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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02272790
Recruitment Status : Active, not recruiting
First Posted : October 23, 2014
Results First Posted : November 22, 2019
Last Update Posted : April 28, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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

Condition or disease Intervention/treatment Phase
Ovarian, Fallopian Tube, Peritoneal Cancer, P53 Mutation Drug: Adavosertib Drug: Paclitaxel Drug: Carboplatin Drug: Gemcitabine Drug: PLD Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 95 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicentre Phase II Study of Adavosertib Plus Chemotherapy in Patients With Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Actual Study Start Date : January 30, 2015
Actual Primary Completion Date : December 13, 2018
Estimated Study Completion Date : March 15, 2021

Arm Intervention/treatment
Experimental: Arm A (adavosertib + 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.
Drug: Adavosertib
Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.
Other Name: MK1775

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

Experimental: Arm B (adavosertib + 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.
Drug: Adavosertib
Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.
Other Name: MK1775

Drug: Paclitaxel

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.

Other Name: Taxol

Experimental: Arm C/C2 (adavosertib + 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.

Drug: Adavosertib
Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.
Other Name: MK1775

Drug: Carboplatin
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.
Other Name: Paraplatin

Experimental: Arm D (adavosertib + 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.
Drug: Adavosertib
Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food.
Other Name: MK1775

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




Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 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 :
  1. Disease Control Rate (DCR) [ Time Frame: 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.

  2. Duration of Response (DoR) [ Time Frame: 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.

  3. Progression Free Survival (Median, 80% CI) [ Time Frame: 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.


  4. Progression Free Survival (Median, 95% CI) [ Time Frame: 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.


  5. Overall Survival (Median, 80% CI) [ Time Frame: 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.

  6. Overall Survival (Median, 95% CI) [ Time Frame: 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.

  7. Gynecologic Cancer Intergroup (GCIG) CA-125 Response [ Time Frame: 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.

  8. The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) by Maximum CTCAE Grade. [ Time Frame: 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


  9. The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) Related to Adavosertib by Maximum CTCAE Grade [ Time Frame: 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


  10. The Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) Related to Chemotherapy by Maximum CTCAE Grade [ Time Frame: 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


  11. Serious Adverse Events [ Time Frame: Throughout the duration of the study (up to 19 months) ]
    The number of patients experiencing at least one serious adverse event (SAE).

  12. Serious Adverse Events Leading to Death [ Time Frame: 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.

  13. Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Discontinuation [ Time Frame: 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.

  14. Treatment-Related Adverse Events Related to Adavosertib Leading to Dose Reduction [ Time Frame: 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.

  15. Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Interruption [ Time Frame: 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.

  16. Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Discontinuation [ Time Frame: 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.

  17. Treatment-Related Adverse Events Related to Chemotherapy Leading to Dose Reduction [ Time Frame: 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.

  18. Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Interruption [ Time Frame: 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.

  19. Single Dose Adavosertib Cmax [ Time Frame: 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.

  20. Multiple Dose Adavosertib Cmax [ Time Frame: 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.

  21. Single Dose Adavosertib Tmax [ Time Frame: 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.

  22. Multiple Dose Adavosertib Tmax [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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:

    1. ANC ≥1500/μL
    2. HgB ≥ 9 g/dL with no blood transfusions in the past 28 days
    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.
  • 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:

    1. Unstable angina pectoris
    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).
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02272790


Locations
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United States, Arizona
Research Site
Gilbert, Arizona, United States, 85234
Research Site
Tucson, Arizona, United States, 85724
United States, California
Research Site
La Jolla, California, United States, 92093
Research Site
Los Angeles, California, United States, 90095-6996
Research Site
San Francisco, California, United States, 94158
United States, Florida
Research Site
Tampa, Florida, United States, 33612
Research Site
West Palm Beach, Florida, United States, 33401
United States, Georgia
Research Site
Augusta, Georgia, United States, 30912
United States, Massachusetts
Research Site
Boston, Massachusetts, United States, 02215
United States, New York
Research Site
New York, New York, United States, 10019
Research Site
New York, New York, United States, 10065
United States, Ohio
Research Site
Cleveland, Ohio, United States, 44195
United States, Oklahoma
Research Site
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Research Site
Nashville, Tennessee, United States, 37203
United States, Texas
Research Site
Dallas, Texas, United States, 75390
United States, Wisconsin
Research Site
Milwaukee, Wisconsin, United States, 53226
Canada, Ontario
Research Site
Toronto, Ontario, Canada, M5G 2M9
Netherlands
Research Site
Amsterdam, Netherlands, 1066 CX
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Kathleen Moore, MD Stephenson Cancer Center, University of Oklahoma Health Sciences Center
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol  [PDF] September 5, 2018
Statistical Analysis Plan  [PDF] June 7, 2018

Additional Information:
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02272790    
Other Study ID Numbers: D6010C00004
GYN 49 ( Other Identifier: Sarah Cannon Development Innovations )
First Posted: October 23, 2014    Key Record Dates
Results First Posted: November 22, 2019
Last Update Posted: April 28, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame:

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at:

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

Access Criteria:

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

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

URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Additional relevant MeSH terms:
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Peritoneal Neoplasms
Abdominal Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Peritoneal Diseases
Gemcitabine
Paclitaxel
Carboplatin
MK-1775
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs