A Phase 2 Basket Trial of Ulixertinib (BVD-523) in Combination with Hydroxychloroquine in Patients with Advanced Gastrointestinal Malignancies Harboring MAPK Pathway Mutations.

Inclusion Criteria

1. Male or female patient aged ≥ 18 years.

2. Histologically confirmed esophageal adenocarcinoma, esophageal squamous cell

carcinoma, GEJ adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma,

intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, extrahepatic

cholangiocarcinoma, or colorectal adenocarcinoma harboring a MAPK-mutated GI

malignancy: 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, 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.

- Patients with pancreatic adenocarcinoma must have progressed during or after

first-line therapy of FOLFIRINOX/ mFOLFIRINOX, gemcitabine/nab-paclitaxel unless

deemed ineligible by the treating investigator to receive chemotherapy-based

regimens due to prior comorbidities.

- Patients with colorectal adenocarcinoma must have progressed during or after

their first two lines of therapy, including FOLFOX ± Avastin and FOLFIRI ±

Avastin, unless deemed ineligible by the treating investigator to receive

chemotherapy-based regimens due to prior comorbidities.

- Patients with esophageal adenocarcinoma, esophageal squamous cell carcinoma, GEJ

adenocarcinoma, or gastric adenocarcinoma must have progressed during or after

their first two lines of therapy.

- Acceptable first-line regimens: FOLFOX, 5-FU/Cisplatin, FOLFIRI,

Paclitaxel/Cisplatin or Carboplatin, Docetaxel/Cisplatin, DCF (or modifications

thereof), or ECF (or modifications thereof) unless deemed ineligible by the

treating investigator to receive chemotherapy-based regimens due to prior

comorbidities.

- Acceptable second-line regimens: Ramucirumab/Paclitaxel, Docetaxel, Paclitaxel,

Irinotecan, Trifluridine/Tipiracil, or FOLFIRI, unless deemed ineligible by the

treating investigator to receive chemotherapy-based regimens due to prior

comorbidities.

- Patients with deficient MisMatch Repair/High levels of MicroSatellite Instability

(dMMR/MSI-H) tumors must have progressed during or after pembrolizumab.

4. Measurable disease by RECIST 1.1 criteria by computed tomography (CT) or magnetic

resonance imaging (MRI).

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

Activities.

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 ALT levels

≤ 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 first dose

of study drugs for women of childbearing potential. The following definitions apply:

- 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 or

hysterectomy).

- Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

- Women not of childbearing potential:

- Amenorrheic for 12 months or more following cessation of all exogenous hormonal

treatments, if any.

- Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy

or hysterectomy).

9. Male and female patients of childbearing potential agree to use highly effective

contraception throughout the study and at least 90 days after the last study treatment

administration.

10. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior

cancer therapy, unless considered clinically not significant by the treating

investigator.

11. Able to provide informed consent and willing to sign an approved consent form that

conforms to federal and institutional guidelines.

Exclusion Criteria

1. Received systemic antineoplastic therapy (including unconjugated therapeutic

antibodies and toxin immunoconjugates) or any investigational therapy ≤ 14 days or

within 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 metastasis is

allowed during that timeframe.

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

recovered from major surgery.

4. The diagnosis of another malignancy within ≤ 3 years before study enrollment, except

for those considered to be adequately treated with no evidence of disease or symptoms

and/or will not require therapy during the study duration (i.e., basal cell or

squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix,

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 a

stable dose of steroids (<20 mg of prednisone daily or equivalent) or anticonvulsants,

with no dose change within 4 weeks before the first study drug dose, and no

anticipated dose change, are eligible. In the event of steroid taper post-radiation

therapy, taper must be complete within 2 weeks before Baseline.

6. History or current evidence of central serous retinopathy (CSR) or retinal vein

occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular

hypertension, history of hyperviscosity).

7. 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 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 malabsorption syndrome).

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 the drug through a feeding

tube], social/ psychological issues, etc.)

8. Prior stomach or duodenal resection that in the opinion of the Principal Investigator

and Medical Monitor would affect the breakdown and absorption of the study

medications. A patient with a feeding tube should also be excluded, as ulixertinib

capsules cannot be broken apart.

9. 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.

10. 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 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.

11. 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.

12. Known prior severe hypersensitivity to investigational product (IP) or any component

in its formulations (NCI CTCAE v5.0 Grade ≥ 3).

13. Patients taking prohibited medications as described in protocol. A washout period of

prohibited medications for a period of at least 5 half-lives or as clinically

indicated should occur before the start of treatment.