Clinical Trials /

Genetic Testing in Guiding Treatment for Patients With Brain Metastases

NCT03994796

Description:

This phase II trial studies how well genetic testing works in guiding treatment for patients with solid tumors that have spread to the brain. Several genes have been found to be altered or mutated in brain metastases such as NTRK, ROS1, CDK or PI3K. Medications that target these genes such as abemaciclib, GDC-0084, and entrectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Genetic testing may help doctors tailor treatment for each mutation.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Genetic Testing in Guiding Treatment for Patients With Brain Metastases
  • Official Title: Genomically-Guided Treatment Trial in Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: A071701
  • SECONDARY ID: NCI-2019-00744
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT03994796

Conditions

  • CDK Gene Mutation
  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Malignant Solid Neoplasm
  • NTRK Family Gene Mutation
  • PI3K Gene Mutation
  • ROS1 Gene Mutation

Interventions

DrugSynonymsArms
AbemaciclibArm I (CDK gene mutation)
PI3K Inhibitor GDC-0084Arm II (PI3K gene mutation)
EntrectinibArm III (NTRK/ROS1 gene mutation)

Purpose

This phase II trial studies how well genetic testing works in guiding treatment for patients with solid tumors that have spread to the brain. Several genes have been found to be altered or mutated in brain metastases such as NTRK, ROS1, CDK or PI3K. Medications that target these genes such as abemaciclib, GDC-0084, and entrectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Genetic testing may help doctors tailor treatment for each mutation.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the activity of a CDK inhibitor in patients with progressive brain metastases
      derived from lung cancer, breast cancer, and other cancers harboring actionable genetic
      alterations associated with sensitivity to CDK inhibitors as measured by response rate
      (Response Assessment in Neuro-Oncology [RANO] criteria).

      II. To determine the activity of a PI3K inhibitor in patients with progressive brain
      metastases derived from lung cancer, breast cancer, and other cancers harboring actionable
      genetic alterations in the PI3K pathway as measured by response rate (RANO criteria).

      III: To determine the activity of an NTRK/ROS1 inhibitor in patients with progressive brain
      metastases derived from lung cancer harboring actionable NTRK/ROS1 gene fusions as measured
      by response rate (RANO criteria).

      SECONDARY OBJECTIVES:

      I. To evaluate the systemic response by Response Evaluation Criteria in Solid Tumors (RECIST)
      criteria in each of the cohorts determined by treatment and primary cancer type.

      II. To evaluate the clinical benefit rate (complete response [CR] + partial response [PR] +
      stable disease [SD]) by Brain Metastases (BM)-RANO for central nervous system (CNS) in each
      of the cohorts determined by treatment and primary cancer type.

      III. To evaluate the clinical benefit rate (CR + PR + SD) by RECIST for extracranial disease
      in each of the cohorts determined by treatment and primary cancer type.

      IV. To evaluate the duration of response by BM-RANO in each of the cohorts determined by
      treatment and primary cancer type.

      V. To evaluate the duration of response by RECIST in each of the cohorts determined by
      treatment and primary cancer type.

      VI. To evaluate the progression-free survival for intracranial disease in each of the cohorts
      determined by treatment and primary cancer type.

      VII. To evaluate the progression-free survival for extracranial disease in each of the
      cohorts determined by treatment and primary cancer type.

      VIII. To evaluate the site of first progression (CNS versus [vs] non-CNS) in each of the
      cohorts determined by treatment and primary cancer type.

      IX. To evaluate the overall survival in each of the cohorts determined by treatment and
      primary cancer type.

      X. To evaluate the toxicity profile of agents in patients with brain metastases in each of
      the cohorts determined by treatment and primary cancer type.

      OUTLINE: Patients are assigned to 1 of 3 arms.

      ARM I (CDK GENE MUTATION): Patients receive abemaciclib orally (PO) twice daily (BID) on days
      1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      ARM II (PI3K GENE MUTATION): Patients receive PI3K inhibitor GDC-0084 PO once daily (QD) on
      days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      ARM III (NTRK/ROS1 GENE MUTATION): Patients receive entrectinib PO QD on days 1-28. Cycles
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 8 weeks for 2 years, then
      every 3 months for years 3-4, and then every 6 months thereafter for up to 5 years after
      registration.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (CDK gene mutation)ExperimentalPatients receive abemaciclib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Abemaciclib
Arm II (PI3K gene mutation)ExperimentalPatients receive PI3K inhibitor GDC-0084 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • PI3K Inhibitor GDC-0084
Arm III (NTRK/ROS1 gene mutation)ExperimentalPatients receive entrectinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Entrectinib

Eligibility Criteria

        Inclusion Criteria:

        PRE-REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS) • Tissue available for biomarker
        testing (any brain metastasis tissue and extracranial site from any prior resection or
        biopsy).

        REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS)

          -  Participants must have histologically confirmed metastatic disease to the brain from
             any solid tumor. Note: this includes patients that have controlled extracranial
             disease with progressive intracranial metastasis, as well as patients that have
             progressive intracranial and extracranial disease.

          -  New or progressive brain metastases are defined as any one of the following:

               -  Untreated measurable lesions in patients who have received surgery and/or
                  stereotactic radiosurgery (SRS) to one or more other lesions.

               -  Residual or progressive lesions after surgery if asymptomatic.

               -  Patients who have had prior whole-brain radiotherapy (WBRT) and/or SRS and then
                  whose lesions have progressed by BM-RANO criteria or there are new lesions, are
                  eligible. Lesions treated with SRS may be eligible if there is unequivocal
                  evidence of progression.

               -  Patients who have not previously been treated with cranial radiation (e.g. WBRT
                  or SRS) are eligible, but such patients must be asymptomatic or neurologically
                  stable from their CNS metastases.

          -  Measurable CNS disease (> 10 mm).

          -  Ability to obtain magnetic resonance imaging (MRI)s.

          -  No surgery within 2 weeks prior to or after registration.

          -  No chemotherapy within 14 days prior to registration (Note: for abemaciclib arm, a
             21-day chemotherapy washout is required).

               -  For melanoma, patients must have progressed after prior immune checkpoint
                  blockade or for BRAF positive melanoma, BRAF/MEK inhibitors.

               -  For lung cancer, EGFR mutant patients must have failed EGFR therapies

               -  For HER2-positive breast cancer patients, patients must have received at least
                  one prior HER-2 directed therapy in the metastatic setting.

               -  For triple negative breast cancer (TNBC), patients must have received at least
                  one chemotherapy in the metastatic setting.

               -  For estrogen receptor (ER)/progesterone receptor (PR)+ breast cancer, patients
                  must have received at least one endocrine therapy in the metastatic setting.

               -  Breast cancer patients who have received ribociclib or palbociclib are eligible
                  as long as there is documentation of CDK4 pathway alteration on a biopsy at the
                  point of progression post-ribociclib or palbociclib.

          -  Tissue available for sequencing (any brain metastasis tissue and extracranial site
             from any prior resection or biopsy that was resected as part of clinical care). If the
             patient does not have any evidence of extracranial disease, brain metastasis tissue is
             sufficient for eligibility.

          -  Presence of clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K
             pathway in both a brain metastasis and extracranial site.

          -  Not pregnant and not nursing, because this study involves investigational agents whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown. Therefore, for women of childbearing potential only, a negative pregnancy
             test done =< 14 days prior to registration is required (Note: for abemaciclib arm,
             pregnancy test is required =< 7 days prior to registration).

          -  No known leptomeningeal involvement.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

          -  Adequate organ function.

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3.

          -  Platelet count >= 100,000/mm^3.

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's
             disease.

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
             limit of normal (ULN).

          -  Creatinine =< 1.5 mg/dL OR calculated (Calc.) creatinine clearance > 45 mL/min.

          -  No uncontrolled medical comorbidities per investigator discretion (e.g. interstitial
             lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major
             surgical resection involving the stomach or small bowel, or preexisting Crohn's
             disease or ulcerative colitis or a preexisting chronic condition resulting in baseline
             Grade 2 or higher diarrhea).

          -  Concurrent radiation to symptomatic non-target sites within neural axis is allowed
             (provided there is at least one untreated target lesion).

