Fallopian Tube Carcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian High Grade Serous Adenocarcinoma, Ovarian Serous Adenocarcinoma, Ovarian Serous Surface Papillary Adenocarcinoma, Primary Peritoneal Serous Adenocarcinoma, Triple-Negative Breast Carcinoma
Conditions
Brief summary
This partially randomized phase I/II trial studies the side effects and the best dose of cediranib maleate and olaparib and to see how well they work compared to olaparib alone in treating patients with ovarian, fallopian tube, peritoneal, or triple-negative breast cancer that has returned after a period of improvement (recurrent). Cediranib maleate may help keep cancer cells from growing by affecting their blood supply. Olaparib may stop cancer cells from growing abnormally. The combination of cediranib maleate and olaparib may be safe, tolerable and/or effective in treating patients with recurrent ovarian, fallopian tube, or peritoneal cancer or recurrent triple-negative breast cancer.
Detailed description
PRIMARY OBJECTIVES: I. Assess the maximum tolerated dose (MTD) of cediranib maleate (cediranib) in combination with olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer. (Phase I) II. Assess the efficacy (as measured by progression-free survival \[PFS\]) of the combination of cediranib and olaparib compared to olaparib alone in recurrent grade 2 or 3 platinum-sensitive papillary-serous or endometrioid ovarian, fallopian tube, or peritoneal cancer. (Phase II) III. Assess the MTD of cediranib in combination with olaparib tablet formulation in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer. (Phase I-T) IV. Assess the toxicities of the combination of cediranib and olaparib (tablet formulation) in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer. (Phase I-T) V. Assess clinical benefit, progression-free survival, and overall survival for patients treated with cediranib and olaparib (tablet formulation). (Phase I-T) VI. Assess the pharmacokinetic profile of cediranib and olaparib (tablet formulation) when administered in combination. (Phase I-T) SECONDARY OBJECTIVES: I. Assess the toxicities of the combination of cediranib and olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer. (Phase I) II. Assess clinical benefit, progression-free survival, and overall survival for patients treated with cediranib and olaparib. (Phase I) III. Assess tumor response, clinical response benefit (response or stable disease as defined by Response Evaluation Criteria in Solid Tumors \[RECIST\] response criteria x 16 weeks), and overall survival (OS) for patients treated with cediranib and olaparib at the recommended phase II dose (RP2D) as compared with patients receiving olaparib alone. (Phase II) TRANSLATIONAL OBJECTIVES: I. To evaluate the prognostic and predictive role of measured changes in functional vascular imaging using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) between pre-study and day 3. (Phase II) II. To evaluate in an exploratory fashion the predictive or prognostic value of single nucleotide polymorphisms (SNPs) in key genes involved in angiogenesis and deoxyribonucleic acid (DNA) repair. (Phase II) III. To evaluate the predictive value of baseline peripheral blood mononuclear cells (PBMC) poly adenosine diphosphate (ADP) ribose (PAR) incorporation on response to therapy. (Phase II) IV. To measure early changes in vascular cytokine production and evaluate in an exploratory fashion that these changes may be predictive or prognostic, or differentially affected by the combination of agents. (Phase II) V. To evaluate early changes to circulating endothelial cells and if these changes are predictive or prognostic. (Phase II) VI. To assess changes in measures of DNA damage and repair and angiogenesis in tumor cells (tissue and/or malignant effusions) and correlate to drug/drug/combination. (Phase II) OUTLINE: This is a phase I, dose-escalation study followed by a randomized phase II study. PHASE I: Patients receive cediranib maleate orally (PO) once daily (QD) and olaparib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and as clinically indicated on study. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) as well as blood sample collection on the trial. Patients may also optionally undergo a tissue biopsy on the trial. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive cediranib maleate PO QD and olaparib PO BID on days 1-28. ARM II: Patients receive olaparib PO BID on days 1-28. In both arms, cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo CT or MRI as well as blood sample collection on the trial. Patients may also optionally undergo a tissue biopsy on the trial. After completion of study treatment, patients are followed up every 6 months for up to 3 years.
Interventions
PROCEDUREBiopsy Procedure
Undergo optional tissue biopsy
PROCEDUREBiospecimen Collection
Undergo blood sample collection
DRUGCediranib Maleate
Given PO
PROCEDUREComputed Tomography
Undergo CT
PROCEDUREEchocardiography Test
Undergo ECHO
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
PROCEDUREMultigated Acquisition Scan
Undergo MUGA
DRUGOlaparib
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PHASE I: Participants must have histologically or cytologically confirmed epithelial ovarian cancer, primary peritoneal serous cancer, fallopian tube cancer, or triple-negative breast cancer * PHASE II: Participants must have histologically or cytologically grade 2 or 3 (high-grade) papillary-serous or endometrioid epithelial ovarian cancer, primary peritoneal serous cancer, or fallopian tube cancer; participants with epithelial ovarian, primary peritoneal, or fallopian tube cancers of other high-grade histologies who carry a known deleterious breast cancer gene (BRCA) germline mutation by standard clinical testing (Myriad BRAC Analysis) will also be considered eligible * PHASE I-T: Participants must have histologically or cytologically confirmed epithelial ovarian cancer, primary peritoneal serous cancer, or fallopian tube cancer * Ovarian cancer, primary peritoneal, and fallopian tube participants in the Phase 1 and Phase 1-T portions of this trial must have either measurable cancer by RECIST 1.1 criteria or an elevated cancer antigen (CA)125 level at least twice the upper limit of normal on two separate occasions at least 1 day but not more than 3 months apart; at least one of the samples should be within 1 week of starting treatment; patients with both an elevated CA125 and measurable cancer will be followed by RECIST 1.1 criteria; patients with only an elevated CA125 level will be followed by modified Gynecologic Cancer Intergroup (GCIG) criteria * Participants in the Phase II portion of the trial must have measurable disease by RECIST 1.1 criteria * Breast cancer participants must have measurable disease by RECIST criteria * PRIOR THERAPY PHASE I and PHASE I-T: * Prior chemotherapy for ovarian cancer patients must have included a first-line platinum-based regimen with or without intravenous consolidation chemotherapy * Breast cancer patients must have recurred post both an Adriamycin- and taxane-containing regimen * Prior hormonal-based therapy for ovarian, primary peritoneal serous, fallopian tube cancer, or breast cancer is acceptable * Patients may not have had a prior PAR polymerase (PARP)-inhibitor in the recurrent or metastatic setting; prior treatment with BSI-201 (iniparib) is allowed * Patients may not have had a prior anti-angiogenic agent in the recurrent or metastatic setting * PRIOR THERAPY PHASE II: * Prior chemotherapy must have included a first-line platinum-based regimen with or without intravenous consolidation chemotherapy * Prior hormonal-based therapy for ovarian, primary peritoneal serous, or fallopian tube cancer is acceptable * Patients may not have previously received a PARP-inhibitor; prior treatment with BSI-201 is allowed * Patients may not have had a prior anti-angiogenic agent in the recurrent setting * Patients may have received up to 1 non-platinum-based line of therapy in the recurrent setting * Patients may have received an unlimited number of platinum-based therapies in the recurrent setting * Patients should have platinum-sensitive disease, where platinum-sensitive disease is defined as having had a \> 6 month interval since last receiving platinum therapy prior to disease recurrence; patients must have had a prior response while on the platinum-containing regimen and cannot have experienced disease progression while receiving platinum * Subjects may begin cediranib and olaparib at least 3 weeks after their last dose of chemotherapy or hormonal therapy, assuming they are otherwise eligible * Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of cediranib or olaparib in participants \< 18 years of age, children are excluded from this study but will be eligible for future pediatric trials * Estimated life expectancy of greater than 6 months * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky \> 60%) * Absolute neutrophil count \>= 1,500/mcL * Platelets \>= 100,000/mcL * Hemoglobin \> 9 g/dL * For patients enrolled to the Phase 1-T portion of the protocol, the hemoglobin should be \>= 10 g/dL * Total bilirubin within 1.5 times the upper limit of normal institutional limits * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal * Creatinine =\< the institutional upper limit of normal or creatinine clearance \>= 60 mL/min/1.73 m\^2 for subjects with creatinine levels above