Clinical Trials /

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

NCT03253679

Description:

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 and do not respond to treatment. AZD1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: AZD1775 in Treating Patients With Advanced Refractory Solid Tumors With CCNE1 Amplification
  • Official Title: A Phase 2 Study of AZD1775, a Wee1 Inhibitor, in Patients With CCNE1 Amplification

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01498
  • SECONDARY ID: NCI-2017-01498
  • SECONDARY ID: NCI10136
  • SECONDARY ID: 10136
  • SECONDARY ID: 10136
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT03253679

Conditions

  • Advanced Malignant Solid Neoplasm
  • CCNE1 Gene Amplification
  • Refractory Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
AdavosertibAZD-1775, AZD1775, MK-1775, MK1775Treatment (adavosertib)

Purpose

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 and do not respond to treatment. AZD1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (adavosertib)ExperimentalPatients 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.
  • Adavosertib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 6 months
Safety Issue:
Description: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

Measure:Incidence of adverse events and serious adverse events
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Incidence grade >= 2 adverse events adverse
Time Frame:Up to 2 years
Safety Issue:
Description:According to the NCI CTCAE version 4.0.
Measure:Deaths
Time Frame:Up to 2 years
Safety Issue:
Description:Deaths during the study will be documented.
Measure:Withdrawals
Time Frame:Up to 2 years
Safety Issue:
Description:Withdrawals from the study due to treatment-related adverse events will be documented.
Measure:Change in treatment regimen
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Estimated using the Kaplan-Meier Method.
Measure:Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:Estimated using the Kaplan-Meier Method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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