Overview

This trial is active, not recruiting.

Condition ovarian, fallopian tube, peritoneal cancer, p53 mutation
Treatments azd1775 + carboplatin, azd1775 + pld
Phase phase 2
Target WEE1
Sponsor AstraZeneca
Start date January 2015
End date December 2016
Trial size 70 participants
Trial identifier NCT02272790, D6010C00004, GYN 49

Summary

A Phase II Study of AZD1775 plus Chemotherapy in Patients with Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. Patients will receive AZD1775 plus carboplatin or AZD1775 plus pegylated liposomal doxorubicin (PLD). The primary study objective is to evaluate the objective response rate (ORR).

United States Arizona, California, Florida, Massachusetts, New York, and Texas
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Five doses of AZD1775 will be taken in approximate 12 hour intervals over 2.5 days (Days 1-3). Carboplatin will be administered according to institutional standards on Day 1 of each 21 day cycle. AZD1775 should be taken approximately 2 hours before or 2 hours after food. Patients may continue on study as long as they are benefitting, have no evidence of disease progression, and do not meet any criteria for discontinuation or withdrawal.
azd1775 + carboplatin MK1775 + carboplatin
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the WEE1 kinase that sensitizes tumour cells to cytotoxic agents and is being developed for the treatment of advanced solid tumours and p53 pathway deficient malignancies. Carboplatin is a chemotherapy drug used against some forms of cancer (mainly ovarian carcinoma, lung, head and neck cancers as well as endometrial, esophageal, bladder, breast and cervical; central nervous system or germ cell tumors; osteogenic sarcoma, and as preparation for a stem cell or bone marrow transplant.).
(Experimental)
A dose escalation phase will be conducted for this combination arm to evaluate the safety and tolerability of AZD1775 when combined with PLD. Two dose levels of AZD1775 will be tested in combination with PLD on a 28-day cycle. Five doses of AZD1775 will be taken in approximate 12-hour intervals over 2.5 days on week 1 of a 28-day cycle. PLD will be administered on Day 1 of each cycle.
azd1775 + pld MK1775 + PLD
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the WEE1 kinase that sensitizes tumour cells to cytotoxic agents and is being developed for the treatment of advanced solid tumours and p53 pathway deficient malignancies. Chemotherapy is a category of cancer treatment that uses chemical substances, especially one or more anti-cancer drugs (chemotherapeutic agents) that are given as part of a standardized chemotherapy regimen.

Primary Outcomes

Measure
The primary outcome measure is the Objective Response Rate (ORR) of participants in arms included in the efficacy assessment.
time frame: Objective tumour assessments every 6-8 weeks

Secondary Outcomes

Measure
Duration of Response (DoR)
time frame: Tumour assessments will be performed every 6-8 weeks.
Disease Control Rate (DCR)
time frame: Tumour assessments will be performed every 6-8 weeks.
Gynecologic Cancer Intergroup (GCIG) CA-125 response
time frame: Day 1 of each cycle and every 3 months from last tumour assessment
The incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and deaths.
time frame: The occurrence of TEAEs and SAEs will be assesed at every visit.
Plasma concentration of AZD1775 and carboplatin in patients in the safety lead-in dose escalation and and dose expansion segments of Arm C.
time frame: Blood samples will be collected at several pre-specified time points after the single dose administration of AZD1775 on Cycle 1 Day 1. A sample will also be taken pre-dose on Day 3 of alternate cycles starting with Cycle 3.
Plasma concentration of AZD1775 and pegylated liposomal doxorubicin (PLD) in patients in the safety lead-in dose escalation segment of Arm D.
time frame: Blood samples will be collected at several pre-specified time points after the single dose administration of AZD1775 on Cycle 1 Day 1. A sample will also be taken pre-dose on Day 3 of alternate cycles starting with Cycle 3.

Eligibility Criteria

Female participants from 18 years up to 130 years old.