institutional normal * Less than or equal to 1+ proteinuria on two consecutive dipsticks taken no less than 1 week apart, or \< 1 gm protein on 24-hour urine collection or a urine protein: creatinine ratio of \< 1 * Troponin T or I within normal institutional limits * Coagulation parameters (international normalized ratio \[INR\], activated partial thromboplastin time \[aPTT\]) within 1.25 x upper limit of normal institutional limits, except where a Lupus anti-coagulant has been confirmed * Toxicities of prior therapy (except alopecia) should be resolved to less than or equal to grade 1 as per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0); patients with long-standing stable grade 2 neuropathy may be considered after discussion with the overall principal investigator (PI) * Subjects with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible; subjects with prior cancer treated with a curative intent with no evidence of recurrent disease 5 years following diagnosis and judged by the investigator to be at low risk of recurrence are eligible; subjects with any other concomitant or prior invasive malignancies are ineligible * Patients who have the following risk factors are considered to be at increased risk for cardiac toxicities; these patients should have increased monitoring: * Prior treatment with anthracyclines * Prior treatment with trastuzumab * A New York Heart Association classification of II controlled with treatment * Prior central thoracic radiation therapy (RT), including RT to the heart * History of myocardial infarction within 12 months (patients with history of myocardial infarction within 6 months are excluded from the study) * The effects of cediranib and olaparib on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months following treatment discontinuation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * Ability to understand and the willingness to sign a written informed consent * Patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of cediranib or olaparib * Patients must be willing and able to check and record daily blood pressure readings
Exclusion criteria
* Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier * Participants may not be receiving any other investigational agents nor have participated in an investigational trial within the past 4 weeks; subjects may not have received prior treatment affecting the vascular endothelial growth factor (VEGF) pathway in the recurrent setting, including thalidomide, bevacizumab, sunitinib, or sorafenib; in the Phase I portion of the trial, subjects may not have received prior treatment with oregovomab (OvaRex) or any other antibodies that may interfere with CA-125 measurements * Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or MRI scans should not be included on this study, since neurologic dysfunction may confound the evaluation of neurologic and other adverse events; screening imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated; patients with treated brain metastases and resolution of any associated symptoms must demonstrate stable post-therapeutic imaging for at least 6 months following therapy prior to starting study drug * History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib maleate or olaparib * Participants receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; dihydropyridine calcium-channel blockers are permitted for management of hypertension * Patients with any of the following: * History of myocardial infarction within six months * Patients with corrected QT (QTc) prolongation \> 500 msec or other significant electrocardiogram (ECG) abnormality noted within 14 days of treatment * For patients enrolled in the Phase 1-T portion of the protocol, the QTc should not exceed 470 msec * New York Heart Association (NYHA) classification of III or IV * If cardiac function assessment is clinically indicated or performed: left ventricular ejection fraction (LVEF) less than normal per institutional guidelines, or \< 55%, if threshold for normal not otherwise specified by institutional guidelines * Condition requiring concurrent use of drugs or biologics with pro-arrhythmic potential * History of stroke or transient ischemic attack within six months * Patients may not have any evidence of pre-existing inadequately controlled hypertension (defined as a systolic blood pressure \[BP\] of \> 140 mmHg or a diastolic BP of \> 90 mmHg), and must have a normal blood pressure (=\< 140/90 mmHg) taken in the clinic setting by a medical professional within 2 weeks prior to starting study; patients with hypertension may be managed with up to a maximum of three antihypertensive medications; patients who are on three antihypertensive medications must be actively followed by a cardiologist or blood pressure specialist for management of blood pressure while on protocol * Any prior history of hypertensive crisis or hypertensive encephalopathy * Clinical significant peripheral vascular disease or vascular disease (aortic aneurysm or aortic dissection) * Unstable angina * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib * History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess * Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel obstruction within 3 months prior to starting study drugs * Current dependency on intravenous (IV) hydration or total parenteral nutrition (TPN) * Evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted * Uncontrolled intercurrent illness including, but not limited to 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 * Pregnant women are excluded from this study because cediranib and olaparib are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with cediranib and olaparib, breastfeeding should be discontinued if the mother is treated with cediranib or olaparib; these potential risks may also apply to other agents used in this study * Known human immunodeficiency virus (HIV)-positive individuals are ineligible because of the potential for pharmacokinetic interactions with cediranib or olaparib; in addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy * Patients may not use natural herbal products or other "folk remedies" while participating in this study * No features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities of Cediranib Maleate in Combination With Olaparib (Phase I) | At 28 days | Was determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 |
| The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Metastatic Triple-negative Breast Cancer (Phase I) | At 28 Days | This trial employed a 3+3 design, escalating on 0/3 or 1/6 DLT, and de-escalating if 2 DLTs were encountered. The MTD (maximum tolerated dose) was the dose at which no more than 1 patient developed a dose-limiting toxicity (DLT) when at least 6 patients had been treated. |
| Progression-free Survival (PFS) at the Maximum Tolerated Dose/Recommended Phase 2 Dose of Cediranib Maleate With Olaparib Compared to That of Olaparib Alone (Phase II) | Time from start of treatment to time of objective disease progression, assessed up to 5 years | Evaluated by Kaplan-Meier analysis and log-rank test for between group comparison, and median survival times reported. PFS is defined as time from randomization to investigator-assessed radiographic progression by RECIST 1.1 criteria or death. Patients alive without evidence of progression were censored at the last disease assessment. |
| The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib Tablet Formulation in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer (Phase I-T). | At 28 days | The Phase 1-T component of this trial employed a 3+3 design, escalating on 0/3 or 1/6 DLT, and de-escalating if 2 DLTs were encountered. The MTD (maximum tolerated dose) was the dose at which no more than 1 patient developed a DLT when at least 6 patients had been treated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Toxicities of the Combination of Cediranib Maleate and Olaparib (Phase I) | Adverse Events monitored for 3 years, mortality assessed up to 5 years | Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, study-related adverse events observed in \>10% of participants (n=28). |
| Tumor Response Rate (Objective Response Rate) Defined by Response Evaluation Criteria in Solid Tumors Criteria (Phase II) | Up to 5 years | The response rates are compared by an exact test and 95% confidence intervals will also be reported. Objective response rate (ORR) is defined as the best confirmed RECIST response, ORR is defined as the number of participants with CR, PR or SD. |
| Overall Survival (Phase II) | Up to 5 years | Will be evaluated by Kaplan-Meier analysis and log-rank test for between-group comparison, and median survival time will be reported. |
| Number of Participants With Treatment-related Toxicities of the Combination of Cediranib and Olaparib (Tablet Formulation) in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer (Phase I-T). | Up to 3 years | Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. This outcome reports treatment-related adverse events that occurred in at least 10% of participants. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJoyce F Liu
Dana-Farber Cancer Institute
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Dose Level 0 (3 Participants) Assess the maximum tolerated dose (MTD) of cediranib in combination with olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer.
