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 paxalisib 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.
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.
