UAB - Center for Clinical and Translational Science

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Patient must have enrolled onto EAY191 and must have been given a treatment
assignment to ComboMATCH to EAY191-A3 based on the presence of an actionable
mutation as defined in EAY191.

- GENERAL ComboMATCH EAY191 REGISTRATION INCLUSION CRITERIA:

- Patients must be enrolled on the EAY191 registration study and be assigned to this
protocol by EAY191

- Patients must have KRAS/NRAS/HRAS or RAF mutations or rare RAF fusions as determined
by the ComboMATCH screening assessment

- Patients with low grade serous ovarian cancer who have progressed on a prior MEK
inhibitor are not required to have a KRAS/NRAS/HRAS or BRAF alteration

- Patients must not have a BRAF V600E alteration as determined by the ComboMATCH
screening assessment

- Patients with a tumor harboring KRAS G12C mutation will be eligible either after
they have received a G12C inhibitor or can be enrolled if they do not meet
eligibility for a G12C inhibitor. However, patients with tumors harboring KRAS G12C
mutation will be prioritized for a G12C inhibitor-based substudy if eligible

- Patients must have disease that can be safely biopsied and agree to a pre-treatment
biopsy or have archival tissue available from within 12 months prior to registration

- Please note the current actionable marker of interest (aMOI)/actionable alteration
list for this treatment trial can be found on the Cancer Trials Support Unit (CTSU)
website

- EAY191-A3 IELIGIBILITY CRITERIA:

- Histologically confirmed cancer for each cohort for which curable treatment
modalities are not an option. Rare BRAF fusions and non-BRAF V600E aMOIs are
acceptable. RB1 mutations or two copy RB1 deletions are excluded

- Tumor tissue must be available:

- Adequate archival tumor specimen (obtained within 12 months of EAY191
registration which has not had a Response Evaluation Criteria in Solid Tumors
(RECIST) response, complete response (CR) or partial response (PR), to any
intervening therapy after collection of the tissue) must be available with
formalin-fixed paraffin-embedded tumor tissue (blocks or slides) OR

- Consent to a new tumor tissue biopsy which is not a representative target
lesion. This lesion must be amenable to a minimal risk image-guided or direct
vision biopsy A new biopsy is preferred but is not required for enrollment in
EAY191-A3 if sufficient archival tissue is available as described above

- Measurable disease per RECIST 1.1. Of note, in the case when a baseline biopsy is
done after scans are obtained, a lesion separate from one that is biopsied needs to
be measurable per RECIST 1.1. All radiologic studies must be performed within 28
days prior to registration

- COHORT 1: Low grade serous ovarian cancer with KRAS, NRAS non-BRAF V600E aMOIs or
rare RAF fusions are acceptable

- COHORT 1: No prior MEK inhibitor or CDK4/6 inhibitor therapy

- COHORT 1: Any number of prior therapies permitted

- COHORT 1: No major surgery within 4 weeks (excluding placement of vascular access),
minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks prior to
registration

- COHORT 1: No prior cancer-directed therapy within 28 days prior to registration.
Patients may have received cancer-directed hormonal therapy up to 14 days prior to
registration

- COHORT 2: Low grade serous ovarian cancer

- COHORT 2: Prior progression of disease on a MEK inhibitor (prior binimetinib
permitted)

- COHORT 2: If patient has previously received binimetinib, they cannot have required
dose reduction or discontinuation of binimetinib due to adverse events

- COHORT 2: No prior receipt of a CDK4/6 inhibitor

- COHORT 2: No major surgery within 4 weeks (excluding placement of vascular access),
minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks prior to
registration

- COHORT 2: No prior cancer-directed therapy within 28 days prior to registration.
Patients may have received cancer-directed hormonal therapy up to 14 days prior to
registration

- COHORT 3: Pancreatic cancer with KRAS/NRAS/HRAS, non-BRAF V600E aMOIs or rare RAF
fusions are acceptable

- COHORT 3: No prior MEK inhibitor (MEKi) and CDK4/6i therapy

- COHORT 3: Progression after at least one line of prior therapy as long as there is
no standard therapy available or acceptable to patients that is thought to be of
benefit

