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Safety, Tolerance, PK, and Anti-tumour Activity of AZD1775 Monotherapy in Patients With Advanced Solid Tumours

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02482311
First received: June 11, 2015
Last updated: August 17, 2017
Last verified: August 2017
  Purpose
This is an open-label, multi-centre, Phase Ib study of AZD1775 designed to assess the safety, tolerability, pharmacokinetics, and anti-tumour activity of AZD1775 monotherapy in patients with advanced solid tumours.

Condition Intervention Phase
Ovarian Cancer, TNBC, SCLC, Other Solid Tumours Drug: AZD 1775 Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib, Open-Label, Multi-Centre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumour Activity of AZD1775 Monotherapy in Patients With Advanced Solid Tumours

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Number of treatment emergent adverse events (TEAEs), serious adverse events (SAEs) and dose-limiting toxicities (DLTs) as a measure of safety and tolerability. [ Time Frame: From first dose of study treatment up to last day of Cycle 1 (21 days) ]
    The AZD1775 dose is considered safe and tolerable if ≤ 1 of 6 patients experiences a DLT.


Secondary Outcome Measures:
  • Objective Response Rate (ORR) [ Time Frame: Every 6 weeks until treatment discontinuation as defined by RECIST 1.1, projected 12 months. ]
    The proportion of patients achieving a complete or partial tumour response (CR or PR) according to RECIST 1.1 criteria.

  • Disease Control Rate (DCR) [ Time Frame: Every 6 weeks until treatment discontinuation as defined by RECIST 1.1, projected 12 months ]
    The proportion of patients achieving a complete response (CR) or partial response (PR), or stable disease (SD) according to RECIST v1.1 criteria

  • Duration of Response (DoR) [ Time Frame: Every 6 weeks until treatment discontinuation as defined by RECIST 1.1, projected 12 months ]
    The time from first documented tumor response until the date of documented progression or death from any cause.

  • Progression Free Survival (PFS) [ Time Frame: Every 6 weeks until treatment discontinuation as defined by RECIST 1.1, project 12 months. ]
    Defined as the time from date of first dose of AZD1775 until the date of objective disease progression or death by any cause as defined by RECIST 1.1.

  • PK profile: Plasma concentrations of AZD1775 and PK parameters (Cmax, C8hr, tmax, AUC, tlast, t½λz) [ Time Frame: Pre-dose and 1, 2, 4, 6, 8 and 12 hours post-dose of AZD1775 during Cycle 1-Day 1 and Cycle 1-Day3 or Day-10 of the safety lead-in part of study ]
    Blood samples will be collected at various timepoints post-dosing

  • QTc prolongation [ Time Frame: ECGs collected pre-dose and 1, 2, 4, 6, 8 and 12 hours post-dose in Cycle 1-Day 1 and on Cycle 1-Day 3 or Day 10. ]
    ECGs will be obtained at various timepoints


Enrollment: 97
Actual Study Start Date: July 1, 2015
Estimated Study Completion Date: August 31, 2017
Estimated Primary Completion Date: August 31, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AZD1775

Single-arm study. AZD1775 will be administered for 3 consecutive days at the start of week 1 and week 2 of each 21-day cycle.

This study will be conducted in two parts, designated Part A and Part B. Part A is a safety lead-in. Part B will commence after the safety lead-in and will investigate the safety and efficacy of AZD1775 monotherapy in expansion cohorts of specific tumour types.

Drug: AZD 1775

AZD1775 will be taken orally approximately every 12 hours over 3 days at the start of week 1 and week 2 of each 21-day cycle (Days 1-3 and 8-10), for a total of 12 doses with each treatment cycle.

AZD1775 should be taken approximately 2 hours before or 2 hours after food.


Detailed Description:

This study is being conducted in two parts, designated Parts A and B. Part A is a safety lead-in consisting of a cohort of approximately 12 patients with advanced solid tumours.

Part B expansion cohorts will investigate AZD1775 monotherapy in advanced tumour types with molecular biomarkers of interest. The tumour types to be evaluated are: 1) ovarian cancer (BRCA1/2 mutation [PARP-failures]), 2) ovarian cancer (BRCA wild-type) with more than three prior lines of treatment, 3) triple negative breast cancer (TNBC), and 4) small-cell lung cancer (SCLC).