          -  Concurrent systemic corticosteroids are allowed if stable dose of dexamethasone for 7
             days prior to registration. Baseline doses and changes in steroid dosing will be
             captured.

          -  No concurrent administration of anticancer therapies (except for endocrine therapy or
             continuation of hormonal therapy or trastuzumab in breast cancer patients). No
             chemotherapy, targeted therapy or immunotherapy within 14 days prior to entering the
             study (Note: For abemaciclib arm, a 21-day chemotherapy washout is required).

          -  Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this
             study. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to
             registration on the study.

          -  Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients
             must discontinue the drug 14 days prior to the start of study treatment.

        ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR GDC-0084 ARM

          -  Urine protein to creatinine (UPC) ratio < 1 or urine protein =< 1.

          -  Recent acute myocardial infarction in the last 6 months or current angina pectoris are
             excluded. Patients with symptomatic bradycardia should have an electrocardiogram at
             baseline. If QT interval > 470 msec, the patient is excluded.

          -  Patients with uncontrolled type I or II diabetes mellitus should be excluded.
             Uncontrolled diabetes is defined as glycosylated hemoglobin (HbA1c) > 9% in addition
             to fasting glucose > 140 mg/dL on at least 2 occasions within 14 days prior to
             registration.

        ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ENTRECTINIB ARM

        • Concurrent use of H2 receptor antagonists, receptor antagonists, proton pump inhibitors
        (PPIs), and/or antacids are prohibited.

        ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ABEMACICLIB ARM

          -  Hemoglobin >= g/dL. Patients may receive erythrocyte transfusions to achieve this
             hemoglobin level at the discretion of the investigator. Initial treatment must not
             begin earlier than the day after the erythrocyte transfusion.

          -  Patients who received chemotherapy must have recovered (Common Terminology Criteria
             for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for
             residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout
             period of at least 21 days is required between last chemotherapy dose and registration
             (provided the patient did not receive radiotherapy).

          -  Patients who received adjuvant radiotherapy must have completed and fully recovered
             from the acute effects of radiotherapy. A washout period of at least 14 days is
             required between end of radiotherapy and registration.

          -  For females of childbearing potential: A female of childbearing potential, must have a
             negative serum pregnancy test within 7 days prior to registration and agree to use a
             highly effective contraception method during the treatment period and for 3 weeks
             following the last dose of abemaciclib. Contraceptive methods may include an
             intrauterine device [IUD] or barrier method. If condoms are used as a barrier method,
             a spermicidal agent should be added as a double barrier protection. Cases of pregnancy
             that occur during maternal exposures to abemaciclib should be reported. If a patient
             or spouse/partner is determined to be pregnant following abemaciclib initiation, she
             must discontinue treatment immediately. Data on fetal outcome and breast-feeding are
             to be collected for regulatory reporting and drug safety evaluation.

          -  Patients with active bacterial infection (requiring intravenous [IV] antibiotics at
             time of initiating study treatment), fungal infection, or detectable viral infection
             (such as known human immunodeficiency virus positivity or with known active hepatitis
             B or C [for example, hepatitis B surface antigen positive] are excluded. Screening is
             not required for enrollment.

          -  Patients with personal history of any of the following conditions: syncope of
             cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
             not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
             cardiac arrest, are excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate in the brain
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed per Response Assessment in Neuro-Oncology (RANO) criteria for brain metastases. The response rate is defined as the number of patients who have achieved complete response (CR) or partial response (PR) per RANO for brain metastases criteria during treatment with CDK, PI3K, or NTRK/ROS inhibitors divided by total number of evaluable patients. The response rate and associated exact confidence interval will be estimated within each cohort defined by the targeted agent and histology.

