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

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

Detailed Description
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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.

Official Title
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A Multicentre Phase II Study of Adavosertib Plus Chemotherapy in Patients With Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Conditions
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Ovarian, Fallopian Tube, Peritoneal Cancer, P53 Mutation

Intervention / Treatment
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* Drug: Adavosertib
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Gemcitabine
* Drug: PLD


Participation Criteria
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Eligibility Criteria
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Inclusion Has read and understands the informed consent form (ICF) and has given written IC prior to any study specific procedures. 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 2-4 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). Subjects without any prior anthracycline exposure can also be included. Applies to Arm D only. At least 1 measurable lesion according to RECIST v1.1. Any prior palliative 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. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 - 1. Baseline Laboratory Values: ANC ≥1500/μL HgB ≥ 9 g/dL with no blood transfusions in the past 28 days 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 of the institution as determined by multiple uptake gated acquisition (MUGA) or echocardiography (ECHO) (applies to Arm D only). Female patients, ≥18, (not of childbearing potential and fertile female patients of childbearing potential) who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation, 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 Use of a study drug (approved or investigational drug therapy) ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment. For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the study drug and administration of study treatment is required. Major surgical procedures ≤ 28 days of beginning study, or minor surgical procedures ≤ 7 days. No waiting period following port-a-cath placement, or any other central venous access placement. Grade >1 toxicity from prior therapy (except alopecia or anorexia). Known malignant CNS disease other than neurologically stable, treated brain metastases, defined as metastasis having no evidence of progression or haemorrhage after treatment for at least 2 weeks (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment. Patient has had prescription or non-prescription 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 of dosing and withheld throughout the study until 2 weeks after last dose of study drug. Caution should be exercised when inhibitors or substrates of P-gP, substrates of CYP1A2 with a narrow therapeutic range, sensitive substrates of CYP2C19 or CYP2C19 substrates with a narrow therapeutic range are administered with adavosertib. Herbal medications should be discontinued 7 days prior to the first dose of study treatment. 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 pectoris 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). Adavosertib should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. Adavosertib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome. Pregnant or lactating. Serious active infection at the time of enrolment, or another 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (adavosertib + gemcitabine)<br>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. | Drug: Adavosertib<br>* Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.<br>* Other names: MK1775;Drug: Gemcitabine<br>* Gemcitabine 800 mg/m² will be administered IV on Days 1, 8, and 15 of each 28-Day cycle.<br>|
| Experimental: Arm B (adavosertib + paclitaxel)<br>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. | Drug: Adavosertib<br>* Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.<br>* Other names: MK1775;Drug: Paclitaxel<br>* Paclitaxel will be administered as a 1-hour IV infusion (± 10 minutes) at a dose of 80 mg/m2 according to institutional standards on Days 1, 8, and 15 of each 28 Day cycle. Patients should be pre-medicated with corticosteroids, diphenhydramine and/or H2 antagonists according to institutional standards.<br>* Other names: Taxol;|
| Experimental: Arm C/C2 (adavosertib + carboplatin)<br>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. | Drug: Adavosertib<br>* Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.<br>* Other names: MK1775;Drug: Carboplatin<br>* Carboplatin, at a dose calculated to produce an AUC of 5 will be administered by intravenous infusion according to institutional standards on Day 1 of each 21 Day cycle. The carboplatin dose will be calculated using the Calvert Formula based on the patient's glomerular filtration rate (GFR) which is estimated by using the creatinine clearance.<br>* Other names: Paraplatin;|
| Experimental: Arm D (adavosertib + PLD)<br>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. | Drug: Adavosertib<br>* Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.<br>* Other names: MK1775;Drug: PLD<br>* PLD (pegylated liposomal doxorubicin) 40 mg/m² IV will be given on Day 1 of each 28-Day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | 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. | Throughout the duration of the study (up to 19 months) | 
| Duration of Response (DoR) | 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. | Throughout the duration of the study, approximately 19 months. | 
| Progression Free Survival (Median, 80% CI) | 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. | Throughout the Study, Approximately 4 years | 
| Progression Free Survival (Median, 95% CI) | 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. | Throughout the Study, Approximately 4 years | 
| Overall Survival (Median, 80% CI) | 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. | Throughout the Study, Approximately 4 years | 
| Overall Survival (Median, 95% CI) | 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. | Throughout the Study, Approximately 4 years | 
| Gynecologic Cancer Intergroup (GCIG) CA-125 Response | 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. | Throughout the study, approximately 4 years | 
| The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) by Maximum CTCAE Grade. | 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 | Throughout the duration of the study (up to 19 months) | 
| The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) Related to Adavosertib by Maximum CTCAE Grade | 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 | Throughout the duration of the study (up to 19 months) | 
| The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) Related to Chemotherapy by Maximum CTCAE Grade | 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 | Throughout the duration of the study (up to 19 months) | 
| Serious Adverse Events | The number of patients experiencing at least one serious adverse event (SAE). | Throughout the duration of the study (up to 19 months) | 
| Serious Adverse Events Leading to Death | The number of patients experiencing at least one serious adverse event (SAE) leading to death. | Throughout the duration of the study (up to 19 months) | 
| Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Discontinuation | The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to treatment discontinuation. | Throughout the duration of the study (up to 19 months) | 
| Treatment-Related Adverse Events Related to Adavosertib Leading to Dose Reduction | The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to dose reduction. | Throughout the duration of the study (up to 19 months) | 
| Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Interruption | The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to treatment interruption. | Throughout the duration of the study (up to 19 months) | 
| Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Discontinuation | The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to treatment discontinuation. | Throughout the duration of the study (up to 19 months) | 
| Treatment-Related Adverse Events Related to Chemotherapy Leading to Dose Reduction | The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to dose reduction. | Throughout the duration of the study (up to 19 months) | 
| Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Interruption | The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to treatment interruption. | Throughout the duration of the study (up to 19 months) | 
| Single Dose Adavosertib Cmax | 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. | Pre-dose, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr | 
| Multiple Dose Adavosertib Cmax | 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. | Pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr | 
| Single Dose Adavosertib Tmax | 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. | Pre-dose, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr | 
| Multiple Dose Adavosertib Tmax | 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. | Pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian, Fallopian Tube, or Primary Peritoneal Cancer