Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors
Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors
This phase I study is designed to establish the safety, maximally tolerated dose (MTD) and
 recommended phase II dose (RP2D) of the ERK inhibitor ulixertinib (BVD-523) when combined
 with the CDK4/6 inhibitor palbociclib.
This phase I study is designed to establish the safety, maximally tolerated dose (MTD) and
 recommended phase II dose (RP2D) of the ERK inhibitor ulixertinib (BVD-523) when combined
 with the CDK4/6 inhibitor palbociclib.

 Up to a maximum of 30 adult patients will be enrolled in the 5 possible dose escalation
 cohorts. These patients will have histologically confirmed advanced solid tumor disease
 refractory to standard of care therapy, or for which there is no accepted standard of care.

 Finally, 15 adult patients will be treated at the recommended phase II dose (RP2D) in the
 expansion cohort involving metastatic pancreatic cancer patients who have received at least
 one line of therapy in the metastatic setting.
Inclusion Criteria:

 1. Written informed consent and HIPAA authorization for release of personal health
 information. NOTE: HIPAA authorization may be included in the informed consent or
 obtained separately.

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

 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 (see Section 10.1
 Appendix A)

 4. Tumor Eligibility:

 1. Dose escalation cohorts: Histologically confirmed advanced solid tumor refractory
 to standard of care therapy, or for which there is no accepted standard of care

 2. Expansion cohort (at RP2D): metastatic pancreatic cancer patients who have
 received at least one line of therapy in the metastatic setting

 5. Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 for dose
 escalating cohorts; measurable disease as per RECIST v1.1 required for expansion
 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 neuropathy that is ≤
 grade 2 are eligible for enrollment.

 8. Demonstrate adequate organ function as defined in the table below; all screening labs
 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 creatinine
 clearance ≥ 60 mL/min using the Cockcroft-Gault formula Bilirubin ≤ 1.5 x ULN Aspartate
 aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN; if tumor involvement
 of the liver ≤ 5 x ULN

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

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

 11. 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

 12. 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.

 13. Subject is willing and able to comply with study procedures based on the judgement
 of the investigator or protocol designee.

 14. Willing to provide archival tissue (if available) and consent to mandatory
 pretreatment 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 while the
 mother is being treated on study)

 2. 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

 3. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous
 retinopathy (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 day -6 of ulixertinib and during
 the entire study due to potential CYP3A4 interaction with the study medications.

 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 to day -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 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; see
 section 10.3 Appendix C)

 8. Unable or unwilling to discontinue use of any drug known to be a sensitive CYP3A4
 substrate with a narrow therapeutic index; see section 10.3 Appendix C

 9. Known metastases of the central nervous system (CNS)

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

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

 12. Has a known additional malignancy that is active and/or progressive requiring
 treatment; exceptions include basal cell or squamous cell skin cancer, in situ
 cervical or bladder cancer, or other cancer for which the patient has been disease
 free for at least five years

 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