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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 : Suspended (Other - Protocol amendment required for expansion)
First Posted : August 18, 2017
Last Update Posted : October 20, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE August 17, 2017
First Posted Date  ICMJE August 18, 2017
Last Update Posted Date October 20, 2020
Actual Study Start Date  ICMJE September 24, 2018
Estimated Primary Completion Date September 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2020)
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. The ORR rate will be compared against a null benchmark value of 5%.
Original Primary Outcome Measures  ICMJE
 (submitted: August 17, 2017)
Objective response rate (ORR) defined as a complete response or partial response [ Time Frame: Up to 6 months ]
Defined as consistent with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 22, 2019)
  • 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.
  • Incidence grade >= 2 adverse events adverse [ Time Frame: Up to 2 years ]
    According to the NCI CTCAE version 4.0.
  • Deaths [ Time Frame: Up to 2 years ]
    Deaths during the study will be documented.
  • Withdrawals [ Time Frame: Up to 2 years ]
    Withdrawals from the study due to treatment-related adverse events will be documented.
  • 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.
  • Progression free survival (PFS) [ Time Frame: Up to 2 years ]
    Estimated using the Kaplan-Meier Method.
  • Overall survival (OS) [ Time Frame: Up to 2 years ]
    Estimated using the Kaplan-Meier Method.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 17, 2017)
  • Change in treatment regimen [ Time Frame: Up to 1.5 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.
  • Deaths [ Time Frame: Up to 1.5 years ]
    Deaths during the study will be documented.
  • Incidence grade >= 2 adverse events adverse [ Time Frame: Up to 1.5 years ]
    According to the NCI CTCAE version 4.0.
  • Incidence of adverse events and serious adverse events according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 1.5 years ]
    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.
  • Overall survival [ Time Frame: Up to 1.5 years ]
    Estimated using the Kaplan-Meier Method.
  • Progression free survival [ Time Frame: Up to 1.5 years ]
    Estimated using the Kaplan-Meier Method.
  • Withdrawals [ Time Frame: Up to 1.5 years ]
    Withdrawals from the study due to treatment-related adverse events will be documented.
Current Other Pre-specified Outcome Measures
 (submitted: April 22, 2019)
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: August 17, 2017)
  • 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.
  • Potential biomarkers predicting major clinical outcomes and potential mechanisms of acquired resistance [ Time Frame: Up to 1.5 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.
 
Descriptive Information
Brief Title  ICMJE AZD1775 in Treating Patients With Advanced Refractory Solid Tumors With CCNE1 Amplification
Official Title  ICMJE A Phase 2 Study of AZD1775, a Wee1 Inhibitor, in Patients With CCNE1 Amplification
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Malignant Solid Neoplasm
  • Refractory Malignant Solid Neoplasm
Intervention  ICMJE Drug: Adavosertib
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775
Study Arms  ICMJE 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.
Intervention: Drug: Adavosertib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: April 22, 2019)
32
Original Estimated Enrollment  ICMJE
 (submitted: August 17, 2017)
35
Estimated Study Completion Date  ICMJE September 30, 2021
Estimated Primary Completion Date September 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03253679
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Siqing Fu University of Texas MD Anderson Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP