Testing AZD1775 in Advanced Solid Tumors That Have a Mutation Called SETD2

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT03284385
Collaborator
(none)
60
Enrollment
29
Locations
1
Arm
51.7
Anticipated Duration (Months)
2.1
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies how well adavosertib works in treating patients with SETD2-deficient solid tumors that have spread to other places in the body (advanced/metastatic). Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVES:
  1. To determine the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria of adavosertib (AZD1775) in advanced solid tumor malignancies other than clear cell renal cell carcinoma with evidence of pathogenic loss of SETD2 using next-generation sequencing panel.

  2. To determine the objective response rate by RECIST 1.1 criteria of AZD1775 in clear cell renal cell carcinoma with evidence of loss of SETD2 using next-generation sequencing panel.

SECONDARY OBJECTIVES:
  1. To determine the clinical benefit rate and duration of response of AZD1775 in SETD2-deficient tumors other than clear cell renal cell carcinoma.

  2. To determine the clinical benefit rate and duration of response of AZD1775 in SETD2-deficient clear cell renal cell carcinoma subgroup.

  3. To characterize the safety profile of AZD1775. IV. To determine whether H3K36me3 expression by immunohistochemical assay is associated with clinical outcomes.

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 30 days.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
60 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Study of AZD1775 in SETD2-Deficient Advanced Solid Tumor Malignancies
Actual Study Start Date :
May 10, 2018
Anticipated Primary Completion Date :
Aug 30, 2022
Anticipated Study Completion Date :
Aug 30, 2022

Arms and Interventions

ArmIntervention/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
  • Outcome Measures

    Primary Outcome Measures

    1. Objective response rate [Up to 2 years]

      Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The median duration of response will be descriptively reported using Kaplan-Meier product limit method along with 95% confidence interval. The objective response rate between cohorts will be compared using the chi-squared test.

    Secondary Outcome Measures

    1. Clinical benefit rate [Up to 2 years]

      Will be defined as patients who experience either objective response or stable disease for >= 6 months from start of study treatment. The clinical benefit rate across the entire study cohort will be descriptively reported along with 95% confidence interval.

    2. Duration of response [Up to 2 years]

      The median duration of response will be descriptively reported using Kaplan-Meier product limit method along with 95% confidence interval.

    3. Incidence and severity of adverse events [Up to 2 years]

      Will be graded by Common Toxicity Criteria version 5.0, will be descriptively reported for the safety-evaluable population.

    4. H3K36me3 mark [Up to 2 years]

      Will be assessed by immunohistochemistry.

    5. Progression free survival [Up to 2 years]

      The median progression-free survival for each cohort will be determined using the Kaplan-Meier product limit method and compared between cohorts using the log-rank test.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Cohort A: Histologically confirmed locally advanced or metastatic solid tumor malignancy other than clear cell renal cell carcinoma with progression on at least one prior systemic therapy and presence of pathogenic loss of SETD2 detected in tumor tissue detected using a Clinical Laboratory Improvement Act (CLIA)-certified next generation sequencing panel (e.g. UCSF500, FoundationOne)

    • Cohort B: Patients with histologically confirmed locally advanced or metastatic clear cell renal cell carcinoma (with clear cell component on pathology), who have been treated with at least one prior systemic therapy for locally advanced or metastatic disease, including either tyrosine kinase inhibitor and/or immune checkpoint inhibitor, with evidence of SETD2 mutation on CLIA-certified next generation sequencing panel

    • All next generation sequencing (NGS) sequencing reports will be reviewed by the University of California at San Francisco (UCSF) Molecular Tumor Board to verify pathogenicity of SETD2 mutation. Each NGS report will be redacted for Protected Health Information (PHI) prior to submission from investigational site to UCSF MTB.

    • Measurable disease by RECIST 1.1 criteria

    • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

    • Absolute neutrophil count >= 1,500/mcL

    • Platelets >= 100,000/mcL

    • Hemoglobin >= 9 g/dL

    • Total bilirubin within normal institutional limits (WLN) or =< 1.5 x upper limit of normal (ULN) in patients with liver metastases; or total bilirubin =< 3 x ULN with direct bilirubin WLN in patients with well documented Gilbert's syndrome

    • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3.0 x institutional upper limit of normal (=< 5 x ULN if known liver metastases)

    • Serum creatinine =< 1.5 x ULN, OR

    • Creatinine clearance >= 45 ml/min (24 hour urine creatinine clearance or calculated by Cockcroft-Gault equation)

