Description:
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.
Title
- Brief Title: Efficacy and Safety Study of Cediranib in Combination With Olaparib in Patients With Recurrent Platinum-Resistant Ovarian Cancer
- Official 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
Clinical Trial IDs
- ORG STUDY ID:
D8488C00001
- NCT ID:
NCT02889900
Conditions
- Recurrent Platinum Resistant Ovarian Cancer
Interventions
| Drug | Synonyms | Arms |
|---|
| cediranib and olaparib | Olaparib: also known as Lynparza | combination of cediranib and olaparib |
Purpose
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.
Detailed Description
The study will recruit approximately 60 patients aged ≥18 years, with histologically proven
diagnosis of platinum-resistant relapsed high grade serous, high grade endometroid or clear
cell ovarian, fallopian tube or primary peritoneal carcinoma who have received at least 3
prior lines of therapy, and who do not carry a deleterious or suspected deleterious germline
BRCA mutation. All patients should have recurrent platinum resistant disease. The receipt of
prior antiangiogenic treatment (e.g. bevacizumab) is optional. If used, it can be in the
first line or recurrent setting. To be eligible to enter the study, all patients should have
measurable disease (as assessed by the Investigator).
There is no maximum duration for taking the study treatments (cediranib+olaparib). Patients
should continue on study treatments until objective radiological disease progression, as
defined by RECIST version 1.1 guidelines, or they meet other discontinuation criteria.
Following discontinuation of study treatment patients will be followed for disease
progression (if they have not already progressed), survival and post-progression anti cancer
therapies until the data cut-off for the primary analysis, approximately 8 months after
enrollment of the last patient.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| combination of cediranib and olaparib | Experimental | Open label | |
Eligibility Criteria
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
| Maximum Eligible Age: | 120 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Mean Objective Response Rate (ORR) by Independent Central Review (ICR) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | ORR by Investigator Assessment Using RECIST 1.1 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Median Duration of Response (DoR) by ICR and Investigator Assessment Using RECIST 1.1 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Disease Control Rate (DCR) by ICR and Investigator Assessment Using RECIST 1.1 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Median PFS by ICR and Investigator Assessment Using RECIST 1.1 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Median Time to Treatment Discontinuation or Death (TDT) |
| Time Frame: | From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Median Overall Survival (OS) |
| Time Frame: | From baseline until death due to any cause, assessed until primary analysis DCO (8 months after last patient received their first dose of IPs). |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Best Observed Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 Scales |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Best Observed Change From Baseline in EORTC QLQ-OV28 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | AstraZeneca |
Trial Keywords
Last Updated
June 11, 2021
