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AZD1775 in Treating Patients With Advanced Refractory Solid Tumors With CCNE1 Amplification

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ClinicalTrials.gov Identifier: NCT03253679
Recruitment Status : Recruiting
First Posted : August 18, 2017
Last Update Posted : August 22, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well AZD1775 works in treating patients with solid tumors with CCNE1 amplification that have spread to other places in the body (advanced) and do not respond to treatment (refractory). AZD1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm CCNE1 Gene Amplification Refractory Malignant Solid Neoplasm Drug: Adavosertib Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate the proportion of patients with the objective response rate (ORR) to adavosertib (AZD1775) in patients with advanced refractory cancers with CCNE1 amplification.

SECONDARY OBJECTIVES:

I. To evaluate the proportion of patients alive and progression free at 6 months of treatment with AZD1775 in patients with advanced refractory cancers with CCNE1 amplification.

II. To evaluate proportion of patients with extended time to progression (time to progression on AZD1775/ time to progression on last line of therapy >= 1.3).

III. To evaluate time until death or disease progression. IV. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.

OUTLINE:

Patients receive adavosertib orally (PO) once daily (QD) on days 1-5 and 8-12. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of AZD1775, a Wee1 Inhibitor, in Patients With CCNE1 Amplification
Actual Study Start Date : September 24, 2018
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2020

Arm Intervention/treatment
Experimental: Treatment (adavosertib)
Patients receive adavosertib PO QD on days 1-5 and 8-12. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Adavosertib
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775




Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Up to 6 months ]
    ORR is defined as a complete response or partial response and consistent with Response Evaluation Criteria in Solid Tumors version 1.1 criteria.


Secondary Outcome Measures :
  1. Incidence of adverse events and serious adverse events [ Time Frame: Up to 2 years ]
    Will be assessed according to the National Cancer (NCI) Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Will assess clinical symptoms and laboratory values, evaluate vital signs and perform physical exams, with a special attention to treatment-related fatigue, gastrointestinal symptoms, cardiovascular events, myelosuppression, and neurotoxicity.

  2. Incidence grade >= 2 adverse events adverse [ Time Frame: Up to 2 years ]
    According to the NCI CTCAE version 4.0.

  3. Deaths [ Time Frame: Up to 2 years ]
    Deaths during the study will be documented.

  4. Withdrawals [ Time Frame: Up to 2 years ]
    Withdrawals from the study due to treatment-related adverse events will be documented.

  5. Change in treatment regimen [ Time Frame: Up to 2 years ]
    Change of the treatment regimen such as dose delay and dose reduction over time by dose level due to treatment-related adverse events will be documented. Differences in categorical variables will be assessed using the Fisher exact test.

  6. Progression free survival (PFS) [ Time Frame: Up to 2 years ]
    Estimated using the Kaplan-Meier Method.

  7. Overall survival (OS) [ Time Frame: Up to 2 years ]
    Estimated using the Kaplan-Meier Method.


Other Outcome Measures:
  1. Molecular profiling [ Time Frame: Baseline ]
    Fisher exact test is used to associate the baseline molecular profiling, with ORR. Log rank test is used to associate the baseline molecular profiling, with estimated PFS and OS.

  2. Potential biomarkers predicting major clinical outcomes and potential mechanisms of acquired resistance [ Time Frame: Up to 2 years ]
    Immunohistochemistry, reverse phase protein arrays, and next generation sequencing for targeted exome panel are used to reveal potential biomarkers predicting major clinical outcomes, and potential mechanisms of acquired resistance by comparing molecular signatures at baseline versus at time of relapse in responders.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have one of the histologically advanced solid tumors harboring CCNE1 amplification: Their diseases are refractory to, or do not have, standard-of-care therapy; or they declined standard-of-care therapy; CCNE1 amplification is defined in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory: CCNE1 amplification > 7 based on targeted custom Ampliseq panel on the Ion Torrent Personal Genoma Machine (PGM); or CCNE1 amplification on alternate CLIA platforms such as Foundation One, University of Washington (UW)-OncoPlex-Cancer Gene Panel, Memorial Sloan Kettering (MSK)-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT), Solid Tumor Genomic Assay (Life Technologies), etc. will also be eligible to be treated after principal investigator (PI) approval; patients with known CCNE1 amplification on local or commercial platforms can start treatment after planned biopsy or submission of recent archival sample; central next generation sequencing (NGS) CCNE1 and fluorescence in-situ hybridization (FISH) testing will be performed to confirm the result
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • Has read and understands the informed consent form (ICF) and has given written ICF prior to any study procedures; patients with impaired decision making capacity (IDMC) must have a close caregiver or legally authorized representative (LAR)
  • Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment
  • Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1
  • Absolute neutrophil count (ANC) >= 1500/uL (within 14 days of study drug[s] initiation)
  • Hemoglobin (HgB) >= 9 g/dL for mono-therapy (within 14 days of study drug[s] initiation)
  • Platelets >= 100,000/uL (within 14 days of study drug[s] initiation)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) or =< 5 x ULN if known hepatic metastases (within 14 days of study drug[s] initiation)
  • Serum bilirubin < ULN or < 1.5 x ULN in patients with liver metastases; or total bilirubin < 3.0 x ULN with direct bilirubin within normal limits (WNL) in patients with well documented Gilbert's syndrome (within 14 days of study drug[s] initiation)
  • Serum creatinine =< 1.5 x ULN, or calculated creatinine clearance (CrCl) >= 45 mL/min as calculated by the Cockcroft-Gault method or 24-hour measured urine CrCl >= 45 mL/min (within 14 days of study drug[s] initiation)
  • Female patients who are not of child-bearing potential and fertile females of childbearing potential who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 3 days prior to the start of study treatment; male patients willing to abstain or use barrier contraception (i.e. condoms) for the duration of the study and for 3 months after treatment stops
  • Willingness and ability to comply with study and follow-up procedures
  • Ability to take oral medications without medical history of malabsorption or other chronic gastrointestinal disease, or other conditions that may hamper compliance and/or absorption of the study agent
  • No prior treatment with wee1 kinase inhibition
  • Provision of an archival tissue block, or 10 formalin-fixed paraffin-embedded (FFPE) slides, if available, and if not available having biopsiable disease and agreeing to pre-treatment biopsies

Exclusion Criteria:

  • Use of anti-cancer treatment drug =< 21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775; for drugs for which 5 half-lives is =< 21 days, a minimum of 10 days between termination of the prior treatment and administration of AZD1775 treatment is required
  • Previous radiation therapy completed =< 7 days prior to the start of study drugs
  • Major surgical procedures =< 28 days of beginning AZD1775, or minor surgical procedures =< 7 days; no waiting period required following port-a-cath or other central venous access placement
  • Unresolved grade 2 toxicity from prior therapy (except alopecia or anorexia)
  • Patient has an inability to swallow oral medications; Note: Patient may not have a percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN)
  • No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or other novel agent is to be permitted while the patient is receiving study medication; patients on luteinizing hormone-releasing hormone (LHRH) analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the investigator
  • Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases - defined as metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment; must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment
  • Patient has had 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 2 weeks prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug; co-administration of aprepitant or fosaprepitant during this study is prohibited; 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 (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients should stop using these herbal medications 7 days prior to first dose of study treatment
  • Any known hypersensitivity or contraindication to the components of the study drug AZD1775
  • Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) >= class 2

    • Unstable angina pectoris
    • Congestive heart failure
    • Acute myocardial infarction
    • Conduction abnormality not controlled with pacemaker or medication
    • Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
  • Mean resting corrected QTc interval using the Fridericia formula (QTcF) > 450 msec/male and > 470 msec/female (as calculated per institutional standards) obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome
  • Pregnant or breastfeeding women
  • Serious active infection at the time of study entry, or another serious underlying medical condition that would impair the ability of the patient to receive study treatment
  • Symptomatic and uncontrolled metastasis in the central nervous system or leptomeningeal or lymphangitic carcinomatosis
  • Presence of other active invasive cancers that do not harbor CCNE1 amplification
  • Grade 2 or higher peripheral neuropathy
  • Human immunodeficiency virus requiring highly active antiretroviral therapy (HAART) treatment due to unknown drug-drug interactions or has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive or C virus [e.g., hepatitis C virus (HCV) RNA (quantitative) is detected]) infection

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03253679


Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Site Public Contact    800-826-4673    becomingapatient@coh.org   
Principal Investigator: Yuan Yuan         
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Site Public Contact    720-848-0650      
Principal Investigator: Brandon D. Bernard         
United States, District of Columbia
MedStar Georgetown University Hospital Suspended
Washington, District of Columbia, United States, 20007
United States, Florida
University of Florida Health Science Center - Gainesville Recruiting
Gainesville, Florida, United States, 32610
Contact: Site Public Contact    352-273-8010    cancer-center@ufl.edu   
Principal Investigator: Thomas J. George         
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Site Public Contact    859-257-3379      
Principal Investigator: Susanne M. Arnold         
United States, New York
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center Not yet recruiting
New York, New York, United States, 10032
Contact: Site Public Contact    212-305-6361    nr2616@cumc.columbia.edu   
Principal Investigator: Richard D. Carvajal         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Site Public Contact    888-275-3853      
Principal Investigator: James L. Abbruzzese         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Site Public Contact    412-647-8073      
Principal Investigator: Sarah E. Taylor         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Site Public Contact    877-632-6789    askmdanderson@mdanderson.org   
Principal Investigator: Siqing Fu         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Siqing Fu University of Texas MD Anderson Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03253679     History of Changes
Other Study ID Numbers: NCI-2017-01498
NCI-2017-01498 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NCI10136
10136 ( Other Identifier: University of Texas MD Anderson Cancer Center LAO )
10136 ( Other Identifier: CTEP )
UM1CA186688 ( U.S. NIH Grant/Contract )
First Posted: August 18, 2017    Key Record Dates
Last Update Posted: August 22, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Neoplasms
MK-1775
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action