Trial of Ulixertinib in Combination With Hydroxychloroquine in Patients With Advanced Gastrointestinal (GI) Malignancies

Inclusion Criteria:

1. Male or female patient aged ≥ 18 years.

2. Histologically confirmed esophageal adenocarcinoma, esophageal squamous cellcarcinoma, GEJ adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma,intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, extrahepaticcholangiocarcinoma, or colorectal adenocarcinoma harboring a MAPK-mutated GImalignancy: KRAS, NRAS, HRAS, BRAF non-V600, MEK 1/2 (MAP2K1/2), or ERK 1/2 (MAPK3/1).

3. Progression on or during standard lines of therapy:

• Patients with intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, orextrahepatic cholangiocarcinoma must have progressed during or after receivinga first-line regimen of gemcitabine/cisplatin unless deemed ineligible by thetreating investigator to receive chemotherapy-based regimens due to priorcomorbidities.

• Patients with pancreatic adenocarcinoma must have progressed during or afterfirst-line therapy of FOLFIRINOX/ mFOLFIRINOX, gemcitabine/nab-paclitaxelunless deemed ineligible by the treating investigator to receivechemotherapy-based regimens due to prior comorbidities.

• Patients with colorectal adenocarcinoma must have progressed during or aftertheir first two lines of therapy, including FOLFOX ± Avastin and FOLFIRI ±Avastin, unless deemed ineligible by the treating investigator to receivechemotherapy-based regimens due to prior comorbidities.

• Patients with esophageal adenocarcinoma, esophageal squamous cell carcinoma,GEJ adenocarcinoma, or gastric adenocarcinoma must have progressed during orafter their first two lines of therapy.

• Acceptable first-line regimens: FOLFOX, 5-FU/Cisplatin, FOLFIRI,Paclitaxel/Cisplatin or Carboplatin, Docetaxel/Cisplatin, DCF (or modificationsthereof), or ECF (or modifications thereof) unless deemed ineligible by thetreating investigator to receive chemotherapy-based regimens due to priorcomorbidities.

• Acceptable second-line regimens: Ramucirumab/Paclitaxel, Docetaxel, Paclitaxel,Irinotecan, Trifluridine/Tipiracil, or FOLFIRI, unless deemed ineligible by thetreating investigator to receive chemotherapy-based regimens due to priorcomorbidities.

• Patients with deficient MisMatch Repair/High levels of MicroSatelliteInstability (dMMR/MSI-H) tumors must have progressed during or afterpembrolizumab.

4. Measurable disease by RECIST 1.1 criteria by computed tomography (CT) or magneticresonance imaging (MRI).

5. Willing to provide a biopsy at the time points indicated on the Schedule ofActivities.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.

7. Adequate organ function as defined as: Hematologic:

• Absolute neutrophil count (ANC) ≥ 1500/mm3

• Platelet count ≥ 100,000/mm3

• Hemoglobin ≥ 9 g/dL Hepatic:

• Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

• Asparate animotransferace /Alanine aminotransferase (AST(SGOT)/ALT(SGPT)) ≤ 3 ×institutional ULN

• Patients with liver metastases will be allowed to enroll with AST and ALTlevels ≤ 5 x ULN. Renal:

• Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula:

• Males: (140-age) × weight [kg] / serum creatinine [mgdL] × 72

• Females:

((140-age) × weight [kg] / serum creatinine [mgdL] × 72)×0.85

8. For female patients: Negative serum pregnancy test within 72 hours prior to firstdose of study drugs for women of childbearing potential. The following definitionsapply:

• Women of childbearing potential, defined as a sexually mature woman:

• Has not been naturally post-menopausal for at least 12 consecutive months (i.e., who has had menses anytime in the preceding 12 consecutive months).

• Has not undergone menopause, surgical sterilization (bilateral oophorectomy orhysterectomy).

• Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

• Women not of childbearing potential:

• Amenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, if any.

• Underwent surgical sterilization (bilateral oophorectomy, bilateralsalpingectomy or hysterectomy).

9. Male and female patients of childbearing potential agree to use highly effectivecontraception throughout the study and at least 90 days after the last studytreatment administration.

10. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any priorcancer therapy, unless considered clinically not significant by the treatinginvestigator.

11. Able to provide informed consent and willing to sign an approved consent form thatconforms to federal and institutional guidelines.

Exclusion Criteria:

1. Received systemic antineoplastic therapy (including unconjugated therapeuticantibodies and toxin immunoconjugates) or any investigational therapy ≤ 14 days orwithin five half-lives prior to starting study treatment, whichever is shorter.

2. Received radiotherapy ≤ 14 days prior to the first dose of study treatment. Note: Localized radiation therapy for the treatment of symptomatic bone metastasisis allowed during that timeframe.

3. Undergone major surgery ≤ 3 weeks prior to starting study drug or who have not fullyrecovered from major surgery.

4. The diagnosis of another malignancy within ≤ 3 years before study enrollment, exceptfor those considered to be adequately treated with no evidence of disease orsymptoms and/or will not require therapy during the study duration (i.e., basal cellor squamous cell skin cancer, carcinoma in situ of the breast, bladder or of thecervix, or low-grade prostate cancer with Gleason Score ≤ 6).

5. Known uncontrolled brain metastases or cranial epidural disease. Note: Patients with stable brain metastases either treated or being treated with astable dose of steroids (<20 mg of prednisone daily or equivalent) oranticonvulsants, with no dose change within 4 weeks before the first study drugdose, and no anticipated dose change, are eligible. In the event of steroid taperpost-radiation therapy, taper must be complete within 2 weeks before Baseline.

6. History or current evidence of central serous retinopathy (CSR) or retinal veinocclusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma orocular hypertension, history of hyperviscosity).

7. Current evidence of uncontrolled, significant intercurrent illness including, butnot limited to, the following conditions: Cardiovascular disorders:

• Congestive heart failure New York Heart Association Class 3 or 4, unstableangina 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 the first dose.

• Duration of QT interval (QTc prolongation) defined as a QTcF > 500 ms.

• Known congenital long QT.

• Left ventricular ejection fraction < 50%. History of seizures Impairment of gastrointestinal function or gastrointestinal disease (e.g.,ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or malabsorptionsyndrome). Any other condition that would, in the Investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns or compliancewith clinical study procedures (e.g., infection/inflammation, intestinalobstruction, unable to swallow medication, [patients may not receive the drugthrough a feeding tube], social/ psychological issues, etc.)

8. Prior stomach or duodenal resection that in the opinion of the PrincipalInvestigator and Medical Monitor would affect the breakdown and absorption of thestudy medications. A patient with a feeding tube should also be excluded, asulixertinib capsules cannot be broken apart.

9. Known HIV infection with a detectable viral load within 6 months of the anticipatedstart of treatment. Note: Patients on effective antiretroviral therapy with an undetectable viral loadwithin 6 months of the anticipated start of treatment are eligible for this trial.

10. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination, radiographic findings, and tuberculosis (TB) testingin 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 ofhepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA.

11. Medical, psychiatric, cognitive or other conditions that may compromise thepatient's ability to understand the patient information, give informed consent,comply with the study protocol or complete the study.

12. Known prior severe hypersensitivity to investigational product (IP) or any componentin its formulations (NCI CTCAE v5.0 Grade ≥ 3).

13. Patients taking prohibited medications as described in protocol. A washout period ofprohibited medications for a period of at least 5 half-lives or as clinicallyindicated should occur before the start of treatment.