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Combined Treatment of Durvalumab, Bevacizumab, Tremelimumab and Transarterial Chemoembolization (TACE) in Subjects With Hepatocellular Carcinoma or Biliary Tract Carcinoma

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ClinicalTrials.gov Identifier: NCT03937830
Recruitment Status : Recruiting
First Posted : May 6, 2019
Last Update Posted : March 2, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Most people with advanced HCC survive an average of 6 to 9 months. Researchers are evaluating a combination of treatment drugs to delay the progression of HCC; aiming to help people with HCC live longer.

Objective:

To study the 6-month progression-free survival in people with advanced HCC treated with bevacizumab, durvalumab, and TACE.

Eligibility:

Adults ages 18 and older with intermediate or advanced HCC

Design:

Participants will be screened with a physical exam and medical history. They will have tests to evaluate their hearts as well as blood and urine. A CT and/or MRI scans will be done during the study. If a prior tumor sample is not available; participants may undergo a biopsy. They may undergo an endoscopy of their esophagus and stomach.

Participants will get the study drugs in 21-day cycles:

Two treatment drugs will be injected into a vein every 3 weeks.

Patients will have an interventional treatment procedure done by interventional radiology under sedation; chemotherapy beads will be infused into artery branches in the liver. Participants may have to stay in the hospital for 24 hours for observation, after this procedure. This interventional procedure may be done more than once during the study.

Participants may need to repeat some of the screening tests throughout the study.

Participants may have to stop taking some of their cancer treatment drugs during the study.

Participants will continue on the study until their cancer progresses or until the side effects of the treatment drugs are not tolerable....


Condition or disease Intervention/treatment Phase
Heptocellular Cancer Heptocellular Carcinoma Metastatic Hepatocellular Carcinoma Drug: durvalumab Drug: Doxorubicin-Eluting Beads Procedure: TACE Drug: bevacizumab Drug: Tremelimumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Combined Treatment of Durvalumab, Bevacizuamab, Tremelimumab and Transarterial Chemoembolization (TACE) in Subjects With Hepatocellular Carcinoma (HCC)or Biliary Tract Carcinoma (BTC)
Estimated Study Start Date : March 5, 2021
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/ Arm 1
Durvalumab, bevacizumab and tremelimumab
Drug: durvalumab
1,150 mg flat dose every 21 days, starting on day 1 of cycle 1

Drug: bevacizumab
7.5 mg/kg dose every 21 days, starting on day 1 of cycle 1

Drug: Tremelimumab
300 mg once on day 1 of cycle 1

Experimental: 2/ Arm 2
Durvalumab, bevacizumab, tremelimumab and TACE
Drug: durvalumab
1,150 mg flat dose every 21 days, starting on day 1 of cycle 1

Drug: Doxorubicin-Eluting Beads
used for TACE (only in patients with HCC BCLC stage B)

Procedure: TACE
TACE with Doxorubicin-Eluting Beads (only in patients with HCC BCLC stage B) on Cycle 2. More TACE can be done if clinically necessary.

Drug: bevacizumab
7.5 mg/kg dose every 21 days, starting on day 1 of cycle 1

Drug: Tremelimumab
300 mg once on day 1 of cycle 1




Primary Outcome Measures :
  1. To evaluate the 6-month progression free survival (PFS) in patients with advanced HCC BCLC stage B treated with bevacizumab, durvalumab, tremelimumab and TACE [ Time Frame: 6 months ]
    Proportion of patients with advanced HCC BCLC stage B that have progressive disease after 6 months

  2. To evaluate the 6-month PFS in patients with BTC and HCC BCLC stage C treated with bevacizumab, durvalumab and tremelimumab [ Time Frame: 6 months ]
    Proportion of patients with BTC and HCC BCLC stage C that have progressive disease after 6 months


Secondary Outcome Measures :
  1. To determine the best overall response (BOR) rate according to Response Evaluation Criteria (RECIST 1.1) in patients with advanced HCC and BTC [ Time Frame: every 9 weeks ]
    Proportion of patients whose tumors shrunk after therapy

  2. To characterize overall survival (OS) in patients with advanced HCC and BTC treated on this study [ Time Frame: death ]
    Median amount of time subject survives after therapy

  3. To determine the safety and feasibility of bevacizumab, durvalumab, tremelimumab and TACE in patients with advanced HCC [ Time Frame: every visit to clinical center ]
    List of adverse event type, grade and frequency

  4. To determine the safety and feasibility of bevacizumab, durvalumab, tremelimumab in patients with advanced BTC [ Time Frame: every visit to clinical center ]
    List of adverse event type, grade and frequency



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have:

    • histopathological confirmation of HCC by the NCI Laboratory of Pathology (Cohorts

      1. and 3)

        OR

    • histopathological confirmation of BTC or histopathological confirmation of carcinoma by the NCI Laboratory of Pathology in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of BTC (Cohort 2).
  • Patients should have have progressed on standard of care chemotherapy or been intolerant of or refused standard treatment.
  • Patients must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation
  • Patients must have evaluable or measurable disease per RECIST 1.1
  • Patients must have at least one lesion accessible for TACE (Cohort 3)
  • Patients must have lesions accessible for biopsy and be willing to undergo pre- and posttreatment biopsies
  • ECOG performance status of 0 to 1
  • If liver cirrhosis is present, patient must have a Child-Pugh score <7
  • Subjects with HCC must have BCLC C (Cohort 1) or BCLC B (Cohort 3)
  • Patients must have normal organ and marrow function as defined below:

    • absolute neutrophil count greater than or equal to 1,000/mcL
    • platelets greater than or equal to 60,000/mcL
    • total bilirubin:if cirrhosis present: Part of Child Pugh requirement-If no cirrhosis: bilirubin should be less than or equal to 2 XULN
    • ALT or AST up to 5 x ULN
    • Creatinine OR measured or calcutated Creatinine clearance (crCl) (eGFR may Also be used in place of CrCl) A: less than the institutional limit of normal OR greater than or equal to 45/mL/1.73 m^2 for participant with creatinine levels greater than or equal to 1.5 X institutional ULN
    • No proteinuria: Urine dipstick <2. Patients discovered to have greater than or equal to 2 + proteinuria on dipstick analysis should undergo a 24-hour urine collection and must demonstrate less than or equal to 1g of protein in 24 hours to be eligible
    • Coagulation: PT/aPTT within normal range
  • Age greater than or equal to 18 years
  • Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1.
  • The effects of study drugs on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study treatment and up to 90 days after the last dose of the study drug(s). 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.
  • Patient must be able to understand and willing to sign a written informed consent document.
  • HBV infected subjects must be on antivirals and have HBV DNA <100IU/mL. HCV infected subjects can be enrolled with close HCV RNA level monitoring
  • Body weight >30kg
  • Patient must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

  • Patients who have had standard-of-care anti-cancer therapy or therapy with investigational agents (e.g. chemotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies or other investigation agents) or large field radiotherapy within 4 weeks prior to treatment initiation.
  • Major surgery within 6 weeks prior to treatment initiation. Minor procedures (e.g. port placement, endoscopy with intervention) within 4 weeks prior to treatment initiation.
  • Active central nervous system metastases and/or carcinomatous meningitis. Patients with known active brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses.
  • Medical condition that requires chronic systemic steroid therapy, or any other form of immunosuppressive medication (inhaled and topical steroids are permitted).
  • Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID).
  • A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment.
  • Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic blood pressure > 100 mmHg), based on an average of 3 BP readings on 2 sessions. Note: anti-hypertensive therapy to achieve these parameters is allowable.
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
  • Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  • Current or recent (within 10 days of first dose of study treatment) use of aspirin
  • (> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol
  • Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose. Note: prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an INR < 1.5 ULN and aPTT is within normal limits within 14 days prior to initiation of study treatment.
  • Thromboembolic event within 6 months of initiation of study treatment (including cerebrovascular accident (CVA) and myocardial infarction (MI).
  • Evidence of bleeding diathesis or significant coagulopathy (with or without current therapeutic anticoagulation).
  • History of hemoptysis (>2.5 mL of bright red blood per episode) within 1 month prior to treatment initiation.
  • Serious, non-healing wound, active ulcer, or untreated bone fracture.
  • HIV-positive patients are excluded because HIV causes complicated immune deficiency and study treatment can pose more risks for these patients.
  • History of severe hypersensitivity reaction to any monoclonal antibody.
  • Congestive heart failure, transmural myocardial infarction, angina pectoris requiring medication, clinically significant valvular disease, high-risk arrhythmia within 12 months prior to treatment initiation. Prior history of hypertensive crisis or hypertensive encephalopathy.
  • Prior invasive malignancies within the past 5 years prior to treatment initiation (with the exception of non-melanoma skin cancers, non-invasive bladder cancer or localized prostate cancer for whom systemic therapy is not required)
  • Active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea.
  • History of abdominal fistula or gastrointestinal perforation within 6 months prior to initiation of study treatment.
  • History of chronic autoimmune disease (e.g., Addison s disease, multiple sclerosis, Graves disease, Hashimoto s thyroiditis, rheumatoid arthritis, hypophysitis, systemic lupus erythematosus, Wegener s granulomatosis, sarcoidosis syndrome etc.) or other connective tissue diseases with symptomatic disease within the 3 years of initiation of study treatment. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion.
  • Diverticulitis either active or history of within 2 years of initiation of study treatment. Note that diverticulosis is permitted.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that may impair the patient s tolerance of study treatments.
  • Received any live vaccine within the last 30 days.
  • Patients who have undergone prior liver transplantation.
  • Pregnant women are excluded from this study because durvalumab s and bevacizumab s potential for teratogenic or abortifacient effects is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with durvalumab and bevacizumab, breastfeeding should be discontinued if the mother is treated with study drugs.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03937830


Contacts
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Contact: Donna M Hrones, C.R.N.P. (240) 858-3155 donna.mabry@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Tim F Greten, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03937830    
Other Study ID Numbers: 190094
19-C-0094
First Posted: May 6, 2019    Key Record Dates
Last Update Posted: March 2, 2021
Last Verified: February 22, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Immune Checkpoint Blockade
Combined Treatment
Immunotherapy
Anti-Tumor Immunity
Inhinition of the Blood Vessels Surrounding a Tumor
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Bevacizumab
Durvalumab
Doxorubicin
Tremelimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action