Safety and Efficacy of Tegavivint in Patients With Metastatic Colorectal Carcinoma

This multi-part Phase 1/2 trial dose escalation and expansion trial will evaluate tegavivint in patients with metastatic colorectal carcinoma (mCRC). The trial begins with Part 1, a monotherapy dose escalation using a Bayesian optimal interval (BOIN) design, starting at 6.5 mg/kg intravenously (IV) to determine the maximum tolerated dose (MTD) and/or Recommended Phase 2 dose (RP2D) (9-18 patients enrolled). Following the establishment of the monotherapy RP2D, Part 2 will enroll up to 24 patients in a Phase 2 expansion cohort to evaluate preliminary efficacy of tegavivint monotherapy in mCRC. Part 3 will conduct limited dose escalation of tegavivint in combination with two different standard of care therapy regimens. Each combination arm will follow a BOIN design to establish the combination RP2D. Upon determination of the combination RP2Ds, Part 4 will open two parallel Phase 2 expansion cohorts of up to 24 patients each to evaluate the preliminary efficacy of these combination regimens.

Inclusion criteria

• Signed informed consent form (ICF)
• Male or female, 18 years of age or older
• Histologically and/or cytologically documented metastatic colorectal adenocarcinoma (all other histological types are excluded)

a. RAS, BRAF, and MSI/ dMMR (Mismatch repair deficiency) status for each patient must be documented.

• Disease progression or intolerance to ≥ 2 lines of systemic therapy for advanced/metastatic disease, including the following prior therapies unless contraindicated: fluoropyrimidine-, oxaliplatin- and irinotecan-based regimens, an anti-vascular endothelial growth factor (VEGF) therapy, and if RAS wild-type, an anti-epidermal growth factor receptor (EGFR) therapy.

• Prior treatment with trifluridine-tipiracil or fruquintinib is allowed
• Patients with BRAF-mutant tumors must have been treated with a BRAF inhibitor
• Patients with microsatellite-high or mismatch repair deficient tumors must have been treated with immune checkpoint inhibitors
• Measurable disease as defined by RECIST 1.1. Lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if progression has been demonstrated in such lesions.
• Willingness and ability to provide tumor biopsies during screening and while on treatment. On trial, biopsies considered low risk are required, moderate risk procedures are optional, and no high-risk procedures are allowed.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior to the first dose of the investigational product(s)
• Patients must have organ and marrow function as defined below during screening and performed by local laboratories within 7 days of the first dose of the investigational product(s):

• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
• Platelets ≥ 100 × 109/L; no transfusion within 7 days prior to the screening laboratory assessment
• Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN if liver function abnormalities are due to underlying liver metastasis
• Renal function

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• Estimated creatinine clearance (CrCl) ≥ 50 mL/min by the Cockcroft-Gault equation using actual body weight, or
• Estimated Glomerular Filtration Rate (eGFR) ≥ 50 mL/min/1.73m2 by Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) Creatinine Equation, or
• Measured creatinine clearance ≥ 50 mL/min
• Note: If estimated CrCl or eGFR is abnormal, accurate measurement may be obtained by 24-hour urine collection to measure creatinine clearance.

g. International normalized ratio (INR) ≤ 1.5 × ULN, unless the patient is receiving anticoagulant therapy as long as the patient is within therapeutic range of intended use of anticoagulants h. Urine protein <100mcg on urinalysis or 24-hour urine protein < 2 grams

• Washout or recovery period prior to Day 1 of Cycle 1:

• At least 21 days from the last dose of prior systemic anticancer treatment
• At least 14 days from palliative radiotherapy (≤ 10 fractions or ≤30 gray [Gy] total dose or at least 28 days from radiotherapy > 30 Gy) to extrahepatic tumor lesions
• At least 28 days from local or loco-regional therapy of intrahepatic tumor lesions (e.g., surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation)
• At least 28 days from any major surgery and adequate wound healing has occurred. Major surgery is defined as any significantly invasive procedure into a major body cavity (abdomen, cranium etc.) and/or surgery requiring extensive recuperation (joint replacement). Please discuss with the medical monitor if there are any questions.
• Grade ≤ 1 toxicity due to any previous cancer therapy according to the NCI-CTCAE v.5. Grade 2 is allowed in case of alopecia and/or peripheral sensory neuropathy.
• Patients with past Hepatitis C virus (HCV) infection will be eligible for the trial. The treated patients must have completed their treatment at least 1 month prior to starting trial intervention and HCV viral load must be below the limit of quantification.
• Patients with controlled Hepatitis B virus (HBV) will be eligible if they meet the following criteria:

• Antiviral therapy for HBV must be given for at least 4 weeks, and HBV viral load must be less than 500 IU/mL prior to first dose of trial drug. Patients on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout trial intervention.
• Patients who are positive for anti-hepatitis B core antibody (HBcAb), negative for hepatitis B surface antigen (HBsAg), and negative or positive for anti-hepatitis B surface antibody (HBs), and who have an HBV viral load under 100 IU/mL, do not require HBV antiviral prophylaxis.
• Patients must have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤ 150/90 mm Hg at Screening and no change in antihypertensive medications within 1 week before Cycle 1 Day 1.

Exclusion criteria

• Patients receiving therapy with other anti-neoplastic or experimental agents.
• Patients receiving concomitant strong or moderate inhibitors of CYP3A4/5 that cannot be discontinued 7 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1.
• Patients receiving concomitant strong or moderate inducers of CYP3A4/5 that cannot be discontinued at least 14 days prior to Cycle 1 Day 1.
• Patients with known history of Gilbert's syndrome or other genetic conditions affecting UGT1A1 function.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to tegavivint, or other agents and excipients used in the trial including allergic reactions to Food, Drug, and Cosmetic (FD&C) Yellow No. 5 (Tartrazine) or No. 6 (Sunset Yellow FCF).
• Malignant disease, other than that being treated in this trial. Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) who have undergone potentially curative therapy are not excluded. Other exceptions include malignancies that were treated curatively and have not recurred within 3 years prior to Cycle 1 Day 1 and any malignancy considered indolent and that has never required therapy.
• Lack of peripheral venous or central venous access or any condition that would interfere with drug administration or collection of trial samples.
• Inability to swallow capsules or tablets.
• Known central nervous system (CNS) involvement including carcinomatous meningitis.
• Ongoing or active infection (exception: HBV infection - see inclusion criteria).
• Patients with large varices at risk of significant bleeding that are not being treated with conventional medical intervention: beta blockers or endoscopic treatment. Assessment of varices for patients in whom conventional medical intervention for known varices is already in place should be performed by endoscopy as per local standard of care.
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 6 months before the start of trial medication.
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, or hypertension including any of the following:

• Congestive heart failure, New York Heart Association (NYHA) > Class II
• Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
• Unstable angina pectoris or cardiac arrhythmia
• Baseline QTc (Fridericia) ≥ 450 milliseconds. In the event a QTc (QT interval corrected Fridericia) measurement is not possible due to factors such as a pacemaker or bundle branch block, the patient may be evaluated by a cardiologist who must document no apparent increased risk for Torsades de Point or other morbidity associated with prolonged QTc. With such documentation, the patient may be eligible based with additional medical monitor review.
• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome
• Myocardial infarct within 6 months before Cycle 1 Day 1
• Clinically significant pericardial disease
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions.
• Pregnant and breastfeeding women are excluded from this trial. The effects of tegavivint on the developing human fetus have the potential for teratogenic or abortifacient effects. There is an unknown but potential risk for Adverse Effects in nursing infants secondary to treatment of the mother with tegavivint.
• Women of child-bearing potential (WOCBP) and men who are sexually active with WOCBP who do not agree to use one highly effective method of contraception, including hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device or intrauterine system; vasectomy or tubal ligation; and one effective method of contraception, including male condom, female condom, cervical cap, diaphragm or contraceptive sponge or abstaining from sex for the duration of trial participation and for at least 6 months following completion of dosing (if applicable). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, she should inform her treating physician immediately.
• Any other clinically significant disease or condition that, in the opinion of the investigator, may affect adherence to the protocol, or the signing of the ICF by the patient, or make participation in this clinical trial inappropriate.