This was an open-label, phase 1, dose-escalation trial performed at two participating institutions evaluating increasing doses of once daily cediranib and twice daily olaparib administered continuously in 28-day cycles. Cediranib was administered as 10 and 15 mg tablets and olaparib as 50 mg capsules. The primary objectives were to determine the dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of this combination. Secondary objectives included assessment of treatment-related toxicities and preliminary assessment of clinical activity as measured by response rate, clinical benefit rate (CBR) and progression-free survival (PFS), defined as time from initiation of therapy to disease progression or death from any cause. | 3 |
| Phase 1 Dose Level 1 (3 Participants) Assess the maximum tolerated dose (MTD) of cediranib in combination with olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer.
This was an open-label, phase 1, dose-escalation trial performed at two participating institutions evaluating increasing doses of once daily cediranib and twice daily olaparib administered continuously in 28-day cycles. Cediranib was administered as 10 and 15 mg tablets and olaparib as 50 mg capsules. The primary objectives were to determine the dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of this combination. Secondary objectives included assessment of treatment-related toxicities and preliminary assessment of clinical activity as measured by response rate, clinical benefit rate (CBR) and progression-free survival (PFS), defined as time from initiation of therapy to disease progression or death from any cause. | 3 |
| Phase 1 Dose Level 2 (7 Participants) Assess the maximum tolerated dose (MTD) of cediranib in combination with olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer.
This was an open-label, phase 1, dose-escalation trial performed at two participating institutions evaluating increasing doses of once daily cediranib and twice daily olaparib administered continuously in 28-day cycles. Cediranib was administered as 10 and 15 mg tablets and olaparib as 50 mg capsules. The primary objectives were to determine the dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of this combination. Secondary objectives included assessment of treatment-related toxicities and preliminary assessment of clinical activity as measured by response rate, clinical benefit rate (CBR) and progression-free survival (PFS), defined as time from initiation of therapy to disease progression or death from any cause. | 7 |
| Phase 1 Dose Level 3 (6 Participants) Assess the maximum tolerated dose (MTD) of cediranib in combination with olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer.
This was an open-label, phase 1, dose-escalation trial performed at two participating institutions evaluating increasing doses of once daily cediranib and twice daily olaparib administered continuously in 28-day cycles. Cediranib was administered as 10 and 15 mg tablets and olaparib as 50 mg capsules. The primary objectives were to determine the dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of this combination. Secondary objectives included assessment of treatment-related toxicities and preliminary assessment of clinical activity as measured by response rate, clinical benefit rate (CBR) and progression-free survival (PFS), defined as time from initiation of therapy to disease progression or death from any cause. | 6 |
| Phase 1 Expansion at MTD (9 Participants) Assess the maximum tolerated dose (MTD) of cediranib in combination with olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer.
This was an open-label, phase 1, dose-escalation trial performed at two participating institutions evaluating increasing doses of once daily cediranib and twice daily olaparib administered continuously in 28-day cycles. Cediranib was administered as 10 and 15 mg tablets and olaparib as 50 mg capsules. The primary objectives were to determine the dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of this combination. Secondary objectives included assessment of treatment-related toxicities and preliminary assessment of clinical activity as measured by response rate, clinical benefit rate (CBR) and progression-free survival (PFS), defined as time from initiation of therapy to disease progression or death from any cause. | 9 |
| Phase 2 - Olaparib Alone Assess the efficacy (as measured by progression-free survival (PFS) ) of olaparib alone in recurrent grade 2 or 3 platinum-sensitive papillary-serous or endometrioid ovarian, fallopian tube, or peritoneal cancer. | 46 |
| Phase 2 - Cediranib/Olaparib Assess the efficacy (as measured by progression-free survival (PFS) ) of the combination of cediranib and olaparib in recurrent grade 2 or 3 platinum-sensitive papillary-serous or endometrioid ovarian, fallopian tube, or peritoneal cancer. | 44 |
| Phase 1-T Dose Level 0-TA Cediranib 30mg PO daily; Olaparib (tablet) 150mg PO BID | 3 |
| Phase 1-T Dose Level 1-TA Cediranib 30mg PO daily; Olaparib (tablet) 200mg PO BID | 6 |
| Phase 1-T Dose Level 2-TA Cediranib 30mg PO daily; Olaparib (tablet) 250mgPO BID | 3 |
| Phase 1-T Dose Level 0-TB Cediranib 20mg PO daily; Olaparib (tablet) 200mg PO BID | 3 |
| Phase 1-T Dose Level 1-TB Cediranib 20mg PO daily; Olaparib (tablet) 250mg PO BID | 3 |
| Phase 1-T Dose Level 2-TB Cediranib 20mg PO daily; Olaparib (tablet) 300mg PO BID | 6 |
| Phase 1-T PKOlap Expansion Cediranib 30mg PO daily; Olaparib (tablet) 200mg PO BID; 7-day lead-in of single-agent olaparib | 6 |
| Phase 1-T PKCed Expansion Cediranib 30mg PO daily; Olaparib (tablet) 200mg PO BID; 7-day lead-in of single-agent cediranib | 7 |
| Total | 155 |
Baseline characteristics
| Characteristic | Phase 1 Dose Level 1 (3 Participants) | Phase 1 Dose Level 2 (7 Participants) | Phase 1 Dose Level 3 (6 Participants) | Phase 1 Expansion at MTD (9 Participants) | Phase 2 - Olaparib Alone | Phase 2 - Cediranib/Olaparib | Phase 1-T Dose Level 0-TA | Phase 1-T Dose Level 1-TA | Phase 1-T Dose Level 2-TA | Phase 1-T Dose Level 0-TB | Phase 1-T Dose Level 1-TB | Phase 1-T Dose Level 2-TB | Phase 1 Dose Level 0 (3 Participants) | Phase 1-T PKOlap Expansion | Phase 1-T PKCed Expansion | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59 years | 57 years | 56 years | 57 years | 58.1 years | 57.8 years | 55.6 years | 61.5 years | 58.7 years | 57.8 years | 59.0 years | 59.8 years | 49 years | 58.7 years | 54.5 years | 57.7 years |
| BRCA Status Mutation carrier | 2 Participants | 5 Participants | 3 Participants | 4 Participants | 24 Participants | 23 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 75 Participants |
| BRCA Status Unknown | 1 Participants | 2 Participants | 3 Participants | 3 Participants | 11 Participants | 9 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 32 Participants |
| BRCA Status Wild-type | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 11 Participants | 12 Participants | 1 Participants | 4 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 5 Participants | 48 Participants |
| Diagnosis Breast | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 8 Participants |
| Diagnosis Ovarian | 2 Participants | 5 Participants | 4 Participants | 7 Participants | 46 Participants | 44 Participants | 3 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 2 Participants | 6 Participants | 7 Participants | 147 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 0 Participants | 2 Participants | 1 Participants | 4 Participants | 34 Participants | 31 Participants | 2 Participants | 6 Participants | 2 Participants | 3 Participants | 2 Participants | 4 Participants | 2 Participants | 5 Participants | 7 Participants | 105 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 3 Participants | 5 Participants | 5 Participants | 5 Participants | 12 Participants | 13 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 7 Participants | 5 Participants | 9 Participants | 44 Participants | 43 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 3 Participants | 5 Participants | 7 Participants | 149 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants |
| Histology (ovarian patients only; Phase 1 and Phase 2) Endometrioid | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 0 Participants | 0 Participants | — | — | — | — | — | 0 Participants | — | — | 6 Participants |
| Histology (ovarian patients only; Phase 1 and Phase 2) Mixed | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | — | — | — | — | — | 0 Participants | — | — | 4 Participants |
| Histology (ovarian patients only; Phase 1 and Phase 2) Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | — | — | — | — | — | 0 Participants | — | — | 4 Participants |
| Histology (ovarian patients only; Phase 1 and Phase 2) Papillary-serous | 2 Participants | 3 Participants | 3 Participants | 6 Participants | 40 Participants | 41 Participants | 2 Participants | — | — | — | — | — | 2 Participants | — | — | 99 Participants |
| Histology (Phase 1-T) Clear Cell | — | — | — | — | — | — | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | — | 0 Participants | 0 Participants | 3 Participants |
| Histology (Phase 1-T) Endometrioid | — | — | — | — | — | — | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | — | 1 Participants | 0 Participants | 2 Participants |
