Clinical Trials /

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

NCT02272790

Description:

AZD1775 in combination with carboplatin, paclitaxel, gemcitabine, or PLD.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: AZD1775 Plus Chemotherapy in Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
  • Official Title: A Multicentre Phase II Study of AZD1775 Plus Chemotherapy in Patients With Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Clinical Trial IDs

  • ORG STUDY ID: D6010C00004
  • SECONDARY ID: GYN 49
  • NCT ID: NCT02272790

Conditions

  • Ovarian, Fallopian Tube, Peritoneal Cancer, P53 Mutation

Interventions

DrugSynonymsArms
AZD1775MK1775Arm A (AZD1775 + gemcitabine)
PaclitaxelTaxolArm B (AZD1775 + paclitaxel)
CarboplatinParaplatinArm C/C2 (AZD1775 + carboplatin)
GemcitabineArm A (AZD1775 + gemcitabine)
PLDArm D (AZD1775 + PLD)

Purpose

AZD1775 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (AZD1775 + gemcitabine)ExperimentalAZD1775 (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.
  • AZD1775
  • Gemcitabine
Arm B (AZD1775 + paclitaxel)ExperimentalFive 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.
  • AZD1775
  • Paclitaxel
Arm C/C2 (AZD1775 + carboplatin)ExperimentalArm 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.
  • AZD1775
  • Carboplatin
Arm D (AZD1775 + PLD)ExperimentalFive 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.
  • AZD1775
  • PLD

Eligibility 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.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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

Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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).
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

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