Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

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. Similarly, for patients with
KRAS G12C mutations, MRTX849 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, KRAS G12C 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 for the CDK, PI3K and NTRK arms
(diffuse defined as leptomeningeal involvement throughout the CNS axis).Patients with
focal leptomeningeal disease, with or without documented positive CSF cytology, are
eligible.

- 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 except
for patients in the adagrasib (MRTX849) (KRAS G12C) arm. For this arm, patients must
have creatinine clearance ≥60 mL/min or glomerular filtration rate ≥60 mL/min/1.73m2
calculated using a validated prediction equation (e.g., Cockcroft-Gault, MDRD, or
24-hour urine CrCl).

- 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 for the PI3K
and CDK inhibitor arms). . 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 or 5 or
more half-lives 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.

ADDITIONAL REGISTRATION ELIGIBILITY CRITERION FOR ADAGRASIB (MRTX849) ARM

- Hemoglobin ≥9.0 g/dL. Note: Transfusions will be allowed to achieve this provided the
patient has not received more than 2 units of red blood cells in the prior 4 weeks.

- Any of the following cardiovascular abnormalities within 6 months of study entry are
excluded: symptomatic or uncontrolled atrial fibrillation, unstable angina pectoris or
myocardial infarction, CHF ≥ NYHA Class 3, stroke or transient ischemic attack.

- Ongoing need for medication known to cause prolonged QTc interval or that are
substrates of CYP3A4 with narrow therapeutic index that cannot be switched to
alternative treatment prior to study entry is excluded.

- Prolonged QTc interval >480 milliseconds or family history or medical history of Long
QT syndrome is excluded.•

- Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or
C infection is excluded. Screening is not required for enrollment. Note that the
following are permitted:

- Patients treated for hepatitis C (HCV) with no detectable viral load;

- Patients treated for HIV with no detectable viral load for at least 1 month prior
to randomization while on a stable regimen of agents that are not strong
inhibitors of CYP3A4; and

- Patients with hepatitis B (HBV) receiving prophylaxis against reactivation of
hepatitis B (either [HBsAg-positive with normal ALT and HBV DNA <2,000 IU/mL or
<10,000 copies/mL] or [HBsAg-negative and anti-HBc positive]).

- History of intestinal disease or major gastric surgery likely to alter absorption of
study treatment or inability to swallow oral medications is excluded.

- Recovery from the adverse effects of prior therapy to baseline or Grade 1 (any grade
alopecia and Grade ≤2 peripheral neuropathy are eligible).

- For females of childbearing potential. It is not known whether MRTX849 presents a risk
to the embryo or the fetus; however, based on the mechanism of action (KRAS G12C
inhibition), effects on the reproductive system are not unexpected. MRTX849 is
contraindicated in women who are pregnant or lactating. Women of childbearing
potential and men receiving MRTX849 who are sexually active must employ an effective
method of contraception throughout their period of treatment and for 6 months after
their last treatment with MRTX849.