| Histology (Phase 1-T) Other/Unknown | — | — | — | — | — | — | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | — | 1 Participants | 1 Participants | 4 Participants |
| Histology (Phase 1-T) Serous | — | — | — | — | — | — | 2 Participants | 5 Participants | 2 Participants | 3 Participants | 2 Participants | 4 Participants | — | 4 Participants | 6 Participants | 28 Participants |
| Number of Prior Lines (Phase 2 and 1-T) 1 | — | — | — | — | 17 Participants | 26 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | — | 2 Participants | 2 Participants | 55 Participants |
| Number of Prior Lines (Phase 2 and 1-T) 2 | — | — | — | — | 18 Participants | 10 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants | — | 1 Participants | 5 Participants | 40 Participants |
| Number of Prior Lines (Phase 2 and 1-T) 3 or More | — | — | — | — | 11 Participants | 8 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants | — | 3 Participants | 0 Participants | 32 Participants |
| Number of prior regimens (median; Phase 1) Breast | 3 number of prior regimens | 5 number of prior regimens | 2 number of prior regimens | 2.5 number of prior regimens | — | — | — | — | — | — | — | — | 3 number of prior regimens | — | — | 3 number of prior regimens |
| Number of prior regimens (median; Phase 1) Ovarian | 6.5 number of prior regimens | 2 number of prior regimens | 2 number of prior regimens | 1 number of prior regimens | — | — | — | — | — | — | — | — | 3.5 number of prior regimens | — | — | 2 number of prior regimens |
| Platinum-sensitivity (ovarian patients only) Platinum-resistant | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 2 Participants | 4 Participants | 3 Participants | 28 Participants |
| Platinum-sensitivity (ovarian patients only) Platinum-sensitive | 2 Participants | 4 Participants | 4 Participants | 4 Participants | 46 Participants | 44 Participants | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 4 Participants | 119 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 3 Participants | 6 Participants | 4 Participants | 9 Participants | 42 Participants | 43 Participants | 3 Participants | 5 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 6 Participants | 6 Participants | 141 Participants |
| Region of Enrollment United States | 3 participants | 7 participants | 6 participants | 9 participants | 46 participants | 44 participants | 3 participants | 6 participants | 3 participants | 3 participants | 3 participants | 6 participants | 3 participants | 6 participants | 7 participants | 155 participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 6 Participants | 9 Participants | 46 Participants | 44 Participants | 3 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 3 Participants | 6 Participants | 7 Participants | 155 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 6 / 7 | 6 / 6 | 7 / 9 | 29 / 46 | 26 / 44 | 1 / 3 | 2 / 6 | 2 / 7 | 3 / 6 | 1 / 3 | 1 / 3 | 2 / 3 | 1 / 6 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 7 / 7 | 6 / 6 | 9 / 9 | 45 / 46 | 44 / 44 | 3 / 3 | 6 / 6 | 7 / 7 | 6 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 0 / 7 | 2 / 6 | 0 / 9 | 2 / 46 | 3 / 44 | 0 / 3 | 0 / 6 | 1 / 7 | 0 / 6 | 1 / 3 | 0 / 3 | 0 / 3 | 1 / 6 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities of Cediranib Maleate in Combination With Olaparib (Phase I)
Was determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time frame: At 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Level 0 | Number of Participants With Dose Limiting Toxicities of Cediranib Maleate in Combination With Olaparib (Phase I) | 0 Participants |
| Level 1 | Number of Participants With Dose Limiting Toxicities of Cediranib Maleate in Combination With Olaparib (Phase I) | 0 Participants |
| Level 2 | Number of Participants With Dose Limiting Toxicities of Cediranib Maleate in Combination With Olaparib (Phase I) | 0 Participants |
| Level 3 | Number of Participants With Dose Limiting Toxicities of Cediranib Maleate in Combination With Olaparib (Phase I) | 2 Participants |
Primary
Progression-free Survival (PFS) at the Maximum Tolerated Dose/Recommended Phase 2 Dose of Cediranib Maleate With Olaparib Compared to That of Olaparib Alone (Phase II)
Evaluated by Kaplan-Meier analysis and log-rank test for between group comparison, and median survival times reported. PFS is defined as time from randomization to investigator-assessed radiographic progression by RECIST 1.1 criteria or death. Patients alive without evidence of progression were censored at the last disease assessment.