  Eligibility

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18
  2. Previous chemotherapy for recurrent or metastatic disease.
  3. Measurable disease is required for Part B expansion cohorts according to RECIST v1.1 criteria.
  4. Radiation therapy completed at least 7 days prior to start of study treatment and patients must have recovered from any acute adverse effects.
  5. ECOG Performance Status (PS) score of 0-1.
  6. Baseline laboratory values as follows:

    1. ANC ≥1500/μL
    2. Hgb ≥9 g/dL
    3. Platelets ≥100,000/μL
    4. ALT and AST ≤3 x ULN or ≤5 x ULN if known hepatic metastases.
    5. Serum bilirubin 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.
  7. Negative serum or urine pregnancy test within 3 days prior to start of study treatment.
  8. Fertile male patients willing to use at least one medically acceptable form of birth control for the duration of the study and for 2 weeks after treatment stops.
  9. Predicted life expectancy ≥12 weeks.

Inclusion Criteria Specific for Part A:

  1. Histologically or cytologically documented, locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable.
  2. Has agreed to the collection of archival tumour tissue or recent tumour biopsy tissue, it taken for routine clinical purposes at baseline if archival tissue is not available, for molecular biomarker analyses.

Inclusion Criteria Specific for Part B:

  1. Ovarian cancer defined as a histologically confirmed diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer refractory to standard therapies of for which no standard therapy exists. Confirmed BRCA1 or BRCA2 mutation from a prior test. Patient progressed while receiving and/or following treatment with a PARP-inhibitor for advanced disease (recurrent or metastatic.
  2. Ovarian cancer confirmed BRCA wild-type from a prior test.
  3. Triple-negative breast cancer (TNBC) defined as histologically confirmed diagnosis of breast cancer and must have received at least 1 chemotherapy-containing regimen for advanced disease (recurrent or metastatic). Tumour must be triple-negative, defined as minimal or no expression of estrogen and progesterone receptors [<10% of cells positive by immunohistochemistry (IHC)], and minimal or no expression of HER2 (IHC staining 0 or 1+ or FISH-).
  4. Small-cell lung cancer (SCLC) defined as a histologically confirmed diagnosis of SCLC and must have received at least 1 chemotherapy-containing regimen for advanced disease (recurrent or metastatic).

Exclusion Criteria:

  1. Any chemotherapy within 3 weeks of the first dose of AZD1775, except hormonal therapy in the refractory cohort.
  2. Use of a study drug ≤21 days or 5 half-lives, whichever is shorter.
  3. Major surgical procedures ≤28 days, or minor procedures ≤7 days.
  4. Grade >1 toxicity from prior therapy (except alopecia or anorexia).
  5. CNS disease other than neurologically stable, treated brain metastases.
  6. Prescription or non-prescription drugs or other products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued two weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug.
  7. NYHA ≥ Class 2.
  8. Mean resting corrected QT interval (QTc) ≥450 msec for males and ≥470 msec for females.
  9. Pregnant or lactating.
  10. Serious active infection, or serious underlying medical condition.

12. Presence of other active invasive cancers. 13. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

  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: NCT02482311

Locations
United States, Arkansas
Research Site
Fayetteville, Arkansas, United States, 72703
United States, California
Research Site
La Jolla, California, United States, 92093
Research Site
Los Angeles, California, United States, 90048
Research Site
San Francisco, California, United States, 94115
United States, Florida
Research Site
Fort Myers, Florida, United States, 33905
United States, Indiana
Research Site
Indianapolis, Indiana, United States, 46202
United States, Michigan
Research Site
Detroit, Michigan, United States, 48201
United States, North Carolina
Research Site
Charlotte, North Carolina, United States, 28204
United States, Oklahoma
Research Site
Oklahoma City, Oklahoma, United States, 73104
United States, Pennsylvania
Research Site
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Research Site
Greenville, South Carolina, United States, 29605
United States, Tennessee
Research Site
Nashville, Tennessee, United States, 37203
United States, Texas
Research Site
Houston, Texas, United States, 77030
United States, Wisconsin
Research Site
Milwaukee, Wisconsin, United States, 53226
Canada, Alberta
Research Site
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
Research Site
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
Research Site
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
AstraZeneca
Investigators
Principal Investigator: Todd M. Bauer, MD SCRI Development Innovations, LLC
  More Information

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02482311     History of Changes
Other Study ID Numbers: D6015C00001
REFMAL 383 ( Other Identifier: SCRI Development Innovations, LLC )
Study First Received: June 11, 2015
Last Updated: August 17, 2017

Keywords provided by AstraZeneca:
AZD1775
Ovarian cancer (BRCA1/2 mutation)
Ovarian cancer (PARP-failure)
Triple negative breast cancer (TNBC)
Small-cell lung cancer (SCLC)
Solid tumours

Additional relevant MeSH terms:
Ovarian Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders

ClinicalTrials.gov processed this record on September 21, 2017