Ulixertinib and Palbociclib in Treating Patients with Advanced or Refractory Solid Tumors or Metastatic Pancreatic Cancer or Metastatic Melanoma

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information; NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• Age >= 18 years at the time of consent (no upper age limit)
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Tumor eligibility: * Dose escalation cohorts: histologically confirmed advanced solid tumor refractory to standard of care therapy, or for which there is no accepted standard of care * Expansion cohort (at RP2D): metastatic pancreatic cancer patients who have received at least one line of therapy in the metastatic setting * Expansion cohort (at RP2D) for histologically confirmed unresectable stage III or stage IV melanoma with the following additional eligibility requirements: ** Tumors must have undergone molecular profiling using a Clinical Laboratory Improvement Act (CLIA)-certified targeted panel sequencing method (e.g., FoundationOne CDx, Tempus Labs) documenting any of the following genetic aberrations: NRASG12/G13/Q61, KRASG12/G13, HRASG12/G13, any amplifications of the NRAS, KRAS, or HRAS genes. For NF1mutations, we will only enroll patients with loss-of-function NF1mutations and without any BRAFV600 mutations. Loss-of-function NF1 mutations are defined as: non-sense/stop-codon, splicing (16%), micro-deletions (27%), micro-insertions (11%), indels (2%), gross deletions (13%), gross insertions (2%), complex rearrangement (0.6%), gene copy number deletions. In other words, patients bearing NF1-mutant melanomas with missense mutations are not allowed ** Documented disease refractory to at least one PD1/PD-L1 inhibitor, defined as disease progression following at least two infusions of the same drug. Subjects will be considered refractory to PD-1 inhibitor therapy based on any radiographic evidence (MRI, CT, PET, or other modalities, etc.) of disease progression on two separate radiographic scans obtained at least 4 weeks apart. If patients clinically progress rapidly, the confirmatory 4-week whole body CT scans (CT of neck [if applicable], chest/abdomen and pelvis is acceptable) can be withheld after discussion with the Principal Investigator (NOTE: patients who are not eligible to receive anti PD1/PD-L1 therapy due to requirement for systemic steroid therapy >10 mg of prednisone, or its equivalent, may be eligible for this study after discussion by the Principal Investigator provided that their steroid daily dose is between 10-19 mg of prednisone [or its equivalent]) ** Subjects with RAS-mutant and NF1-mutant (no concurrent BRAFV600 mutations) melanoma that have not taken prior immune checkpoint inhibitors will be allowed if they are not eligible to receive prior immune checkpoint inhibitors due to requirement for immunosuppression (iatrogenic or genetic) for other comorbid factors (e.g., COPD, organ transplant, rheumatologic diseases)
• Measurable or non-measurable (but evaluable) disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 for dose escalating cohorts; measurable disease as per RECIST v1.1 required for expansion cohort
• Life expectancy >= 12 weeks
• Recovered from all reversible acute toxic effects of last anti-cancer treatment (other than alopecia) to =< grade 1 or baseline; patients with baseline neuropathy that is =< grade 2 are eligible for enrollment
• Hemoglobin (Hgb) >= 9 g/dL (within 28 days prior to day -6 of ulixertinib)
• Absolute neutrophil count (ANC) >= 1,500 /mm^3 (within 28 days prior to day -6 of ulixertinib)
• Platelets >= 100,000/mm^3 (within 28 days prior to day -6 of ulixertinib)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance >= 60 mL/min using the Cockcroft-Gault formula (within 28 days prior to day -6 of ulixertinib)
• Bilirubin =< 1.5 x ULN (within 28 days prior to day -6 of ulixertinib)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 28 days prior to day -6 of ulixertinib); if tumor involvement of the liver =< 5 x ULN
• Adequate cardiac function; left ventricular ejection fraction (LVEF) > 50% as assessed by ultrasound/echocardiography (ECHO); corrected QT interval (QTc) < 470 ms
• Females of childbearing potential must have a negative serum pregnancy test within 3 days prior to day -6 of ulixertinib; NOTE: females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• Females of childbearing potential and males must be willing to abstain from heterosexual activity or use effective methods of contraception from the time of informed consent until 120 days after treatment discontinuation; acceptable contraception methods can be comprised of an intrauterine device (IUD), vasectomy of a female subject’s male partner, contraceptive rod implanted into the skin, OR use of two of the following: diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive * Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee
• Willing to provide archival tissue (if available) and consent to mandatory pre-treatment liquid biopsy (expansion cohort only) for research purposes only