Time frame: Time from start of treatment to time of objective disease progression, assessed up to 5 years
Population: Platinum-sensitive recurrent grade 2 or 3 platinum-sensitive papillary-serous or endometrioid ovarian, fallopian tube, or peritoneal cancer.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Level 0 | Progression-free Survival (PFS) at the Maximum Tolerated Dose/Recommended Phase 2 Dose of Cediranib Maleate With Olaparib Compared to That of Olaparib Alone (Phase II) | 8.2 months |
| Level 1 | Progression-free Survival (PFS) at the Maximum Tolerated Dose/Recommended Phase 2 Dose of Cediranib Maleate With Olaparib Compared to That of Olaparib Alone (Phase II) | 16.5 months |
p-value: 0.00695% CI: [0.3, 0.83]Kaplan-Meier Plot
Primary
The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Metastatic Triple-negative Breast Cancer (Phase I)
This trial employed a 3+3 design, escalating on 0/3 or 1/6 DLT, and de-escalating if 2 DLTs were encountered. The MTD (maximum tolerated dose) was the dose at which no more than 1 patient developed a dose-limiting toxicity (DLT) when at least 6 patients had been treated.
Time frame: At 28 Days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Level 0 | The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Metastatic Triple-negative Breast Cancer (Phase I) | Cediranib PO daily | 30 mg |
| Level 0 | The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Metastatic Triple-negative Breast Cancer (Phase I) | Olaparib PO BID | 200 mg |
Primary
The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib Tablet Formulation in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer (Phase I-T).
The Phase 1-T component of this trial employed a 3+3 design, escalating on 0/3 or 1/6 DLT, and de-escalating if 2 DLTs were encountered. The MTD (maximum tolerated dose) was the dose at which no more than 1 patient developed a DLT when at least 6 patients had been treated.
Time frame: At 28 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Level 0 | The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib Tablet Formulation in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer (Phase I-T). | Cediranib PO daily | 30 mg |
| Level 0 | The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib Tablet Formulation in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer (Phase I-T). | Olaparib (tablet) PO BID | 200 mg |
Secondary
Number of Participants With Treatment-related Toxicities of the Combination of Cediranib and Olaparib (Tablet Formulation) in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer (Phase I-T).
Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. This outcome reports treatment-related adverse events that occurred in at least 10% of participants.
Time frame: Up to 3 years
Secondary
Number of Participants With Treatment-related Toxicities of the Combination of Cediranib Maleate and Olaparib (Phase I)
Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, study-related adverse events observed in \>10% of participants (n=28).
Time frame: Adverse Events monitored for 3 years, mortality assessed up to 5 years
Secondary
Overall Survival (Phase II)
Will be evaluated by Kaplan-Meier analysis and log-rank test for between-group comparison, and median survival time will be reported.
Time frame: Up to 5 years
Secondary
Tumor Response Rate (Objective Response Rate) Defined by Response Evaluation Criteria in Solid Tumors Criteria (Phase II)
The response rates are compared by an exact test and 95% confidence intervals will also be reported. Objective response rate (ORR) is defined as the best confirmed RECIST response, ORR is defined as the number of participants with CR, PR or SD.
Time frame: Up to 5 years