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

Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT02482311
Collaborator
(none)
92
17
1
49.7
5.4
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Study Details

Study Description

Brief Summary

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 or Disease Intervention/Treatment Phase
  • Drug: AZD 1775
Phase 1

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 Design

Study Type:
Interventional
Actual Enrollment :
92 participants
Allocation:
N/A
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
Actual Study Start Date :
Jul 1, 2015
Actual Primary Completion Date :
Jan 25, 2018
Actual Study Completion Date :
Aug 22, 2019

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

  1. Number of treatment emergent adverse events (TEAEs), serious adverse events (SAEs) and dose-limiting toxicities (DLTs) as a measure of safety and tolerability. [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

  1. Objective Response Rate (ORR) [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.

  2. Disease Control Rate (DCR) [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

  3. Duration of Response (DoR) [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.

  4. Progression Free Survival (PFS) [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.

  5. PK profile: Plasma concentrations of AZD1775 and PK parameters (Cmax, C8hr, tmax, AUC, tlast, t½λz) [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

  6. QTc prolongation [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

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 99 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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:

  7. ANC ≥1500/μL

  8. Hgb ≥9 g/dL

  9. Platelets ≥100,000/μL

  10. ALT and AST ≤3 x ULN or ≤5 x ULN if known hepatic metastases.

  11. 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.

  12. Serum creatinine ≤1.5 x the ULN and a calculated creatinine clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method.

  13. Negative serum or urine pregnancy test within 3 days prior to start of study treatment.

  14. 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.

  15. 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.

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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Research Site Fayetteville Arkansas United States 72703
2 Research Site La Jolla California United States 92093
3 Research Site Los Angeles California United States 90048
4 Research Site San Francisco California United States 94143
5 Research Site Fort Myers Florida United States 33905
6 Research Site Indianapolis Indiana United States 46202
7 Research Site Detroit Michigan United States 48201
8 Research Site Charlotte North Carolina United States 28204
9 Research Site Oklahoma City Oklahoma United States 73104
10 Research Site Philadelphia Pennsylvania United States 19104
11 Research Site Greenville South Carolina United States 29605
12 Research Site Nashville Tennessee United States 37203
13 Research Site Houston Texas United States 77030
14 Research Site Milwaukee Wisconsin United States 53226
15 Research Site Edmonton Alberta Canada T6G 1Z2
16 Research Site Vancouver British Columbia Canada V5Z 4E6
17 Research Site Toronto Ontario Canada M5G 2M9

Sponsors and Collaborators

  • AstraZeneca

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02482311
Other Study ID Numbers:
  • D6015C00001
  • REFMAL 383
First Posted:
Jun 26, 2015
Last Update Posted:
Sep 25, 2019
Last Verified:
Sep 1, 2019

Study Results

No Results Posted as of Sep 25, 2019