Clinical Trials /

Adavosertib in Treating Patients With SETD2-Deficient Locally Advanced or Metastatic Solid Tumors

NCT03284385

Description:

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. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Adavosertib in Treating Patients With SETD2-Deficient Locally Advanced or Metastatic Solid Tumors
  • Official Title: A Phase 2 Study of AZD1775 in SETD2-Deficient Advanced Solid Tumor Malignancies

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01670
  • SECONDARY ID: NCI-2017-01670
  • SECONDARY ID: 10170
  • SECONDARY ID: 10170
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT03284385

Conditions

  • Clear Cell Renal Cell Carcinoma
  • Locally Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Metastatic Renal Cell Carcinoma
  • Stage III Renal Cell Cancer AJCC v8
  • Stage IV Renal Cell Cancer AJCC v8

Interventions

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

Purpose

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. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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 biallelic loss of SETD2 using
      next-generation sequencing panel.

      II. 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:

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

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

      III. 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.
    

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:

          -  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 biallelic 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 caricnoma (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 congential 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 2 years
Safety Issue:
Description: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

Measure:Clinical benefit rate
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Duration of response
Time Frame:Up to 2 years
Safety Issue:
Description:The median duration of response will be descriptively reported using Kaplan-Meier product limit method along with 95% confidence interval.
Measure:Incidence and severity of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Will be graded by Common Toxicity Criteria version 5.0, will be descriptively reported for the safety-evaluable population.
Measure:H3K36me3 mark
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed by immunohistochemistry.
Measure:Progression free survival
Time Frame:Up to 2 years
Safety Issue:
Description: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.

Details

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

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