A Multicentre Phase II Study of AZD1775 Plus Chemotherapy in Patients With Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Description
Brief 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).
Detailed 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. When a safe and tolerable dose of AZD1775 in
combination with PLD 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.
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.
Once the AZD1775 plus carboplatin (Arm C) and AZD1775 plus PLD (Arm D) arms are evaluated as
safe and tolerated by the SRT, these arms will continue enrolling until 23 patients have
been evaluated for efficacy (i.e., tumour response).
Phase
N/AInclusion and Exclusion Criteria
- Inclusion
- Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer.
- 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.
- No more than 2 prior treatment regimens for Stage III/IV disease, defined as investigational, chemotherapy, hormonal, biologic, or targeted therapy.
- 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).
- At least 1 measurable lesion according to RECIST v1.1.
- 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.
- ECOG Performance Status (PS) score of 0 - 1.
- Baseline Laboratory Values:
- ANC ≥1500/μL
- HgB ≥ 9 g/dL
- Platelets > 100,000/μL
- ALT & AST ≤3 x ULN or ≤5 x ULN if known hepatic metastases
- 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.
- Serum creatinine ≤1.5 x the ULN and a calculated creatinine clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method.
- Left ventricular ejection fraction (LVEF) WNL as determined by multiple gated acquisition (MUGA) or echocardiography (ECHO).
- 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.
- Predicted life expectancy ≥ 12 weeks Exclusion
- Any study drug ≤ 21 days or 5 half-lives (whichever is shorter) prior to the first dose.
- Major surgical procedures ≤ 28 days of beginning study, or minor surgical procedures ≤ 7 days.
- Grade >1 toxicity from prior therapy (except alopecia or anorexia).
- 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)
- 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.
- Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) ≥ Class 2:
- Unstable angina
- Congestive heart failure
- Acute myocardial infarction
- Conduction abnormality not controlled with pacemaker or medication
- Significant ventricular or supraventricular arrhythmias (patients with chronic rate controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
- Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome.
- Pregnant or lactating.
- Serious active infection upon enrolment, or other serious underlying medical condition that would impair the patient's ability to receive study treatment.
- 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.
Sites
Please contact Loriel Liwanag to learn more about where you can participate in this trial. Please use the contact form on the right side.
Presentado por
SC CTSI