- COHORT 3: Any number of prior therapies are permitted

- COHORT 3: No major surgery within 4 weeks (excluding placement of vascular access),
minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks prior to
registration

- COHORT 3: No prior cancer-directed therapy within 28 days prior to registration.
Patients may have received cancer-directed hormonal therapy up to 14 days prior to
registration

- COHORT 4: KRAS/NRAS/HRAS non-BRAF V600E aMOIs or rare RAF fusions are acceptable

- COHORT 4: No prior MEKi and CDK4/6i therapy and progression after at least one line
of prior therapy, as long as there is no standard therapy available or acceptable to
patients that is thought to be of benefit

- COHORT 4: Any number of prior therapies are permitted

- COHORT 4: No more than 6 patients with a given tumor type allowed in this cohort

- COHORT 4: Any tumor type, except: LGSOC/NSCLC/CRC/pancreatic/melanoma

- COHORT 4: No major surgery within 4 weeks (excluding placement of vascular access),
minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks prior to
registration

- COHORT 4: No prior cancer-directed therapy within 28 days prior to registration.
Patients may have received cancer-directed hormonal therapy up to 14 days prior to
registration

- 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 =< 7 days prior to registration is required

- Age >= 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status < 2

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

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

- Hemoglobin > 9 g/dL

- Creatinine =< 1.5 x upper limit of normal (ULN) or calculated (calc.) creatinine
clearance >= 30 mL/min as calculated by the Cockcroft-Gault formula

- Total bilirubin =< 1.5 x upper limit of normal (ULN). Patients with Gilbert syndrome
may enroll if total bilirubin (bili) < 3 mg/dL (51 micromole/L)

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

- Creatine phosphokinase (CPK) =< 2.5 x ULN

- Patients must be able to swallow oral formulations of the agents

- No history of interstitial lung disease. No history of idiopathic pulmonary
fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced
pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on
screening chest computed tomography (CT) scan

- Patients should not have history of bowel perforation or intestinal fistulas in the
last 6 months

- No patients with the inability to swallow oral medications or impaired
gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease

- No active skin disorder that has required systemic therapy within the past 1 year

- No history of rhabdomyolysis

- No concurrent ocular disorders including:

- Subjects with history of glaucoma, history of retinal vein occlusion (RVO),
predisposing factors for RVO, including uncontrolled hypertension, uncontrolled
diabetes

- Subject with history of retinal pathology or evidence of visible retinal
pathology that is considered a risk factor for RVO, intraocular pressure > 21
mm Hg as measured by tonometry, or other significant ocular pathology, such as
anatomical abnormalities that increase the risk for RVO

- Subjects with a history of corneal erosion (instability of corneal epithelium),
corneal degeneration, active or recurrent keratitis, and other forms of serious
ocular surface inflammatory conditions

- No patients with a history of hypersensitivity to any of the study drug(s)

- No prior allogeneic stem cell or solid organ transplantation

- Central nervous system (CNS) metastases must have been treated with local therapy
(surgery, radiation, ablation) and patient off of systemic steroids, and brain
metastases stable for at least 1 month

- No residual Common Terminology Criteria for Adverse Events (CTCAE) >= grade 2
toxicity from any prior anticancer therapy, with the exception of grade 2 alopecia

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated

- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load

- Patients whose left ventricular ejection fraction (LVEF) has been evaluated by
echocardiography (ECHO)/multigated acquisition scan (MUGA) are excluded if the most
recent exam shows an LVEF < 50%

- Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on
this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 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

- No exposure to P-glycoprotein (P-gp) inhibitors or inducers within 14 days prior to
the first dose and during the course of therapy

- Patients treated with Cohort 1 control treatment binimetinib who experience disease
progression may elect to migrate to cohort 2 and receive combination treatment with
palbociclib and binimetinib. Patients who choose to do so must meet laboratory
values and performance status requirements as above and must be begin treatment
within 21 days. For patients who migrate from cohort 1 to cohort 2, the 28-day
window restricting prior anti-cancer directed therapies does not apply to prior
binimetinib. A new biopsy will not be required for migration, but the optional
biopsy at disease progression should be encouraged