Inclusion Criteria:
- Male or female subject aged ≥ 18 years.
- Subject with histologically confirmed MAPK-mutated GI malignancies: KRAS, NRAS, HRAS,
BRAFnon-V600, MEK, and ERK.
- Subject is willing to provide a baseline biopsy.
- Prior lines of therapy:
- For patients with cholangiocarcinoma: subject must have progressed during or
after one line of therapy.
- For patients with pancreatic adenocarcinoma: the subject must have progressed
during or after one line of therapy.
- For patients with colorectal carcinoma: the subject must have progressed during
or after two lines of therapy.
- For patients with stomach or esophageal carcinoma: the subject must have
progressed during or after two lines of therapy.
- Subject must have measurable disease by RECIST 1.1 criteria by CT or MRI.
- ECOG Performance Status ≤ 1.
- Adequate organ function as defined as:
- Hematologic:
- Absolute neutrophil count (ANC) ≥ 1500/mm3
- Platelet count ≥ 100,000/mm3
- Hemoglobin ≥ 10 g/dL
- Hepatic:
- Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)
- AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
- Patients with liver metastases will be allowed to enroll with AST and ALT
levels ≤ 5 x ULN.
- Renal:
- Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula:
- Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)
- Females: (((140-age)×weight[kg])/(serum creatinine [mg/dL]×72))×0.85
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥ 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
- Highly effective contraception for both male and female subjects throughout the study
and for at least 4 months after last study treatment administration (see Section 7.6).
- Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior
treatments, unless AE(s) are clinically non-significant and/or stable on supportive
therapy.
- Able to provide informed consent and willing to sign an approved consent form that
conforms to federal and institutional guidelines.
Exclusion Criteria:
- Subject has received systemic antineoplastic therapy (including unconjugated
therapeutic antibodies and toxin immunoconjugates) or any investigational therapy ≤ 14
days or within 5 half-lives prior to starting study treatment, whichever is shorter.
- Subject has received radiotherapy ≤ 14 days prior to the first dose of study
treatment. Localized radiation therapy for the treatment of symptomatic bone
metastasis is allowed during that timeframe.
- Subjects who have undergone major surgery ≤ 3 weeks prior to starting study drug or
who have not fully recovered from major surgery.
- Presence of peritoneal carcinomatosis (PC).
- Diagnosis of any other malignancy within 2 years prior to study enrollment, except for
adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the
breast, bladder or of the cervix, and low-grade (Gleason 6 or below) prostate cancer
on surveillance with no plans for treatment intervention (eg, surgery, radiation, or
castration) or prostate cancer that has been adequately treated with prostatectomy or
radiotherapy and currently with no evidence of disease or symptoms is allowed.
- Known brain metastases or cranial epidural disease.
--Note: Brain metastases or cranial epidural disease adequately treated with
radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of
study treatment will be allowed on trial. Subjects must be neurologically asymptomatic
and without corticosteroid treatment at the time of first dose of study treatment.
- History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
or hypercoagulability syndromes).
- Current evidence of uncontrolled, significant intercurrent illness including, but not
limited to, the following conditions:
- Cardiovascular disorders:
- Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
pectoris, serious cardiac arrhythmias.
- Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),
or other ischemic events, or thromboembolic event (eg, deep venous thrombosis,
pulmonary embolism) within 3 months before first dose.
- QTc prolongation defined as a QTcF > 500 ms.
- History of seizures
- Impairment of gastrointestinal function or gastrointestinal disease (e.g.,
ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption
syndrome, or small bowel resection under the judgment of the PI may impair
absorption of study drugs).
- Any other condition that would, in the Investigator's judgment, contraindicate
the patient's participation in the clinical study due to safety concerns or
compliance with clinical study procedures, e.g., infection/inflammation,
intestinal obstruction, unable to swallow medication.(patients may not receive
drug through a feeding tube), social/ psychological issues, etc.
- Known HIV infection with a detectable viral load within 6 months of the anticipated
start of treatment.
--Note: Patients on effective antiretroviral therapy with an undetectable viral load
within 6 months of the anticipated start of treatment are eligible for this trial.
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination, radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or
hepatitis C.
--Note: Patients with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction
is negative for HCV RNA.
- Medical, psychiatric, cognitive or other conditions that may compromise the patient's
ability to understand the patient information, give informed consent, comply with the
study protocol or complete the study.
- Known prior severe hypersensitivity to investigational product or any component in its
formulations (NCI CTCAE v5.0 Grade ≥ 3).
- Subjects taking prohibited medications as described in Section 6.4. A washout period
of prohibited medications for a period of at least 5 half-lives or as clinically
indicated should occur prior to the start of treatment.
