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. 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 or malign melanoma
patients who have received at least one line of therapy in the metastatic setting. 3. Expansion cohort (at RP2D) for histologically confirmed unresectable stage III or
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 HRAS
genes.
For NF1 mutations, subjects with loss-of-function NF1mutations and
without any BRAFV600 mutations will be enrolled.
- - Documented disease refractory to at least one PD1/PD-L1 inhibitor, defined
as disease progression following at least two infusions of the same drug.
- - Patients must have previously received treatment with ipilimumab.
- - 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.
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 the
criteria for study entry are allowed. Furthermore, changes in laboratory parameters
during the study should not be considered adverse events unless they meet the criteria
for dose modification(s) of study medication outlined by the protocol and/or worsen
from baseline during therapy.
9. Adequate cardiac function; left ventricular ejection fraction (LVEF) >50% as assessed
by ultrasound/echocardiography (ECHO); corrected QT interval (QTc) <470ms. 110. 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 childbearing 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. 11. 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.
12. Subject is willing and able to comply with study procedures based on the judgment of
the investigator or protocol designee.
13. 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 the 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 to 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 as defined in the protocol.
9. Central nervous system metastases are allowed only for patients enrolling to the
PD1-inhibitor refractory RAS-mutated melanoma cohort provided that
- (1) no
leptomeningeal disease is present, (2) intracranial disease is controlled by prior
local therapies (craniotomy, stereotactic radiosurgery, whole brain irradiation), as
evidenced by brain MRI 4 weeks post-treatment indicating no new intracranial disease,
and (3) stable or decreasing dose of steroids is provided patient on ≤ 20mg of
prednisone or it's equivalent daily.
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 non-melanoma skin cancers, non-invasive bladder cancer, and
carcinoma in situ of the cervix, prostate carcinoma in remission and did not receive
systemic treatment, Papillary thyroid cancer did not receive adjuvant radioactive
iodine, Stage Rai stage 0 Chronic lymphocytic leukemia does not require systemic
treatment, Lymphoma, hairy-cell leukemia, or myelodysplasia is in complete remission
and or other cancer for which the patient has been disease-free for at least two
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. 15. Patients with autoimmune diseases that require systemic corticosteroid treatment.
