CLINICAL TRIAL / NCT05797805
A Study of Tegavivint (BC2059) in Patients With Advanced Hepatocellular Carcinoma
- Interventional
- Recruiting
- NCT05797805
Contact Information
A Phase 1/2 Exploratory Study of the TBL1 Inhibitor, Tegavivint (BC2059), in Patients With Advanced Hepatocellular Carcinoma
This study will be conducted in 2 parts. The first part is a phase 1 single-agent dose escalation,optimization, and expansion study of tegavivint in patients with advanced HCC after failure of at least one line of prior systemic therapy. In the second part of the study, the combination of tegavivint plus pembrolizumab will be assessed with a limited dose escalation followed by a randomized dose optimization.
This study will be conducted in patients with advanced hepatocellular carcinoma (HCC) who
have progressed after at least one prior line of systemic therapy.
Tegavivint will be administered as a single agent first in a dose escalation and
optimization design. Single agent dose escalation will follow a standard 3+3 design to
determine the tegavivint maximum tolerated dose (MTD). Upon completion of the dose
escalation design and review of all available safety, efficacy, PK and PD data the Safety
Review Committee (SRC) will recommend two dose levels for dose selection optimization.
The dose selection optimization will expand the two dose levels to approximately 20
patients randomized (1:1) per dose level (approximately 40 patients total) before
declaring the recommended phase 2 dose (RP2D).
If sufficient clinical benefit is observed, the combination of tegavivint plus
cabozantinib and tegavivint plus lenvatinib will be explored in the second part of the
study. The second part of the study will begin with a brief dose escalation part for each
combination (tegavivint plus cabozantinib or tegavivint plus lenvatinib). The starting
dose level of tegavivint will be decided by the SRC and will start at either one dose
level below the MTD or at a lower dose as defined by the SRC. The dose escalations will
follow a standard 3+3 design, and the dose escalation increments for tegavivint will
follow the monotherapy dose escalation schedule to determine the combinations MTDs. Upon
completion of the combination dose escalations, approximately 12 additional patients will
be enrolled in each combination arm at the tegavivint combination MTDs.
Gender
All
Age Group
18 Years and up
Accepting Healthy Volunteers
No
Inclusion Criteria:
- Male or female, 18 years of age or older
- Confirmed diagnosis of HCC by either:
Histologically or cytologically documented HCC based on pathology report or Clinically
confirmed diagnosis of HCC according to American Association for the Study of Liver
Diseases (AASLD) criteria
- Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not
amenable to locoregional therapy or refractory to locoregional therapy, and not
amenable to a curative treatment approach
- Child-Pugh class A or ≤ 7 class B liver score (no hepatic encephalopathy) within 7
days of first dose of the investigational product(s)
- Disease progression, intolerance or contraindication to at least one line of
systemic therapy for advanced HCC Prior treatment with cabozantinib or lenvatinib is
allowed in the combination dose escalation and expansion parts of the study.
- Measurable disease as defined by RECIST 1.1 with spiral computerized tomography (CT)
scan or magnetic resonance imaging (MRI). 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.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days
prior to the first dose of the investigational product(s)
- Patients must have organ and marrow function as defined below within 7 days of the
first dose of the investigational product(s):
- Absolute neutrophil count (ANC) ≥ 1.2 x 109/L
- Platelets ≥ 60 x 10^9/L; no transfusion within 7 days prior to assessment
- Hemoglobin ≥ 9 g/dL (red blood cell transfusion or growth factors support is
not allowed in the 14 days prior to the screening laboratory assessment)
- Total bilirubin ≤ ULN
- AST and ALT ≤ 5 x ULN
- Renal Function : 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 CKD-EPI Creatinine Equation, or
Measured creatinine clearance ≥ 50 mL/min
- Albumin ≥ 2.8 g/dL
- International normalized ratio (INR) ≤ 1.7, unless the patient is receiving
anticoagulant therapy as long as the patient is within therapeutic range of
intended use of anticoagulants
- Washout 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)
- 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.
- Participants with past HCV infection will be eligible for the study. The treated
participants must have completed their treatment at least 1 month prior to starting
study intervention and HCV viral load must be below the limit of quantification.
- Participants with controlled 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 study drug. Patients on
active HBV therapy with viral loads under 100 IU/mL should stay on the same
therapy throughout study intervention.
- Patients who are positive for anti-hepatitis B core antibody HBc, 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:
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
- Patients receiving therapy with other anti-neoplastic or experimental agents
- Patients receiving concomitant strong 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 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 used in study
- Malignant disease, other than that being treated in this study. 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 study samples
- Known central nervous system (CNS) involvement
- Uncontrolled concurrent illness including, but not limited to:
- Ongoing or active infection (exception: HBV infection - see inclusion criteria)
- Unhealed wounds or presence of any external drainage
- Psychiatric illness/social situations that would limit compliance with study
requirements; discuss with Medical Monitor if there are any questions
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormality, including any of the following:
- Congestive heart failure, NYHA > Class II
- Left ventricular ejection fraction < 50%
- Unstable angina pectoris or cardiac arrhythmia
- Baseline QTc (Fridericia) ≥ 450 milliseconds. In the event a QTc (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
- Any major surgery within 21 days prior to Cycle 1 Day 1. 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.
- Pregnant and breastfeeding women are excluded from this study. 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 AEs 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
must 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 study participation and for at least 4 months following completion
of tegavivint and pembrolizumab (if applicable) administration. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately.
- HIV-positive patients on combination antiretroviral therapy are ineligible because
of the potential for PK interactions with tegavivint.
- Exclusions for patients treated on study with cabozantinib or lenvatinib:
- Patients with large esophageal varices at risk of bleeding that are not being
treated with conventional medical intervention: beta blockers or endoscopic
treatment. Assessment of esophageal varices for patients in whom conventional
medical intervention for known esophageal varices is already in place should be
performed by endoscopy as per local standard of care.
- Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic
pressure >90 mmHg despite optimal medical management).
- Persistent proteinuria of NCI-CTCAE version 5.0 grade 3 or higher. Urine
dipstick result of 3+ is allowed if protein excretion (estimated by urine
protein/creatinine ratio on a random urine sample) is <3.5 g/24 hours.
- Clinically significant bleeding NCI-CTCAE version 5.0 grade ≥ 3 within 30 days
before randomization.
- 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 study medication.
- Patients treated with medications with a known potential to prolong the QT/QTc
interval.
- Hypersensitivity or intolerance to cabozantinib (patients with hypersensitivity
or intolerance to cabozantinib may enroll in treatment arms exploring
tegavivint plus lenvatinib if they did not have hypersensitivity or intolerance
to lenvatinib).
- Hypersensitivity or intolerance to lenvatinib (patients with hypersensitivity
or intolerance to lenvatinib may enroll in treatment arms exploring tegavivint
plus cabozantinib if they did not have prior hypersensitivity or intolerance to
cabozantinib)