Inclusion 1. Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer. 2. Progressed within 6 months of completing at least 4 cycles of a first-line platinum-containing regimen for Stage III/IV disease. Patients with refractory disease (progression during platinum-containing therapy) are ineligible. 3. No more than 2 prior treatment regimens for Stage III/IV disease, defined as investigational, chemotherapy, hormonal, biologic, or targeted therapy. 4. Prior doxorubicin (or other anthracycline) at a cumulative dose of ≤ 360 mg/m2 or cumulative epirubicin dose of ≤ 720 mg/m2 (calculated using doxorubicin equivalent doses: 1 mg of doxorubicin = 1 mg PLD = 0.3 mg mitoxantrone = 0.25 mg idarubicin). 5. At least 1 measurable lesion according to RECIST v1.1. 6. Radiation therapy must be completed at least 7 days prior to start of study treatment and patients must have recovered from any acute adverse effects prior to start of study treatment. 7. ECOG Performance Status (PS) score of 0 - 1. 8. Baseline Laboratory Values: 1. ANC ≥1500/μL 2. HgB ≥ 9 g/dL 3. Platelets > 100,000/μL 4. ALT & AST ≤3 x ULN or ≤5 x ULN if known hepatic metastases 5. Serum bilirubin within normal limits (WNL) or ≤1.5 x the ULN in patients with liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert's Syndrome. 6. Serum creatinine ≤1.5 x the ULN and a calculated creatinine clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method. 9. Left ventricular ejection fraction (LVEF) WNL as determined by multiple gated acquisition (MUGA) or echocardiography (ECHO). 10. Female patients, ≥18, (not of childbearing potential and fertile female patients of childbearing potential) who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start. 11. Predicted life expectancy ≥ 12 weeks Exclusion 1. Any study drug ≤ 21 days or 5 half-lives (whichever is shorter) prior to the first dose. 2. Major surgical procedures ≤ 28 days of beginning study, or minor surgical procedures ≤ 7 days. 3. Grade >1 toxicity from prior therapy (except alopecia or anorexia). 4. Known CNS disease other than neurologically stable, treated brain metastases (e.g., metastasis having no evidence of progression or haemorrhage after treatment for ≥2 weeks) 5. Any Rx or non Rx drugs or other products (i.e. grapefruit juice) known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4 which cannot be discontinued 2 weeks prior to Day 1 and withheld throughout the study until 2 weeks after last dose. Co-administration of aprepitant during this study is prohibited. 6. Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) ≥ Class 2: 1. Unstable angina 2. Congestive heart failure 3. Acute myocardial infarction 4. Conduction abnormality not controlled with pacemaker or medication 5. Significant ventricular or supraventricular arrhythmias (patients with chronic rate controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible). 7. Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome. 8. Pregnant or lactating. 9. Serious active infection upon enrolment, or other serious underlying medical condition that would impair the patient's ability to receive study treatment. 10. Presence of other active cancers, or history of treatment for invasive cancer within 3 years. Patients with Stage I cancer who have received definitive local treatment within 3 years, and whom are considered unlikely to recur, are eligible. Patients with previously treated in-situ carcinoma (i.e., non-invasive) are eligible, as are patients with prior non-melanoma skin cancers.

Additional Information

Official title A Multicentre Phase II Study of AZD1775 Plus Chemotherapy in Patients With Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Principal investigator Kathleen Moore, MD
Description This is a phase II study of AZD1775 plus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients will receive AZD1775 plus carboplatin or AZD1775 plus pegylated liposomal doxorubicin (PLD). The primary endpoint for the study is overall response rate (ORR) defined as the proportion of patients achieving a complete or partial tumour response according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Secondary endpoints include assessment of the duration of response (DoR), overall survival (OS), progression-free survival (PFS), disease control rate (DCR), Gynecologic Cancer Intergroup (GCIG) cancer antigen-125 response, safety and tolerability, clinically significant changes in safety-related laboratory parameters, pharmacokinetics (PK) and drug-drug interactions of AZD1775 plus carboplatin and AZD1775 plus PLD. Six (6) patients will be enrolled in the AZD1775 plus carboplatin arm (designated Arm C) in a dose escalation scheme as a safety lead-in cohort. When a safe and tolerable dose of AZD1775 in combination with carboplatin is determined, 17 additional patients will be enrolled to be treated at that dose level. Patients may continue on study as long as they are benefitting, have no evidence of disease progression, and do not meet any criteria for discontinuation or withdrawal. Up to 12 patients will be enrolled in the AZD1775 plus PLD arm (designated Arm D) in a dose escalation scheme as a safety lead-in cohort. Dose expansion will not be conducted in Arm D. Patients may continue on study as long as they are benefitting, have no evidence of disease progression, and do not meet any criteria for discontinuation or withdrawal. A Safety Review Team (SRT) will assess the safety and tolerability of the first 6 patients in each arm by incidence and severity of adverse events (AEs) after a minimum of 1 treatment cycle as determined by NCI CTCAE v4.03 and the occurrence of pre-defined dose-limiting toxicities (DLTs). Patients must complete Cycle 1 safety evaluations, and return to the study centre for Cycle 2 Day 1 evaluations to be considered evaluable for the safety lead-in. Following a positive safety assessment for the AZD1775 plus carboplatin arm (Arm C) by the SRT, Arm C will continue enrolling until 23 patients have been evaluated for efficacy (i.e., tumour response). Enrollment will not continue in Arm D.
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by AstraZeneca.