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AZD1775 Plus Chemotherapy in Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

This study is currently recruiting participants.
Verified November 2017 by AstraZeneca
Sponsor:
ClinicalTrials.gov Identifier:
NCT02272790
First Posted: October 23, 2014
Last Update Posted: November 17, 2017
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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
AstraZeneca
  Purpose
AZD1775 in combination with carboplatin, paclitaxel, gemcitabine, or PLD.

Condition Intervention Phase
Ovarian, Fallopian Tube, Peritoneal Cancer, P53 Mutation Drug: AZD1775 Drug: Paclitaxel Drug: Carboplatin Drug: Gemcitabine Drug: PLD Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicentre Phase II Study of AZD1775 Plus Chemotherapy in Patients With Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • The primary outcome measure is the Objective Response Rate (ORR), defined as the proportion of patients achieving a complete or partial tumour response according to RECIST v 1.1, of participants in arms included in the efficacy assessment. [ Time Frame: Baseline, every 8 weeks (every 6 weeks for carboplatin arm) from first dose (every 12 weeks for patients on study > 1 year) until progression, death or until the study is terminated by the sponsor, or until study completion, approximately 7 months. ]
    RECIST v1.1 criteria will be used to assess patient response to treatment. Categorisation of objective tumour response will be based on RECIST v1.1: complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD).


Secondary Outcome Measures:
  • Duration of Response (DoR) [ Time Frame: Baseline, every 8 weeks (every 6 weeks for carboplatin arm) from first dose (every 12 weeks for patients on study > 1 year) until progression, death or until the study is terminated by the sponsor, or until study completion, approximately 7 months. ]
    Duration of Response (DoR) is defined as the length of time from the first documented tumour response until the date of documented progression or death from any cause.

  • Disease Control Rate (DCR) [ Time Frame: Baseline, every 8 weeks (every 6 weeks for carboplatin arm) from first dose (every 12 weeks for patients on study > 1 year) until progression, death or until the study is terminated by the sponsor, approximately 7 months. ]
    Disease Control Rate (DCR) is defined as the proportion of patients achieving a complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1.

  • Gynecologic Cancer Intergroup (GCIG) CA-125 response [ Time Frame: CA-125 serum sample collected at baseline (within 14 days prior to first study treatment), Day 1 of each cycle, and through study completion, an average of one year. ]
    Gynecologic Cancer Intergroup (GCIG) CA-125 response is defined as the proportion of patients achieving a 50% reduction in CA-125 levels compared to baseline, if the 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 incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and deaths. [ Time Frame: The occurrence of TEAEs and SAEs will be assesed at every visit through study completion, an average of one year. ]
    A Safety Review Committee (SRC) will assess the safety and tolerability of the combinations treatment in the first 6 patients in each treatment arm and for both cohorts in Arm D by examining the incidence and severity of adverse events after a minimum of 1 treatment cycle as determined by NCI CTCAE v4.03 and the occurrence of pre-defined dose-limiting toxicities (DLTs).

  • Plasma concentration of AZD1775 plus gemcitabine. [ Time Frame: Blood samples will be collected pre-dose, and at pre-specified time points up to approxiamtely 8 hours after drug administration. ]
    The actual time of each sample collection will be recorded and will be used in the parameter calculations. Pharmacokinetic parameters will be derived using standard non-compartmental methods. Drug interaction will be assessed.

  • Plasma concentration of AZD1775 plus carboplatin. [ Time Frame: Blood samples will be collected pre-dose, and at pre-specified time points up to approxiamtely 8 hours after drug administration. ]
    The actual time of each sample collection will be recorded and will be used in the parameter calculations. Pharmacokinetic parameters will be derived using standard non-compartmental methods. Drug interaction will be assessed.

  • Clinically significant changes in safety-related laboratory parameters according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03); and abnormal vital signs. [ Time Frame: Laboratory results and vital signs will be reviewed at each visit through study completion, an average of one year. ]
  • Plasma concentration of AZD1775 plus paclitaxel. [ Time Frame: Blood samples will be collected pre-dose, and at pre-specified time points up to approxiamtely 8 hours after drug administration. ]
    The actual time of each sample collection will be recorded and will be used in the parameter calculations. Pharmacokinetic parameters will be derived using standard non-compartmental methods. Drug interaction will be assessed.

  • Plasma concentration of AZD1775 plus PLD. [ Time Frame: Blood samples will be collected pre-dose, and at pre-specified time points up to approxiamtely 8 hours after drug administration. ]
    The actual time of each sample collection will be recorded and will be used in the parameter calculations. Pharmacokinetic parameters will be derived using standard non-compartmental methods. Drug interaction will be assessed.


Estimated Enrollment: 97
Actual Study Start Date: January 30, 2015
Estimated Study Completion Date: May 31, 2018
Estimated Primary Completion Date: March 2, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (AZD1775 + gemcitabine)
AZD1775 (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: AZD1775
AZD1775 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 (AZD1775 + paclitaxel)
Five doses of AZD1775 (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: AZD1775
AZD1775 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 (AZD1775 + carboplatin)

Arm C: Five doses of AZD1775 (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 AZD1775 (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: AZD1775
AZD1775 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 (AZD1775 + PLD)
Five doses of AZD1775 (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: AZD1775
AZD1775 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.

Detailed Description:

This is an open-label, four-arm lead-in safety and efficacy study in which AZD1775 will be combined in four separate treatment arms as follows: AZD1775 plus gemcitabine (Arm A); AZD1775 plus weekly paclitaxel (Arm B); AZD1775 plus carboplatin (Arm C); and AZD1775 plus PLD (Arm D). A subset of patients will be evaluated for the safety assessment of each treatment arm.

The AZD1775 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 AZD1775 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 AZD1775 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 AZD1775 exposure may increase the clinical activity.

  Eligibility

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.


Ages Eligible for Study:   18 Years to 130 Years   (Adult, Senior)
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 AZD1775.
  • 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).
  • AZD1775 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. AZD1775 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.
  Contacts and Locations
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


Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: AstraZeneca Cancer Study Locator Service 1-877-400-4656 AstraZeneca@emergingmed.com

  Show 31 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
Principal Investigator: Kathleen Moore, MD Stephenson Cancer Center, University of Oklahoma Health Sciences Center
  More Information

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02272790     History of Changes
Other Study ID Numbers: D6010C00004
GYN 49 ( Other Identifier: Sarah Cannon Development Innovations )
First Submitted: October 14, 2014
First Posted: October 23, 2014
Last Update Posted: November 17, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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:
Peritoneal Neoplasms
Abdominal Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Peritoneal Diseases
Paclitaxel
Gemcitabine
Albumin-Bound Paclitaxel
Carboplatin
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