Secondary Outcome Measures

Measure:Systemic response for extracranial disease
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Will be estimated using the systemic response rate (SRR) - where SRR is defined as the number of evaluable patients achieving a response (PR or CR per RECIST 1.1) during treatment with study therapy divided by the total number of evaluable patients. Point estimates will be generated for systemic response rates within each cohort with corresponding 95% binomial confidence intervals.
Measure:Clinical benefit rate for central nervous system (CNS)
Time Frame:Up to 5 years
Safety Issue:
Description:Evaluated by Response Assessment in Neuro-Oncology (RANO) criteria. Will be estimated as the number of evaluable patients achieving stable disease (SD), partial response (PR), or complete response (CR) as their best objective response during treatment with protocol therapy divided by the total number of evaluable patients. Point estimates will be generated for clinical benefit rates within each cohort with corresponding 95% binomial confidence intervals.
Measure:Clinical benefit rate for extracranial disease
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Will be estimated as the number of evaluable patients achieving stable disease (SD), partial response (PR), or complete response (CR) as their best objective response (per RECIST for extracranial disease) during treatment with protocol therapy divided by the total number of evaluable patients. Point estimates will be generated for clinical benefit rates within each cohort with corresponding 95% binomial confidence intervals.
Measure:Duration of response for brain metastases
Time Frame:From the time measurement criteria are met for CR or PR for brain metastases until the first date that progressive CNS disease or death is documented, assessed up to 5 years
Safety Issue:
Description:Duration of response for brain metastases is defined for all evaluable patients who have achieved a confirmed response as the time from the date at which the patient's objective status for brain metastases is first noted to be a CR or PR (per Response Assessment in Neuro-Oncology [RANO] for brain metastases) to the date of the earliest progressive CNS disease is documented or death. The median and 95% confidence intervals will be estimated using the Kaplan-Meier estimator. No formal comparison will be made among the cohorts.
Measure:Duration of response for extracranial disease
Time Frame:From the time measurement criteria are met for CR or PR for extracranial disease until the first date that progressive disease for extracranial disease or death is documented, assessed up to 5 years
Safety Issue:
Description:Duration of response for extracranial disease is defined for all evaluable patients who have achieved a confirmed response as the time from the date at which the patient's objective status for extranial disease is first noted to be a CR or PR (per RECIST1.1) to the date of the earliest progression (PD) for extracranial disease is documented or death. The median and 95% confidence intervals will be estimated using the Kaplan-Meier estimator. No formal comparison will be made among the cohorts.
Measure:Progression-free survival (PFS) - intracranial
Time Frame:From first day of study treatment to the earliest date documentation of intracranial disease progression or death from any cause, assessed up to 5 years
Safety Issue:
Description:Intracranial PFS is defined as the time from the first day of study treatment to the earliest date of intracranial disease progression (per RANO for brain metastases) or death from any cause, whichever comes first. The median and 95% confidence intervals will be estimated using the Kaplan-Meier estimator. No formal comparison will be made among the cohorts.
Measure:Progression-free survival (PFS) - extracranial
Time Frame:From the first day of study treatment to the earliest date of documentation of extracranial disease progression or death from any cause, assessed up to 5 years
Safety Issue:
Description:Extracranial PFS is defined as the time from the first day of study treatment to the earliest date of extracranial disease progression (per RECIST1.1) or death from any cause, whichever comes first. The median and 95% confidence intervals will be estimated using the Kaplan-Meier estimator. No formal comparison will be made among the cohorts.
Measure:Site of first progression
Time Frame:Up to 24 months
Safety Issue:
Description:The site of first progression will be estimated descriptively within each cohort within 12 and 24 months after starting protocol treatment. The first progression is defined as the first documented central nervous system (CNS) progression per Response Assessment in Neuro-Oncology (RANO) or extracranial progression per Response Evaluation Criteria in Solid Tumors (RECIST), whichever occurs first. The percentage of extracranial progression at first progression within 12 and 24 months after starting protocol treatment will be estimated as number of patients who experience the first progression which is extracranial progression divided by number of patients who are still at risk up to 12 and 24 months, respectively.
Measure:Overall survival
Time Frame:From the first day of study treatment to death due to any cause, assessed up to 5 years
Safety Issue:
Description:Overall survival is defined as the time from the first day of study treatment to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. No formal comparison will be made among the cohorts.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, toxicity is defined as adverse events that are classified as possibly, probably, or definitely related to study treatment. Toxicities will be evaluated via the ordinal CTCAE standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by patient and treatment cohort will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of the analysis. No formal comparison will be made among the cohorts.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Alliance for Clinical Trials in Oncology

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