AZD1775 for Advanced Solid Tumors

NCT01748825 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 13003213-C-0032
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 1

Brief Summary

BACKGROUND:

• Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in response to deoxyribonucleic acid (DNA) damage to allow time for DNA repair. Recent preclinical data additionally implicates Wee1 in maintenance of genomic integrity during S phase.
• Adavosertib (AZD1775) is a selective inhibitor of Wee1 kinase. Recent preclinical model data additionally show single agent anti-tumor activity in multiple cancer cell lines and tumor xenografts.
• Preliminary data show AZD1775 is tolerable at lower doses in combination with chemotherapeutic agents. We propose to demonstrate single-agent activity for AZD1775. PRIMARY OBJECTIVE:
• To establish the safety and tolerability of single-agent AZD1775 in patients with refractory solid tumors
• To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors SECONDARY OBJECTIVES:
• To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells
• To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors EXPLORATORY OBJECTIVES:
• To identify tumor genomic alterations and gene expression patterns potentially associated with AZD1775 antitumor activity ELIGIBILITY:
• Patients must have histologically confirmed solid tumors for which all standard therapy known to prolong survival have failed, or for which standard therapies do not exist.
• No major surgery, radiation, or chemotherapy within 3 weeks or (5 half-lives, whichever is shorter) prior to entering the study.
• Adequate organ function STUDY DESIGN:
• This study will follow a traditional 3+3 design.
• In Arm A starting at dose level 1, AZD1775 will be administered orally, twice a day (BID), for 5 doses (Day (D) 1-3) during each cycle. Starting at dose level 2 and onwards, AZD1775 will be administered orally, BID, for 5 doses for the first 2 weeks of each cycle (D1-3 and 8- 10). Each cycle is 21 days (+/- 1 day for scheduling).
• Once maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled at the MTD to further evaluate that dose for pharmacokinetics (PK) and pharmacodynamics (PD) endpoints.
• A further expansion arm of 6 additional patients with documented tumors harboring breast cancer type 1 or 2 (BRCA)-1 or -2 mutations will also be enrolled at the MTD to further explore the safety of the agent and obtain preliminary evidence of activity in this patient population.
• Based on preliminary evidence of drug activity in an alternative once-daily dosing schedule, patients without a documented BRCA mutation will be accrued to a once-daily dosing schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated single daily dose, to further evaluate PD endpoints. AZD1775 will be administered orally once daily for 5 days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (+/- 1 day for scheduling).
• During the escalation phase, tumor biopsies will be optional and will be evaluated for pharmacodynamic (PD) studies for evidence of Wee1 inhibition DNA damage and repair, and apoptosis (gamma H2A histone family member X (yH2AX), phosphorylated Nbs1 (pNbs1), Rad51, Rabbit polyclonal phospho-cyclin-dependent kinases (pTyr15-Cdk) and caspase 3). During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be pursued in up to 20 additional patients enrolled at the MTD to further evaluate PD endpoints.

Conditions

Solid Tumors

Keywords

AZD1775; Adavosertib; MK-1775; Refractory; Solid Tumors; Wee1 Inhibitor; Tyrosine Kinase

Outcome Measures

Primary Outcomes (3)

• To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors

  Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  Date treatment consent signed to date off study, approx.19 mo/8 d for A1, 3 mo/28 d for A2, 10 mo/28 d for A3, 2 mo/14 d for A4, 20 mo/24 d for A5, 10 mo/23 d for A6, 4 mo/23 d for A7, 14 mo/11 d for A8, 15 mo/24 d for A9, and 77 mo/6 d for A10.

• Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors

  Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant but not immediately life-threatening. Grade 4 is life-threatening.

  Date treatment consent signed to date off study, approx.19 mo/8 d for A1, 3 mo/28 d for A2, 10 mo/28 d for A3, 2 mo/14 d for A4, 20 mo/24 d for A5, 10 mo/23 d for A6, 4 mo/23 d for A7, 14 mo/11 d for A8, 15 mo/24 d for A9, and 77 mo/6 d for A10.

• To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors.

