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

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02272790
First received: October 14, 2014
Last updated: May 22, 2017
Last verified: May 2017
  Purpose
A Phase II Study of AZD1775 plus Chemotherapy in Patients with Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. Patients will receive AZD1775 plus carboplatin or AZD1775 plus weekly paclitaxel. The primary study objective is to evaluate the objective response rate (ORR).

Condition Intervention Phase
Ovarian, Fallopian Tube, Peritoneal Cancer, P53 Mutation Drug: AZD1775 + carboplatin Drug: AZD1775 + paclitaxel Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
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

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • The primary outcome measure is the Objective Response Rate (ORR) of participants in arms included in the efficacy assessment. [ Time Frame: Objective tumour assessments every 6-8 weeks ]

    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).

    GCIG criteria will be used to assess CA-125 tumour markers. Patients with elevated CA-125 levels that can be monitored for response will be assessed according to GCIG CA-125 response criteria in addition to RECIST v1.1.



Secondary Outcome Measures:
  • Duration of Response (DoR) [ Time Frame: Tumour assessments will be performed every 6-8 weeks. ]
    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: Tumour assessments will be performed every 6-8 weeks. ]
    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: Day 1 of each cycle and every 3 months from last tumour assessment ]
    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. ]
    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 in patients in Arm B. [ Time Frame: Blood samples will be collected pre-dose, 1-hour post-dose and 2-4 hours post-dose on Day 3, 10, or 17 of Cycles 1, 3, 5, and 7. ]
    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 in patients in Arm C2. [ Time Frame: Blood samples will be collected pre-dose, 1-hour post-dose and 2-4 hours post-dose on Day 3, 10, or 17 of Cycles 1, 3, 5, and 7. ]
    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: April 30, 2018
Estimated Primary Completion Date: April 30, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm B (AZD1775 + paclitaxel)
Five doses of AZD1775 will be taken in approximate 12 hour intervals over the first 2.5 days of Weeks 1, 2, and 3 (i.e., Days 1-3, 8-10, and 15-17) of each 28 day cycle. Paclitaxel will be administered according to institutional standards on Day 1, 8, and 15 of each 28 day cycle. AZD1775 should be taken approximately 2 hours before or 2 hours after food. Patients may continue on study as long as they are benefitting, have no evidence of disease progression, and do not meet any criteria for discontinuation or withdrawal.
Drug: AZD1775 + paclitaxel
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the WEE1 kinase that sensitizes tumour cells to cytotoxic agents and is being developed for the treatment of advanced solid tumours and p53 pathway deficient malignancies. Chemotherapy is a category of cancer treatment that uses chemical substances, especially one or more anti-cancer drugs (chemotherapeutic agents) that are given as part of a standardized chemotherapy regimen.
Other Name: MK1775 + paclitaxel
Experimental: Arm C2 (AZD1775 + carboplatin)
Initially, 6 patients will be enrolled to receive 5 doses of AZD1775 in approx. 12 hour intervals over the first 2.5 days of Weeks 1, 2, and 3 (i.e., Days 1-3, 8-10, and 15-17) of each 28 day cycle. If 1 patient or less experiences a DLT during Cycle 1, then 6 more patients will be enrolled for a total of 12. However, if 2 or more of the first 6 patients experience a DLT then the AZD1775 dosing may be modified to 2 weeks on followed by 1 week off. Carboplatin will be administered on Day 1 of each 28 day cycle. AZD1775 should be taken approximately 2 hours before or 2 hours after food. Patients may continue on study as long as they are benefitting, have no evidence of disease progression, and do not meet any criteria for discontinuation or withdrawal.
Drug: AZD1775 + carboplatin
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the WEE1 kinase that sensitizes tumour cells to cytotoxic agents and is being developed for the treatment of advanced solid tumours and p53 pathway deficient malignancies. Carboplatin is a chemotherapy drug used against some forms of cancer (mainly ovarian carcinoma, lung, head and neck cancers as well as endometrial, esophageal, bladder, breast and cervical; central nervous system or germ cell tumors; osteogenic sarcoma, and as preparation for a stem cell or bone marrow transplant.).
Other Name: MK1775 + carboplatin

Detailed Description:

This is a phase II study of AZD1775 plus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients will receive AZD1775 plus carboplatin or AZD1775 plus weekly paclitaxel.