    • 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

    • 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

    • Has read and understands the informed consent form and has given written informed consent prior to any study procedures

    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 study treatment, or minor surgical procedures =< 7 days; no waiting period required following port-a-cath or other central venous access placement

    • Grade > 1 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 enrollment; patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

    • Any known hypersensitivity or contraindication to the components of the study drug AZD1775

    • 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; transporter studies (in vitro) have shown that AZD1775 is an inhibitor of breast cancer resistance protein (BCRP); 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 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)

    • AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected; AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction

    • Mean resting corrected QT (QTc) interval using the Fridericia formula (QTcF) > 450 ms (i.e., grade 1 or higher) for males and > 470 ms for females on electrocardiogram (ECG) prior to initiation of study treatment obtained from 3 electrocardiograms (ECGs) obtained 2-5 minutes apart at study entry, or history of congenital long QT syndrome

    • If baseline QTc on screening ECG is > 450 ms for males or > 470 ms for females:

    • Check potassium and magnesium serum levels

    • Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to confirm QTcF interval

    • For patients with baseline heart rate (HR) < 60 bpm or > 100 bpm, manual measurement of QT interval by cardiologist is required, with Fridericia correction applied to that manual measurement to determine the QTc for eligibility consideration

    • Note: For patients with HR 60-100 bpm, manual measurement of QTc interval is NOT required

    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements

    • Pregnant or breastfeeding women; pregnant women are excluded from this study because AZD1775 is WEE1 inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775, breastfeeding should be discontinued if the mother is treated with AZD1775

    • Prior treatment with WEE1 inhibitor

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1UC Irvine Health/Chao Family Comprehensive Cancer CenterOrangeCaliforniaUnited States92868
    2University of California Davis Comprehensive Cancer CenterSacramentoCaliforniaUnited States95817
    3UCSF Medical Center-Mount ZionSan FranciscoCaliforniaUnited States94115
    4UCSF Medical Center-Mission BaySan FranciscoCaliforniaUnited States94158
    5MedStar Georgetown University HospitalWashingtonDistrict of ColumbiaUnited States20007
    6Northwestern UniversityChicagoIllinoisUnited States60611
    7University of Chicago Comprehensive Cancer CenterChicagoIllinoisUnited States60637
    8UC Comprehensive Cancer Center at Silver CrossNew LenoxIllinoisUnited States60451
    9University of Chicago Medicine-Orland ParkOrland ParkIllinoisUnited States60462
    10University of Kansas Clinical Research CenterFairwayKansasUnited States66205
    11University of Kansas Cancer CenterKansas CityKansasUnited States66160
    12University of Kansas Hospital-Westwood Cancer CenterWestwoodKansasUnited States66205
    13Johns Hopkins University/Sidney Kimmel Cancer CenterBaltimoreMarylandUnited States21287
    14Massachusetts General Hospital Cancer CenterBostonMassachusettsUnited States02114
    15Brigham and Women's HospitalBostonMassachusettsUnited States02115
    16Beth Israel Deaconess Medical CenterBostonMassachusettsUnited States02215
    17Dana-Farber Cancer InstituteBostonMassachusettsUnited States02215
    18Wayne State University/Karmanos Cancer InstituteDetroitMichiganUnited States48201
    19Weisberg Cancer Treatment CenterFarmington HillsMichiganUnited States48334
    20Siteman Cancer Center at West County HospitalCreve CoeurMissouriUnited States63141
    21Washington University School of MedicineSaint LouisMissouriUnited States63110
    22Siteman Cancer Center-South CountySaint LouisMissouriUnited States63129
    23Siteman Cancer Center at Christian HospitalSaint LouisMissouriUnited States63136
    24Siteman Cancer Center at Saint Peters HospitalSaint PetersMissouriUnited States63376
    25Laura and Isaac Perlmutter Cancer Center at NYU LangoneNew YorkNew YorkUnited States10016
    26University of Pittsburgh Cancer Institute (UPCI)PittsburghPennsylvaniaUnited States15232
    27Vanderbilt Breast Center at One Hundred OaksNashvilleTennesseeUnited States37204
    28Vanderbilt University/Ingram Cancer CenterNashvilleTennesseeUnited States37232
    29M D Anderson Cancer CenterHoustonTexasUnited States77030

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Rahul R Aggarwal, Yale University Cancer Center LAO

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT03284385
    Other Study ID Numbers:
    • NCI-2017-01670
    • NCI-2017-01670
    • 10170
    • 10170
    • UM1CA186689
    First Posted:
    Sep 15, 2017
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Mar 2, 2022