Recurrent Platinum Resistant Ovarian Cancer Clinical Trial
— CONCERTOOfficial title:
A Single Arm, Open-label, Phase IIb Study to Assess the Efficacy and Safety of the Combination of Cediranib and Olaparib Tablets in Women With Recurrent Platinum Resistant Epithelial Ovarian Cancer, Including Fallopian Tube and/or Primary Peritoneal Cancer Who do Not Carry a Deleterious or Suspected Deleterious Germline BRCA Mutation
| Verified date | March 2022 |
| Source | AstraZeneca |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
This is an open label, single arm, multi-center study to assess the efficacy and safety of the combination of cediranib and olaparib tablets in platinum-resistant relapsed high grade serous, high grade endometroid or clear cell ovarian, fallopian tube or primary peritoneal carcinoma patients who have received at least 3 prior lines of chemotherapy and who do not carry deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA) mutations.
| Status | Completed |
| Enrollment | 62 |
| Est. completion date | March 16, 2021 |
| Est. primary completion date | August 27, 2019 |
| Accepts healthy volunteers | No |
| Gender | Female |
| Age group | 18 Years to 120 Years |
| Eligibility | Inclusion Criteria: 1. Ability and willingness to provide written informed consent, and to comply with the requirements of the protocol 2. Females aged =18 years with previous histologically proven diagnosis of high grade serous, high grade endometroid or clear cell ovarian cancer, fallopian tube or primary peritoneal carcinoma 3. No evidence of deleterious or suspected deleterious germline mutation in BRCA1 or BRCA2 genes 4. Recurrent platinum-resistant disease, defined as disease progression within 6 months (182 days) of the last receipt of platinum-based chemotherapy 5. CT/MRI evidence of measurable disease as per RECIST 1.1 defined as at least one lesion, not previously irradiated, that can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes which must have short axis = 15 mm) and which is suitable for accurate repeated measurements 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 7. Life expectancy =12 weeks 8. Prior receipt of antiangiogenic treatment, including but not limited to bevacizumab, is optional. If used, it can be used in the first line or recurrent setting. 9. At least three prior lines of therapy for advanced ovarian cancer as defined in the protocol 10. Confirmation of the availability of a tumor sample from the primary or recurrent cancer must be provided 11. Patients must have adequate organ and bone marrow function 12. Adequately controlled blood pressure 13. Adequately controlled thyroid function, with no symptoms of thyroid dysfunction 14. Able to swallow and retain oral medications and without gastrointestinal illnesses that would preclude absorption of cediranib or olaparib 15. Postmenopausal or evidence of non-childbearing status for women of childbearing potential as confirmed by a negative urine or serum pregnancy test within 7 days prior to start of IPs Exclusion Criteria: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 2. Previous enrollment in the present study. 3. Exposure to any IP during the last 4 weeks prior to enrollment. 4. Previous treatment with PARP inhibitor. For this study, BSI-201 (iniparib) is not considered as PARPi 5. Recent cancer-directed therapies: Radiotherapy (RT) within 4 weeks, chemotherapy or other systemic anti-cancer therapy within 4 weeks, or prior anti-angiogenic treatment (e.g., bevacizumab) within 6 weeks prior to starting treatment 6. Cancer antigen-125 (CA-125) only disease without RECIST 1.1 measurable disease 7. Major surgical procedure within 2 weeks prior to starting treatment; patients must have recovered from any effects of any major surgery and surgical wound should have healed prior to starting treatment 8. Clinically significant signs and/or symptoms of bowel obstruction within 3 months prior to starting treatment 9. History of intra-abdominal abscess within 3 months prior to starting treatment 10. History of GI perforation. Patients with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months prior to starting treatment, and patient is deemed to be at low risk of recurrent fistula 11. Other malignancy within the last 5 years 12. Persisting =Grade 2 CTCAE toxicity (except alopecia and Grade 2 peripheral neuropathy) from previous anti-cancer treatment(s) 13. Central nervous system metastases 14. Patients with any of the following: History of myocardial infarction within 6 months prior to starting treatment; Unstable angina; Resting electrocardiogram (ECG) with clinically significant abnormal findings; New York Heart Association functional classification of III or IV 15. Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per institutional guidelines, or <55%, if threshold for normal not otherwise specified by institutional guidelines, for patients with the following risk factors: Prior treatment with anthracyclines; Prior treatment with trastuzumab; Prior central thoracic RT, including exposure of heart to therapeutic doses of ionizing RT; History of myocardial infarction within 6-12 months prior to start of IPs; Prior history of other significant impaired cardiac function 16. History of stroke or transient ischemic attack within 6 months 17. Uncontrolled intercurrent illness 18. Patients with myelodysplastic syndrome (MDS)/ treatment-related acute myeloid leukemia (t-AML) or with features suggestive of MDS/AML 19. No prior allogenic bone marrow transplant or double umbilical cord blood transplantation 20. Known active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection on antiviral treatment 21. Concomitant use of known strong or moderate CYP3A inhibitors 22. Concomitant use of known strong or moderate CYP3A inducers |
| Country | Name | City | State |
|---|---|---|---|
| United States | Research Site | Anchorage | Alaska |
| United States | Research Site | Augusta | Georgia |
| United States | Research Site | Billings | Montana |
| United States | Research Site | Boston | Massachusetts |
| United States | Research Site | Charlotte | North Carolina |
| United States | Research Site | Covington | Louisiana |
| United States | Research Site | Downey | California |
| United States | Research Site | Fort Wayne | Indiana |
| United States | Research Site | Greenbrae | California |
| United States | Research Site | Knoxville | Tennessee |
| United States | Research Site | Miami | Florida |
| United States | Research Site | Miami | Florida |
| United States | Research Site | Mobile | Alabama |
| United States | Research Site | New York | New York |
| United States | Research Site | Newnan | Georgia |
| United States | Research Site | Orange | California |
| United States | Research Site | Orlando | Florida |
| United States | Research Site | Rochester | New York |
| United States | Research Site | San Diego | California |
| United States | Research Site | San Francisco | California |
| United States | Research Site | Seattle | Washington |
| United States | Research Site | Towson | Maryland |
| United States | Research Site | West Hollywood | California |
| United States | Research Site | Westwood | Kansas |
| United States | Research Site | Winston-Salem | North Carolina |
| Lead Sponsor | Collaborator |
|---|---|
| AstraZeneca | Merck Sharp & Dohme Corp., Myriad Genetic Laboratories, Inc. |
United States,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Mean Objective Response Rate (ORR) by Independent Central Review (ICR) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | The ORR was defined as the percentage of patients with objective response (complete response [CR] or partial response [PR]) according to RECIST 1.1 and was assessed by ICR. Only patients whose CR/PR response was confirmed by a second scan at least 4 weeks after the initial response, with no evidence of progression between the initial and CR/PR confirmation visit were included. CR: Disappearance of all target lesions (TLs) and non-TLs (NTLS) since baseline; any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 millimeters (mm). PR: At least a 30% decrease in the sum of the diameters of TL, referencing the baseline sum of diameters. Data obtained up until progression, or last evaluable assessment in the absence of progression were included in the assessment of ORR. |
From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. | |
| Secondary | ORR by Investigator Assessment Using RECIST 1.1 | The percentage of patients with a response (CR/PR), including patients with both confirmed and unconfirmed responses, based on investigator assessed RECIST 1.1 data is presented. Confirmed responses included patients whose CR/PR response was confirmed by a second scan at least 4 weeks after the initial response, with no evidence of progression between the initial and CR/PR confirmation visit. CR: Disappearance of all TLs and NTLs since baseline; any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of TL, referencing the baseline sum of diameters. |
From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. | |
| Secondary | Median Duration of Response (DoR) by ICR and Investigator Assessment Using RECIST 1.1 | DoR was defined as the time from date of first documented response (which was subsequently confirmed) until date of documented progression or death in the absence of disease progression (i.e. date of progression free survival [PFS] event or censoring - date of first response + 1). The end of response coincided with the date of progression or death from any cause used for the PFS endpoint. The time of initial response was defined as the latest of the dates used towards the first visit that was CR or PR that was subsequently confirmed. If a patient did not progress following a response, the PFS censoring time was used. The Investigator assessment was based on the FAS and the ICR used the EFR analysis set. The median DoR for each assessment is presented and was calculated using the Kaplan-Meier technique. | From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. | |
