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Genetic Testing in Guiding Treatment for Patients With Brain Metastases

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03994796
Recruitment Status : Recruiting
First Posted : June 21, 2019
Last Update Posted : June 7, 2022
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Genentech, Inc.
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Study Description
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Brief Summary:
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, paxalisib, 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.

Condition or disease Intervention/treatment Phase
CDK Gene Mutation Metastatic Malignant Neoplasm in the Brain Metastatic Malignant Solid Neoplasm NTRK Family Gene Mutation PI3K Gene Mutation ROS1 Gene Mutation Drug: Abemaciclib Drug: PI3K Inhibitor paxalisib Drug: Entrectinib Phase 2

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Genomically-Guided Treatment Trial in Brain Metastases
Actual Study Start Date : August 15, 2019
Estimated Primary Completion Date : October 2024
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Genetic Testing
Drug Information available for: Entrectinib

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (CDK gene mutation)
Patients receive abemaciclib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
 Drug: Abemaciclib
Given PO
Experimental: Arm II (PI3K gene mutation)
Patients receive PI3K inhibitor paxalisib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
 Drug: PI3K Inhibitor paxalisib
Given PO
Experimental: 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.
 Drug: Entrectinib
Given PO


Outcome Measures
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Primary Outcome Measures :
  1. Objective response rate in the brain [ Time Frame: Up to 5 years ]
    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 :
  1. Systemic response for extracranial disease [ Time Frame: Up to 5 years ]
    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.

  2. Clinical benefit rate for central nervous system (CNS) [ Time Frame: Up to 5 years ]
    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.

  3. Clinical benefit rate for extracranial disease [ Time Frame: Up to 5 years ]
    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.

  4. 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 ]
    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.

  5. 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 ]
    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.

  6. 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 ]
    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.

  7. 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 ]
    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.

  8. Site of first progression [ Time Frame: Up to 24 months ]
    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.

  9. Overall survival [ Time Frame: From the first day of study treatment to death due to any cause, assessed up to 5 years ]
    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.

  10. Incidence of adverse events [ Time Frame: Up to 5 years ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 parenchymal 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.
    • Progressive measurable lesions after radiation, surgery, or prior systemic therapy
    • 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. For patients with NTRK or ROS1 mutations, entrectinib may be used for newly diagnosed brain metastases.
    • 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 with contrast
  • 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 (regardless of ER/PR status), 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) and/or progesterone receptor (PR)+ HER2-negative breast cancer, patients must have received at least one endocrine therapy in the metastatic setting.
    • Patients who have received prior treatment with any of the targeted treatments on this study are not eligible for that specific treatment arm(s), but could be eligible for other arms (e.g., a patient who has had prior treatment with abemaciclib would not be eligible for the abemaciclib arm, but could be eligible for another arm).
  • Presence of clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K pathway in both a brain metastasis and extracranial site per central review.
  • 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 current diffuse leptomeningeal involvement (diffuse defined as leptomeningeal involvement throughout the CNS axis; if there is documented positive CSF cytology, patient is ineligible).
  • 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. Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted.
  • 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, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], 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)
  • Radiation to symptomatic non-target sites within neural axis is allowed prior to registration without washout (provided there is at least one untreated target lesion for measurement on study and radiation is completed prior to registration).
  • 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 PAXALISIB 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 CRITERION FOR ENTRECTINIB ARM

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

ADDITIONAL REGISTRATION ELIGIBILITY CRITERION 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 registration. 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.
  • Breast cancer patients who have received ribociclib or palbociclib are eligible as long as there is documentation of CDK4/6 pathway alteration on a biopsy or resection at the point of progression post-ribociclib or palbociclib.
  • 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03994796


Contacts
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Contact: Priscilla Brastianos, MD 617-724-1074 pbrastianos@partners.org

Locations
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Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Genentech, Inc.
Investigators
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Study Chair: Priscilla Brastianos, MD Massachusetts General Hospital
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT03994796    
Other Study ID Numbers: A071701
NCI-2019-00744 ( Registry Identifier: NCI Clinical Trial Reporting Program )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: June 21, 2019    Key Record Dates
Last Update Posted: June 7, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
 Central Nervous System Diseases
Nervous System Diseases
Entrectinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action