Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal healthinformation. NOTE: HIPAA authorization may be included in the informed consent orobtained separately.

2. Age ≥ 18 years at the time of consent (no upper age limit)

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2

4. Tumor Eligibility:

5. Dose escalation cohorts: Histologically confirmed advanced solid tumorrefractory to standard of care therapy, or for which there is no acceptedstandard of care

6. Expansion cohort (at RP2D): metastatic pancreatic cancer or malign melanomapatients who have received at least one line of therapy in the metastaticsetting

7. Expansion cohort (at RP2D) for histologically confirmed unresectable stage IIIor stage IV melanoma with the following additional eligibility requirements:

• Tumors molecular profiling genetic aberrations: NRASG12/G13/Q61,KRASG12/G13, HRASG12/G13, any amplifications of the NRAS, KRAS, or HRASgenes. For NF1 mutations, subjects with loss-of-function NF1mutations andwithout any BRAFV600 mutations will be enrolled.
• Documented disease refractory to at least one PD1/PD-L1 inhibitor, definedas disease progression following at least two infusions of the same drug.
• Subjects with RAS-mutant and NF1-mutant (no concurrent BRAFV600 mutations)melanoma that have not taken prior immune checkpoint inhibitors will beallowed if they are not eligible to receive prior immune checkpointinhibitors due to requirement for immunosuppression

5. Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 fordose escalating cohorts; measurable disease as per RECIST v1.1 required forexpansion cohort

6. Life expectancy ≥ 12 weeks

7. Recovered from all reversible acute toxic effects of last anti-cancer treatment (other than alopecia) to ≤Grade 1 or baseline. Patients with baseline neuropathythat is ≤ grade 2 are eligible for enrollment.

8. Demonstrate adequate organ function as defined in the table below; all screeninglabs to be obtained within 28 days prior to day -6 of ulixertinib Hemoglobin (Hgb) ≥ 9 g/dL Absolute Neutrophil Count (ANC) ≥ 1,500 /mm3 Platelets ≥ 100,000/mm3 Creatinine ≤1.5 x upper limit of normal (ULN) or Calculated creatinineclearance ≥ 60 mL/min using the Cockcroft-Gault formula Bilirubin ≤ 1.5 x ULNAspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN; iftumor involvement of the liver ≤ 5 x ULN

*Note: Hematology and other lab parameters that are ≤ grade 2 but still meet thecriteria for study entry are allowed. Furthermore, changes in laboratory parametersduring the study should not be considered adverse events unless they meet thecriteria for dose modification(s) of study medication outlined by the protocoland/or worsen from baseline during therapy.

9. Adequate cardiac function; left ventricular ejection fraction (LVEF) >50% asassessed by ultrasound/echocardiography (ECHO); corrected QT interval (QTc) <470ms

10. Females of childbearing potential must have a negative serum pregnancy test within 3days prior to day -6 of ulixertinib. NOTE: Females are considered of childbearingpotential unless they are surgically sterile (have undergone a hysterectomy,bilateral tubal ligation, or bilateral oophorectomy) or they are naturallypostmenopausal for at least 12 consecutive months

11. Females of childbearing potential and males must be willing to abstain fromheterosexual activity* or use effective methods of contraception from the time ofinformed consent until 120 days after treatment discontinuation. Acceptablecontraception methods can be comprised of an intrauterine device (IUD), vasectomy ofa female subject's male partner, contraceptive rod implanted into the skin, OR useof two of the following: diaphragm with spermicide (cannot be used in conjunctionwith cervical cap/spermicide), cervical cap with spermicide (nulliparous womenonly), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive.] *Abstinence is acceptable ifthis is the usual lifestyle and preferred contraception for the subject.

12. Subject is willing and able to comply with study procedures based on the judgment ofthe investigator or protocol designee.

13. Willing to provide archival tissue (if available) and consent to mandatorypretreatment and on-treatment biopsy as deemed safe by the treating physician (expansion cohort only) for research purposes only.

Exclusion Criteria:

1. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on the study)

2. Treatment with any cancer-directed therapy (chemotherapy, hormonal therapy,biologic, radiation or immunotherapy, etc.) or investigational drug within 28 daysor 5 half-lives (whichever is shorter) prior to day -6 of ulixertinib

3. A history or current evidence/risk of retinal vein occlusion (RVO) or central serousretinopathy (CSR).

4. Major surgery within 28 days prior to day -6 of ulixertinib

5. Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, oranges,pummelos, and exotic citrus fruits from 7 days prior to day -6 of ulixertinib andduring the entire study due to potential CYP3A4 interaction with the studymedications.

6. 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 today -6 of ulixertinib due to potential CYP3A4 interaction with the study medications

7. Unable or unwilling to discontinue use of any drug known to be a strong inhibitor ofCYP3A4, CYP1A2 or CYP2D6 or strong inducer of CYP3A4 (prohibited inducers andinhibitors must be discontinued within 2 weeks prior to day -6 of ulixertinib; seesection 10.3 Appendix C)

8. Unable or unwilling to discontinue use of any drug known to be a sensitive CYP3A4substrate with a narrow therapeutic index as defined in the protocol.

9. Central nervous system metastases are allowed only for patients RAS-mutated andNF1-mutant melanoma cohorts (1) no leptomeningeal disease is present, (2)Intracranial disease is controlled by prior therapies, as evidenced by brain imaging 2 weeks post treatment indicating no new intracranial disease, (3) stable ordecreasing dose of steroids is provided patient on ≤ 20mg of prednisone or it'sequivalent daily.

10. Any important medical illness or abnormal laboratory finding that would increase therisk of participating in the study (based on the investigator's judgment)

11. Psychiatric illness/social situations that would limit compliance with studyrequirements

12. Has a known additional malignancy that is active and/or progressive requiringtreatment; non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma insitu of the cervix, prior history of prostate cancer provided the patient is notundergoing active systemic treatment other than hormonal therapy and has documentedPSA that is undetectable (<0.2ng/mL), prostate carcinoma in remission and did notreceive systemic treatment, papillary thyroid cancer did not receive adjuvantradioactive iodine, Stage Rai stage 0 Chronic lymphocytic leukemia does not requiresystemic treatment, lymphoma, hairy-cell leukemia, or myelodysplasia is in completeremission and or other cancer for which the patient has been disease-free for atleast two years. Has a known additional malignancy that is active and/or progressive requiringtreatment.

13. Impaired 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)

14. Inability to swallow oral medications

15. Patients with autoimmune diseases that require systemic corticosteroid treatment.