| Secondary | Disease Control Rate (DCR) by ICR and Investigator Assessment Using RECIST 1.1 | The DCR was defined as the percentage of patients who had a best overall response of CR, PR or Stable Disease (SD) at 6 months. CR: Disappearance of all TLs and NTLs since baseline; any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of TL, referencing the baseline sum of diameters. SD: Neither sufficient shrinkage of TLs to qualify for PR nor sufficient increase to qualify for progressive disease (PD) (at least a 20% increase in the sum of diameters of TLs with an absolute increase of at least 5 mm and progression of existing NTLs). Patients had to have demonstrated SD for at least 23 weeks following the start of treatment. The Investigator assessment was based on the FAS and the ICR used the EFR analysis set. The percentage of patients with disease control for each assessment is presented. |
From baseline up to 6 months after first doses of IPs. RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. | |
| Secondary | Median PFS by ICR and Investigator Assessment Using RECIST 1.1 | PFS was defined as the time from date of first dose of IP until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from treatment or received another anti-cancer therapy prior to progression (i.e. date of PFS event or censoring - date of first dose + 1). Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. The median PFS, calculated using the Kaplan-Meier technique, is presented for the ICR and the Investigator assessment, both based on the FAS. |
From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. | |
| Secondary | Median Time to Treatment Discontinuation or Death (TDT) | The median time to discontinuation of IPs or death was defined as the time from the date of first dose of IP to the earlier of the date of discontinuation of both IPs, or death date. If 1 IP was discontinued before the other, the TDT reflected the time from the date of first dose to the earliest IP discontinuation date. The median TDT was calculated using the Kaplan-Meier technique. | From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). | |
| Secondary | Median Overall Survival (OS) | OS was defined as the time from the date of first dose of IP until death due to any cause regardless of whether the patient withdrew from treatment or received another anti-cancer therapy (i.e. date of death or censoring - date of first dose + 1). Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. The median OS was calculated using the Kaplan-Meier technique. | From baseline until death due to any cause, assessed until primary analysis DCO (8 months after last patient received their first dose of IPs). | |
| Secondary | Best Observed Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 Scales | The EORTC QLQ-C30 questionnaire assesses health-related quality of life (HRQoL). The questions are grouped into a global health status/QoL scale, 5 functional scales (physical, role, emotional, cognitive and social), 3 multi-item symptom scales (fatigue, pain, nausea/ vomiting), 5 single items assessing cancer symptoms (dyspnea, loss of appetite, insomnia, constipation, diarrhea), and 1 item on the financial impact of the disease. Each scale/item is scored from 0 to 100. Higher scores on the global health status/QoL scale and functional scales indicate better health status/function. Higher scores on the symptom scales/items indicate a greater symptom burden. A 10-point change in the score was used to identify patients who improved, stayed the same or deteriorated from baseline. The number of patients with a best observed change from baseline response of improved, stayed the same or deteriorated for each EORTC QLQ-C30 scale/item is presented. |
From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). EORTC QLQ-C30 assessments were performed at baseline and every 8 weeks relative to first dose until discontinuation of IPs. | |
| Secondary | Best Observed Change From Baseline in EORTC QLQ-OV28 | The EORTC QLQ-OV28 is specific for ovarian cancer and consists of 28 items assessing abdominal/gastrointestinal symptoms (6 items), peripheral neuropathy (2 items), other chemotherapy side effects (5 items), hormonal symptoms (2 items), body image (2 items), attitudes to disease/treatment (3 items), sexuality (4 items) and 4 other single items. Each scale was scored from 0 to 100 with higher scores on the symptom scales indicating greater symptom burden. The best observed change from baseline is presented for each EORTC QLQ-OV28 scale, where a 10-point change in the score was used to identify patients who improved, stayed the same or deteriorated. The number of patients with a best observed change from baseline response of improved, stayed the same, or deteriorated in the EORTC QLQ-OV28 is presented. |
From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). EORTC QLQ-OV28 assessments were performed at baseline and every 8 weeks relative to first dose until discontinuation of IPs. |
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