Exclusion Criteria

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• Treatment with any cancer-directed therapy (chemotherapy, hormonal therapy, biologic, radiation or immunotherapy, etc.) or investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to day -6 of ulixertinib
• A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
• Major surgery within 28 days prior to day -6 of ulixertinib
• Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, oranges, pummelos, and exotic citrus fruits from 7 days prior day -6 of ulixertinib and during the entire study
• Intake of any herbal preparations or medications (including, but not limited to, Saint John’s wort and ginkgo biloba) and dietary supplements within 7 days prior to day -6 of ulixertinib
• Unable or unwilling to discontinue use of any drug known to be a strong inhibitor of CYP3A4, CYP1A2 or CYP2D6 or strong inducer of CYP3A4 (prohibited inducers and inhibitors must be discontinued within 2 weeks prior to day -6 of ulixertinib
• Unable or unwilling to discontinue use of any drug known to be a sensitive CYP3A4 substrate with a narrow therapeutic index
• Metastases in the central nervous system (CNS) are allowed for patients enrolling to the RAS-mutated and NF1-mutant melanoma cohorts, provided that: * No leptomeningeal disease is present, * Intracranial disease is controlled by prior therapies as evidenced by brain imaging 2 weeks post treatment indicating no new intracranial disease, * Stable or decreasing dose of steroids provided patient on =< 20mg of prednisone or its equivalent daily
• Any important medical illness or abnormal laboratory finding that would increase the risk of participating in the study (based on the investigator’s judgment)
• Psychiatric illness/social situations that would limit compliance with study requirements
• Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include the following: * Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of the cervix * Prior history of prostate cancer provided the patient is not undergoing active systemic treatment other than hormonal therapy and has documented prostate specific antigen (PSA) that is undetectable (< 0.2 ng/mL) * Papillary thyroid cancer, even if patients may have just completed thyroidectomy within the last year (12 months), have not received adjuvant radioactive iodine therapy, and were only recently diagnosed with asymptomatic papillary thyroid cancer, no positive cervical lymph nodes on the scans and that their surgery is pending * Chronic lymphocytic leukemia (CLL) provided patient has isolated lymphocytosis (Rai stage 0) and does not require systemic treatment (for “B” symptoms, Richter’s transformation, lymphocyte doubling time [< 6 months], lymphadenopathy or hepatosplenomegaly) * Lymphoma, hairy-cell leukemia, or myelodysplasia, provided that patient is not on active systemic treatment and is in complete remission, as evidenced by positron emission tomography/computed tomography (PET/CT) scans and bone marrow biopsies for at least 3 months * History of any other malignancy provided patient has completed therapy and is free of disease for >= 2 years. If patient had other malignancy within the last 2 years from which he, or she, may have been completely cured by surgery alone, he may be considered to be enrolled on condition that the risk of development of distant metastatic disease based on the most recent American Joint Committee on Cancer (AJCC) staging system is less than 30%
• Impaired gastrointestinal (GI) function or GI disease that may significantly impair absorption (e.g., inflammatory bowel disease [IBD], malabsorption syndrome, small bowel resection, uncontrolled vomiting or diarrhea)
• Inability to swallow oral medications
• Patients with autoimmune disease requiring systemic corticosteroid treatment are allowed on condition that they do not receive more than 20mg of daily dose methylprednisolone, or its equivalent. This includes patients who are being treated with corticosteroids or other immunomodulatory treatments due to autoimmunities secondary to PD1 inhibitors or ipilimumab