Genetic Testing in Guiding Treatment for Patients With Brain Metastases
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.
- CDK Gene Mutation
- Metastatic Malignant Neoplasm in the Brain
- Metastatic Malignant Solid Neoplasm
- NTRK Family Gene Mutation
- PI3K Gene Mutation
- ROS1 Gene Mutation
- Eligible Ages
- Over 18 Years
- Eligible Genders
- Accepts Healthy Volunteers
PRE-REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS) • Tissue available for biomarker
testing (any brain metastasis tissue and extracranial site from any prior resection or
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
- 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
- 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
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.
- Phase 2
- Study Type
- Intervention Model
- Parallel Assignment
- Primary Purpose
- None (Open Label)
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.||
Arm II (PI3K gene mutation)
|Patients 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.||
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.||
- Alliance for Clinical Trials in Oncology
Study ContactPriscilla Brastianos, MD
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).
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.