Neoplasms

Digestive System Diseases

All Conditions

Peritoneal Neoplasms

Abdominal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Peritoneal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Anti-Allergic Agents

Antiemetics

Central Nervous System Depressants

Gastrointestinal Agents

Dermatologic Agents

Paclitaxel

Carboplatin

Gemcitabine

Doxorubicin

Liposomal doxorubicin

Albumin-Bound Paclitaxel

Diphenhydramine

Promethazine

Histamine H2 Antagonists

Adavosertib

Tubulin Modulators

Antimitotic Agents

Antimetabolites

Enzyme Inhibitors

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.

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: 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.

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.

Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.

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.

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.

Gemcitabine 800 mg/m² will be administered IV on Days 1, 8, and 15 of each 28-Day cycle.

PLD (pegylated liposomal doxorubicin) 40 mg/m² IV will be given on Day 1 of each 28-Day cycle.

Kathleen Moore, MD

Adavosertib in combination with carboplatin, paclitaxel, gemcitabine, or PLD.

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.

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

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

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Objective response rate is defined as the proportion of patients achieving a complete or partial tumour response according to RECIST v1.1 criteria.

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.

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.

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 (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.

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 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 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

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

The number of patients experiencing at least one serious adverse event (SAE).

The number of patients experiencing at least one serious adverse event (SAE) leading to death.

The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to treatment discontinuation.

The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to dose reduction.

The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to treatment interruption.

The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to treatment discontinuation.

The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to dose reduction.

The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to treatment interruption.

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.

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.

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.

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.

AstraZeneca

Adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. Gemcitabine 800 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Arm A

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 28 day cycles. Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Arm B

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 21 day cycles.

Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Arm C

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Arm C2

Adavosertib 175 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles.

Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Arm D-175 mg

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles.

Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Arm D-225 mg

Adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles.

Gemcitabine 800 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 28 day cycles.

Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 21 day cycles.

Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

Netherlands

Region of Enrollment

< 65

≥ 65

Age, Categorical

ECOG Performance Status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory, able to carry out light or sedentary work; 2 = Ambulatory and capable of all self care but unable to carry out any work activities. Up and about \> 50% of waking hours; 3 = Capable of only limited self care, confined to bed or chair \> 50% of waking hours; 4 = Completely disabled, cannot carry on any self care. Totally confined to bed or chair; 5 = Dead.

ECOG Performance Status

Time from 1st positive biopsy for disease to consent for this study (mean)

Time from 1st positive biopsy for disease to consent for this study (median)

Local or Regional Recurrence

Sixty-seven (67) patients has a local or regional recurrence.

Time from local/regional recurrence to consent for this study (mean)

Time from local/regional recurrence to consent for this study (median)

Distant Metastases

Histology

Histological Grade

Stage at Initial Diagnosis

Metastatic Disease

Bone

Breast

Distant Lymph Nodes

Liver

Local or Regional Lymph Nodes

Lung

Other

Skin or Subcutaneous

Sites of Metastatic Disease

Prior Systemic Therapy

Time from end of most recent prior systemic therapy to consent for this trial (mean)

Time from end of most recent prior systemic therapy to consent for this trial (median)

Number of prior treatment regimens

Disease setting for most recent prior regimen

Best overall response to most recent prior regimen

Reason most recent prior regimen ended

Prior Surgery

Prior Radiotherapy

Weight (mean)

Weight (median)

Systolic Blood Pressure (mean)

Systolic Blood Pressure (median)

Diastolic Blood Pressure (mean)

Diastolic Blood Pressure (median)

Body Surface Area (mean)

Body Surface Area (median)

Pejvack Motlagh, MD

This analysis was conducted on the Full Analysis Set, comprised of all patients who received at least dose of study treatment (n = 94).

Objective Response Rate (ORR)

Disease Control Rate (DCR)

Duration of Response (DoR) was calculated for all responders (N = 30)

Duration of Response (DoR)

Progression Free Survival (Median, 80% CI)

Progression Free Survival (Median, 95% CI)

Overall Survival (Median, 80% CI)

Overall Survival (Median, 95% CI)

The CA-125 analysis set was comprised of all dosed patients with pre-treatment serum sample showing CA-125 ≥ 2 x ULN within 2 weeks before starting treatment.

Gynecologic Cancer Intergroup (GCIG) CA-125 Response

Number of patients with ≥1 TEAE of max Grade 1

Number of patients with ≥1 TEAE of max Grade 2

Number of patients with ≥1 TEAE of max Grade 3

Number of patients with ≥1 TEAE of max Grade 4

Number of patients with ≥1 TEAE of max Grade 5

The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) by Maximum CTCAE Grade.

The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) Related to Adavosertib by Maximum CTCAE Grade

The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) Related to Chemotherapy by Maximum CTCAE Grade

Pts. with ≥ one serious TEAE related to AZD1775.

Pts. with ≥ one serious TEAE related to Chemo.

Serious Adverse Events

No. with STEAE related to AZD1775 leading to death

No. with STEAE related to chemo leading to death

Serious Adverse Events Leading to Death

Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Discontinuation

Treatment-Related Adverse Events Related to Adavosertib Leading to Dose Reduction

Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Interruption

Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Discontinuation

Treatment-Related Adverse Events Related to Chemotherapy Leading to Dose Reduction

Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Interruption

Adavosertib175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles.

Gemcitabine 800 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Arm A 800 mg/m² Gemcitabine

Adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles.

Gemcitabine 1000 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Arm A 1000 mg/m² Gemcitabine

The PK Analysis Set included all dosed patients who had at least one measurable plasma concentration collected post-dose which was obtained without any protocol deviation, violation, or other event which may have significantly affected the pharmacokinetics.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Adavosertib Plus Chemotherapy in Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer	NCT02272790	Ovarian, Fallop...	Adavosertib Paclitaxel Carboplatin Gemcitabine PLD	18 Years - 130 Years	AstraZeneca
Adavosertib Plus Chemotherapy in Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer	NCT02272790	Ovarian, Fallop...	Adavosertib Paclitaxel Carboplatin Gemcitabine PLD	18 Years - 130 Years	AstraZeneca

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