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

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

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.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer, TNBC, SCLC, Other Solid Tumours
• Intervention / Treatment: Drug: AZD 1775

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).

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Research Site
  • California
    • San Francisco, California, United States, 94143
      • Research Site
    • West Hollywood, California, United States, 90048
      • Research Site
  • Florida
    • Fort Myers, Florida, United States, 33905
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Research Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	The proportion of patients achieving a complete or partial tumour response (CR or PR) according to RECIST 1.1 criteria.	Every 6 weeks until treatment discontinuation as defined by RECIST 1.1, projected 12 months.
Disease Control Rate (DCR)	The proportion of patients achieving a complete response (CR) or partial response (PR), or stable disease (SD) according to RECIST v1.1 criteria	Every 6 weeks until treatment discontinuation as defined by RECIST 1.1, projected 12 months
Duration of Response (DoR)	The time from first documented tumor response until the date of documented progression or death from any cause.	Every 6 weeks until treatment discontinuation as defined by RECIST 1.1, projected 12 months
Progression Free Survival (PFS)	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.	Every 6 weeks until treatment discontinuation as defined by RECIST 1.1, project 12 months.
PK profile: Plasma concentrations of AZD1775 and PK parameters (Cmax, C8hr, tmax, AUC, tlast, t½λz)	Blood samples will be collected at various timepoints post-dosing	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
QTc prolongation	ECGs will be obtained at various timepoints	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.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Todd M. Bauer, MD, SCRI Development Innovations, LLC

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): January 25, 2018
• Study Completion (Actual): August 22, 2019

Study Registration Dates

• First Submitted: June 11, 2015
• First Submitted That Met QC Criteria: June 25, 2015
• First Posted (Estimated): June 26, 2015

Study Record Updates

• Last Update Posted (Actual): July 3, 2023
• Last Update Submitted That Met QC Criteria: June 30, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Triple negative breast cancer (TNBC); Solid tumours; AZD1775; Ovarian cancer (BRCA1/2 mutation); Ovarian cancer (PARP-failure); Small-cell lung cancer (SCLC)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Adavosertib
• Other Study ID Numbers: D6015C00001; REFMAL 383 (Other Identifier: SCRI Development Innovations, LLC)