Adavosertib Plus Chemotherapy in Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Phase 2

Completed

Conditions: Ovarian, Fallopian Tube, Peritoneal Cancer, P53 Mutation

Interventions: Drug: Adavosertib
Drug: PLD
Drug: Gemcitabine
Drug: Paclitaxel
Drug: Carboplatin

Registration Number: NCT02272790

Lead Sponsor: AstraZeneca

Brief Summary: Adavosertib in combination with carboplatin, paclitaxel, gemcitabine, or PLD.

Detailed Description: This is an open-label, four-arm lead-in safety and efficacy study in which adavosertib will be combined in four separate treatment arms as follows: adavosertib plus gemcitabine (Arm A); adavosertib plus weekly paclitaxel (Arm B); adavosertib plus carboplatin (Arm C); and adavosertib plus PLD (Arm D). A subset of patients will be evaluated for the safety assessment of each treatment arm.

The adavosertib plus paclitaxel arm (Arm B) will enrol approximately 30 additional patients at selected sites as part of a further efficacy evaluation based on emerging data that suggests clinical activity.

In addition, the adavosertib plus carboplatin arm (Arm C) will enrol approximately 23 patients overall at selected sites as part of a further efficacy evaluation based on emerging data that suggests clinical activity.

To further optimise the dosing schedule of adavosertib in Arm C, a safety expansion arm (referred to as Arm C2) of approximately 12 additional patients will be enrolled at selected sites to explore emerging pre-clinical and clinical data that suggest that prolonged adavosertib exposure may increase the clinical activity.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 95

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm D (adavosertib + PLD)	PLD	Five doses of adavosertib (175 mg or 225 mg) will be taken in approximate 12 hour intervals over 2.5 days (Days 1, 2, and 3) of each 28-day cycle. PLD will administered IV on Day 1 of each cycle.
Arm A (adavosertib + gemcitabine)	Gemcitabine	Adavosertib (175 mg PO) will be taken on Days 1-2, 8-9, and 15-16. Gemcitabine 800 mg/m² will be administered IV on days 1, 8, and 15 of each 28 day cycle.
Arm A (adavosertib + gemcitabine)	Adavosertib	Adavosertib (175 mg PO) will be taken on Days 1-2, 8-9, and 15-16. Gemcitabine 800 mg/m² will be administered IV on days 1, 8, and 15 of each 28 day cycle.
Arm B (adavosertib + paclitaxel)	Adavosertib	Five doses of adavosertib (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days weekly (Days 1-3, 8-10, and 15-17). Weekly paclitaxel 80 mg/m² IV will be administered according to institutional standards on Day 1, 8, and 15 of each 28 day cycle.
Arm B (adavosertib + paclitaxel)	Paclitaxel	Five doses of adavosertib (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days weekly (Days 1-3, 8-10, and 15-17). Weekly paclitaxel 80 mg/m² IV will be administered according to institutional standards on Day 1, 8, and 15 of each 28 day cycle.
Arm C/C2 (adavosertib + carboplatin)	Adavosertib	Arm C: Five doses of adavosertib (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days (Days 1-3). Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21-Day cycle. Arm C2: Five doses of adavosertib (225 mg PO BID) 2.5 days per dosing week (QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 (D15-17), or on Weeks 1 (D1-3) and 2 (D8-10) ( 2 weeks on followed by 1 week off.) Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21 day cycle.
Arm C/C2 (adavosertib + carboplatin)	Carboplatin	Arm C: Five doses of adavosertib (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days (Days 1-3). Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21-Day cycle. Arm C2: Five doses of adavosertib (225 mg PO BID) 2.5 days per dosing week (QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 (D15-17), or on Weeks 1 (D1-3) and 2 (D8-10) ( 2 weeks on followed by 1 week off.) Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21 day cycle.
Arm D (adavosertib + PLD)	Adavosertib	Five doses of adavosertib (175 mg or 225 mg) will be taken in approximate 12 hour intervals over 2.5 days (Days 1, 2, and 3) of each 28-day cycle. PLD will administered IV on Day 1 of each cycle.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Throughout the duration of the study (up to 19 months)	Objective response rate is defined as the proportion of patients achieving a complete or partial tumour response according to RECIST v1.1 criteria.

