Ulixertinib and Palbociclib in Treating Patients with Advanced or Refractory Solid Tumors or Metastatic Pancreatic Cancer
- 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
- 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
- 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 and on-treatment biopsy as deemed safe by the treating physician (expansion cohort only) for research purposes only
- 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
- Known metastases of the central nervous system (CNS)
- 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 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
- 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
I. To estimate the maximum tolerated dose (MTD) and determine the recommended phase 2 dose (RP2D) of ulixertinib in combination with palbociclib in patients with advanced solid tumors. (Dose escalation)
II. To estimate overall survival (OS) at 6 months after treatment with the RP2D of ulixertinib in combination with palbociclib in an expansion cohort of patients with metastatic pancreatic cancer. (Expansion cohort)
I. To characterize the safety profile of ulixertinib in combination with palbociclib.
II. To estimate objective response rate (ORR) after treatment with ulixertinib in combination with palbociclib.
III. To estimate progression-free survival (PFS) after treatment with ulixertinib in combination with palbociclib.
IV. To estimate OS after treatment with ulixertinib in combination with palbociclib (expansion cohort only).
V. To estimate CA19-9 response after treatment with ulixertinib in combination with palbociclib (expansion cohort only).
I. To characterize the pharmacokinetics (PK) profile of ulixertinib when administered alone and to characterize the PK profile of both ulixertinib and palbociclib when taken concomitantly.
II. To explore differential kinome activation before and after the first cycle of treatment with ulixertinib in combination with palbociclib in patients with metastatic pancreatic cancer in the expansion cohort.
III. To correlate pancreatic cancer subtypes via ribonucleic acid sequencing (RNAseq) with clinical outcomes from archived samples in patients with metastatic pancreatic cancer in the expansion cohort.
IV. To evaluate protein expression to determine potential predictive biomarkers of response and resistance to treatment with ulixertinib in combination with palbociclib in patients with metastatic pancreatic cancer in the expansion cohort.
OUTLINE: This is a dose-escalation study.
Patients receive ulixertinib orally (PO) twice daily (BID) on days 1-28 and palbociclib PO once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years.
Trial Phase Phase I
Trial Type Treatment
UNC Lineberger Comprehensive Cancer Center
Autumn Jackson McRee
- Primary ID LCCC1736
- Secondary IDs NCI-2017-02445
- Clinicaltrials.gov ID NCT03454035