy (example: olaparib):
Key exclusion criteria (15 listed)
- Patients with current bowel obstruction.
- Patients with known brain metastases.
- Unacceptable mean corrected QT (QTc) in screening electrocardiograms within 7 days of registration or history of familial long QT syndrome.
- Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- A New York Heart Association classification of III or IV.
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 |
|---|---|---|
| CediranibSmall-molecule inhibitor of several tyrosine kinases including VEGFR-1, VEGFR-2, VEGFR-3 and c-kit. | Drug | Cediranib and Olaparib |
| OlaparibPoly (ADP-ribose) polymerase (PARP) inhibitor. | Drug | Cediranib and Olaparib |
Primary outcome
Objective Response Rate
Time frame: 8 weeks
objective response rate by RECIST 1.1
Progression-Free Survival Rate
Time frame: 16 weeks
objective response rate by RECIST 1.1 or death
4 secondary outcomes
CA125 response rate
Time frame: 2 years
Disease control rate
Time frame: 2 years
Overall survival rate
Time frame: 2 years
Number of Adverse Events Experienced
Time frame: 2 years
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 9 May 2022.
- Derived from this study: PubMed 32444417Lheureux S, Oaknin A, Garg S, Bruce JP, Madariaga A, Dhani NC, Bowering V, White J, Accardi S, Tan Q, Braunstein M, Karakasis K, Cirlan I, Pedersen S, Li T, Farinas-Madrid L, Lee YC, Liu ZA, Pugh TJ, Oza AM. EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression. Clin Cancer Res. 2020 Aug 15;26(16):4206-4215. doi: 10.1158/1078-0432.CCR-19-4121. Epub 2020 May 22.
- Individual participant dataSharing planned: No
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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.
Amit Oza, M.D. principal investigator
Princess Margaret Cancer Centre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Cediranib and Olaparib in people with Ovarian Cancer, run by University Health Network, Toronto at 1 site in Canada.
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 17 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 9 May 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 Canada. 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.
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?
Objective Response Rate (time frame: 8 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02681237, which also lists 1 linked publication.
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 9 May 2022.