  Mean plasma concentration (± standard deviation) of AZD1775 at baseline and after AZD1775 administration.

  Pre-Treatment (Baseline) and Cycle 1 Days 1 and 3 (Arms 3 and 7) or Days 1 and 5 (Arms 1-2, 5-6, and 8)

Secondary Outcomes (1)

• To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors

  21 days

Other Outcomes (1)

• Number of Participants With a Dose-Limiting Toxicity (DLT)

  First cycle (21 days) of treatment

Study Arms (10)

ARM 1 AZD1775 200 mg Once Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 2 AZD1775 225 mg Once Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 3 AZD1775 225 mg Twice Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 4 AZD1775 225 mg Twice Daily (week 1-only dosing)

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 5 AZD1775 250 mg Once Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 6 AZD1775 300 mg Once Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 7 AZD1775 300 mg Twice Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 8 AZD1775 400 mg Once Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily

EXPERIMENTAL

Drug: MK-1775 (AZD1775)

Interventions

MK-1775 (AZD1775) DRUG

MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.

Also known as: Adavosertib

ARM 1 AZD1775 200 mg Once Daily; ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily; ARM 2 AZD1775 225 mg Once Daily; ARM 3 AZD1775 225 mg Twice Daily; ARM 4 AZD1775 225 mg Twice Daily (week 1-only dosing); ARM 5 AZD1775 250 mg Once Daily; ARM 6 AZD1775 300 mg Once Daily; ARM 7 AZD1775 300 mg Twice Daily; ARM 8 AZD1775 400 mg Once Daily; ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator.
• Eligibility of subjects receiving any medications or substances with the potential to affect the activity or pharmacokinetics of AZD1775 will be determined following review by the principal investigator.
• Patients receiving any medications or substances that are inhibitors or inducers of Cytochrome P450 3A4 (CYP3A4), or CYP3A4 substrates need to be reviewed by the principal investigator. Continuation of such medications will be at the discretion of the principal investigator. Concomitant use of aprepitant or fosaprepitant is prohibited. As grapefruit and Seville oranges are known to contain moderate inhibitors of CYP3A4, these fruits or their products (including marmalade, juice, etc.) should be avoided while taking AZD1775. The use of sensitive substrates of CYP3A4, such as atorvastatin, simvastatin and lovastatin, is also prohibited in this study. Herbal preparations are not allowed throughout the study. These herbal medications include but are not limited to: St. John's wort, kava, ephedra (mahung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because the effects of the study drugs on the developing fetus are unknown.
• Human immunodeficiency virus (HIV) positive patients on antiretroviral therapy are ineligible because of the potential for pharmacokinetics (PK) interactions.
• Both men and women of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Watanabe N, Broome M, Hunter T. Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J. 1995 May 1;14(9):1878-91. doi: 10.1002/j.1460-2075.1995.tb07180.x.

  PMID: 7743995 BACKGROUND

• Dai Y, Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res. 2010 Jan 15;16(2):376-83. doi: 10.1158/1078-0432.CCR-09-1029. Epub 2010 Jan 12.

  PMID: 20068082 BACKGROUND

• Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol. 2006 Jan;8(1):37-45. doi: 10.1038/ncb1337. Epub 2005 Dec 4.

  PMID: 16327781 BACKGROUND

• Do K, Wilsker D, Ji J, Zlott J, Freshwater T, Kinders RJ, Collins J, Chen AP, Doroshow JH, Kummar S. Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors. J Clin Oncol. 2015 Oct 20;33(30):3409-15. doi: 10.1200/JCO.2014.60.4009. Epub 2015 May 11.

  PMID: 25964244 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

adavosertib

Results Point of Contact

• Title: Dr. Naoko Takebe
• Organization: National Cancer Institute

takeben@nih.gov

240-781-3320

Study Officials

• Naoko Takebe, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 11, 2012
• First Posted: December 13, 2012
• Study Start: December 19, 2012
• Primary Completion: May 19, 2020
• Study Completion: May 19, 2020
• Last Updated: July 26, 2021
• Results First Posted: July 26, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)