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DoR)	Throughout the duration of the study, approximately 19 months.	Duration of Response (DoR) is defined as the time from first documented tumour response until the date of documented progression or death from any cause.
Disease Control Rate (DCR)	Throughout the duration of the study (up to 19 months)	The Disease Control Rate is defined as the proportion of patients achieving a complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1 criteria.
Progression Free Survival (Median, 95% CI)	Throughout the Study, Approximately 4 years	Progression-free survival (PFS) was defined as the elapsed time from date of first dose of AZD1775 until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to progression. 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. Progression-free survival was derived based on scan/assessment dates, not visit dates.
Overall Survival (Median, 80% CI)	Throughout the Study, Approximately 4 years	Overall survival (OS) was defined as the elapsed time from the date of first dose of AZD1775 until death due to any cause. Any patient not known to have died at the time of the analysis was censored based on the last recorded date on which the patient was known to be alive.
Treatment-Related Adverse Events Related to Chemotherapy Leading to Dose Reduction	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to dose reduction.
Serious Adverse Events Leading to Death	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one serious adverse event (SAE) leading to death.
Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Discontinuation	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to treatment discontinuation.
Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Discontinuation	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to treatment discontinuation.
Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Interruption	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to treatment interruption.
Single Dose Adavosertib Tmax	Pre-dose, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr	The time to reach maximum plasma concentration of adavosertib after a single oral dose (Cycle 1 Day 1) in combination with IV infusion of commonly used chemotherapy agents, including gemcitabine, paclitaxel, and carboplatin.
Progression Free Survival (Median, 80% CI)	Throughout the Study, Approximately 4 years	Progression-free survival (PFS) was defined as the elapsed time from date of first dose of AZD1775 until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to progression. 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. Progression-free survival was derived based on scan/assessment dates, not visit dates.
Overall Survival (Median, 95% CI)	Throughout the Study, Approximately 4 years	Overall survival (OS) was defined as the elapsed time from the date of first dose of AZD1775 until death due to any cause. Any patient not known to have died at the time of the analysis was censored based on the last recorded date on which the patient was known to be alive.
Gynecologic Cancer Intergroup (GCIG) CA-125 Response	Throughout the study, approximately 4 years	The GCIG CA-125 response is defined as the proportion of patients achieving a 50% reduction in CA-125 levels from baseline, if baseline level is ≥2 x the upper limit of normal (ULN) within 2 weeks prior to starting treatment. Response must be confirmed and maintained for at least 28 days.
The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) by Maximum CTCAE Grade.	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one treatment-related adverse event (TEAE) by maximum CTCAE grade. Severity Grade 1 = Mild; Severity Grade 2 = Moderate; Severity Grade 3 = Severe; Severity Grade 4 = Life Threatening; Severity Grade 5 = Fatal
The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) Related to Chemotherapy by Maximum CTCAE Grade	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one treatment-related adverse event (TEAE) related to chemotherapy by maximum CTCAE grade. Severity Grade 1 = Mild; Severity Grade 2 = Moderate; Severity Grade 3 = Severe; Severity Grade 4 = Life Threatening; Severity Grade 5 = Fatal
Serious Adverse Events	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one serious adverse event (SAE).
Treatment-Related Adverse Events Related to Adavosertib Leading to Dose Reduction	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to dose reduction.
Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Interruption	Throughout the duration of the study (up to 19 months)	The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to treatment interruption.
Multiple Dose Adavosertib Tmax	Pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr	The time to reach maximum plasma concentration of adavosertib after multiple oral doses (Cycle 1 Day 3) in combination with IV infusion of 40 mg/m² pegylated liposomal doxorubicin.
The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) Related to Adavosertib by Maximum CTCAE Grade	Throughout the duration of the study (up to 19 months)	The number and proportion of patients experiencing at least one treatment-related adverse event (TEAE) related to adavosertib by maximum CTCAE grade Severity Grade 1 = Mild; Severity Grade 2 = Moderate; Severity Grade 3 = Severe; Severity Grade 4 = Life Threatening; Severity Grade 5 = Fatal
Single Dose Adavosertib Cmax	Pre-dose, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr	Maximum plasma concentration of adavosertib after a single oral dose (Cycle 1 Day 1) in combination with IV infusion of commonly used chemotherapy agents, including gemcitabine, paclitaxel, and carboplatin.
Multiple Dose Adavosertib Cmax	Pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr	Maximum plasma concentration of adavosertib after a multiple oral doses (Cycle 1 Day 3) in combination with IV infusion of 40 mg/m² pegylated liposomal doxorubicin.