The primary endpoint for the study is overall response rate (ORR) defined as the proportion of patients achieving a complete or partial tumour response according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Secondary endpoints include assessment of the duration of response (DoR), overall survival (OS), progression-free survival (PFS), disease control rate (DCR), Gynecologic Cancer Intergroup (GCIG) cancer antigen-125 response, safety and tolerability, clinically significant changes in safety-related laboratory parameters, pharmacokinetics (PK) and drug-drug interactions.

A Safety Review Team (SRT) will assess the safety and tolerability of the first 6 patients in each arm by incidence and severity of adverse events (AEs) after a minimum of 1 treatment cycle as determined by NCI CTCAE v4.03 and the occurrence of pre-defined dose-limiting toxicities (DLTs). Patients must complete Cycle 1 safety evaluations, and return to the study centre for Cycle 2 Day 1 evaluations to be considered evaluable for the safety lead-in.

Arm B: Arm B (AZD1775 + paclitaxel) will enroll approximately 30 additional patients at selected sites as part of a further efficacy evaluation based on emerging data that suggests clinical activity.

Arm C2: Initially, 6 patients will be enrolled to receive 5 doses of AZD1775 in approx. 12 hour intervals over the first 2.5 days of Weeks 1, 2, and 3 (i.e., Days 1-3, 8-10, and 15-17) of each 28 day cycle. If 1 patient or less experiences a DLT during Cycle 1, then 6 more patients will be enrolled for a total of 12. However, if 2 or more of the first 6 patients experience a DLT then the AZD1775 dosing may be modified to 2 weeks on followed by 1 week off. All patients will receive carboplatin on Day 1 of each 28 day cycle. AZD1775 should be taken approximately 2 hours before or 2 hours after food. Patients may continue on study as long as they are benefitting, have no evidence of disease progression, and do not meet any criteria for discontinuation or withdrawal.

Enrollment in Arms A and C is complete. Enrollment will not continue in Arm D.

  Eligibility

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

Inclusion

  1. Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer.
  2. 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.
  3. No more than 2 prior treatment regimens for Stage III/IV disease, defined as investigational, chemotherapy, hormonal, biologic, or targeted therapy.
  4. 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).
  5. At least 1 measurable lesion according to RECIST v1.1.
  6. 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.
  7. ECOG Performance Status (PS) score of 0 - 1.
  8. Baseline Laboratory Values:

    1. ANC ≥1500/μL
    2. HgB ≥ 9 g/dL
    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.
  9. Left ventricular ejection fraction (LVEF) WNL as determined by multiple gated acquisition (MUGA) or echocardiography (ECHO).
  10. Female patients, ≥18, (not of childbearing potential and fertile female patients of childbearing potential) who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start.
  11. Predicted life expectancy ≥ 12 weeks

Exclusion

  1. Any study drug ≤ 21 days or 5 half-lives (whichever is shorter) prior to the first dose.
  2. Major surgical procedures ≤ 28 days of beginning study, or minor surgical procedures ≤ 7 days.
  3. Grade >1 toxicity from prior therapy (except alopecia or anorexia).
  4. Known CNS disease other than neurologically stable, treated brain metastases (e.g., metastasis having no evidence of progression or haemorrhage after treatment for ≥2 weeks)
  5. Any Rx or non Rx 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 and withheld throughout the study until 2 weeks after last dose. Co-administration of aprepitant during this study is prohibited.
  6. 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
    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).
  7. Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome.
  8. Pregnant or lactating.
  9. Serious active infection upon enrolment, or other serious underlying medical condition that would impair the patient's ability to receive study treatment.
  10. 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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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 26 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 )
Study First Received: October 14, 2014
Last Updated: May 22, 2017

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
Albumin-Bound Paclitaxel
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 22, 2017