Ulixertinib and Hydroxychloroquine for the Treatment of Advanced MAPK-Mutated Gastrointestinal Cancers, UTAH Study

Inclusion Criteria

• Male or female subject aged >= 18 years
• Subject with histologically confirmed esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, gall bladder adenocarcinoma, intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, extrahepatic cholangiocarcinoma, duodenal adenocarcinoma, appendiceal adenocarcinoma, or colorectal adenocarcinoma harboring a MAPK mutation: KRAS, NRAS, HRAS, BRAFnon-V600, MEK, and ERK
• Subject is willing to provide a baseline biopsy
• Prior lines of therapy: * Patients with gall bladder adenocarcinoma, intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, or extrahepatic cholangiocarcinoma must have progressed during or after receiving a first-line regimen of gemcitabine/cisplatin unless deemed ineligible by the treating investigator to receive chemotherapy based regimens due to prior comorbidities. Comorbidities prohibiting prior therapy must be clearly documented in the patient’s research chart * Patients with pancreatic adenocarcinoma must have progressed during or after first-line therapy of fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX)/modified (m) FOLFIRINOX, or gemcitabine/nab-paclitaxel unless deemed ineligible by the treating investigator to receive chemotherapy based regimens due to prior comorbidities. Comorbidities prohibiting prior therapy must be clearly documented in the patient’s research chart * Patients with duodenal adenocarcinoma, appendiceal adenocarcinoma, or colorectal adenocarcinoma must have progressed during or after their first two lines of therapy including leucovorin calcium (calcium folinate), 5-fluorouracil and oxaliplatin (FOLFOX) +/- Avastin and leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan (FOLFIRI) +/- Avastin unless deemed ineligible by the treating investigator to receive chemotherapy based regimens due to prior comorbidities. Comorbidities prohibiting prior therapy must be clearly documented in the patient’s research chart * Patients with esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastroesophageal junction (GEJ) adenocarcinoma, or gastric adenocarcinoma must have progressed during or after their first two lines of therapy ** Acceptable first-line regimens: FOLFOX, fluorouracil (5-FU)/cisplatin, FOLFIRI, paclitaxel/cisplatin or carboplatin, docetaxel/cisplatin, docetaxel, cisplatin and fluorouracil (DCF) (or modifications thereof) or epirubicin, cisplatin and fluorouracil (ECF) (or modifications thereof) unless deemed ineligible by the treating investigator to receive chemotherapy based regimens due to prior comorbidities. Comorbidities prohibiting prior therapy must be clearly documented in the patient’s research chart ** Acceptable second-line regimens: ramucirumab/paclitaxel, docetaxel, paclitaxel, irinotecan, trifluridine/tipiracil, FOLFIRI, unless deemed ineligible by the treating investigator to receive chemotherapy based regimens due to prior comorbidities. Comorbidities prohibiting prior therapy must be clearly documented in the patient’s research chart * Patients with mismatch repair deficiency (dMMR)/microsatellite instability (MSI) - high (H) tumors must have progressed during or after pembrolizumab
• Subject must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria by computed tomography (CT) or magnetic resonance imaging (MRI)
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Absolute neutrophil count (ANC) >= 1500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 10 g/dL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3. x institutional ULN * Patients with liver metastases will be allowed to enroll with AST and ALT levels =< 5 x ULN
• Estimated creatinine clearance >= 50 mL/min by Cockcroft-Gault formula
• 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 subjects and female subjects of child bearing potential throughout the study and for at least 4 months after last study treatment administration
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 from toxicities related to any prior treatments, unless adverse event (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 (e.g., 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 (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before first dose. ** Corrected QT (QTc) prolongation defined as a QT interval by Fridericia (QTcF) > 500 ms. ** Left ventricular ejection fraction < 55% * 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 principal investigator [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 human immunodeficiency virus (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 tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [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 ribonucleic acid (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 (National Cancer Institute [NCI] CTCAE v5.0 grade >= 3)
• Subjects taking prohibited medications. 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