Clinical Trials /

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

NCT03937830

Description:

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....

Related Conditions:
  • Biliary Tract Carcinoma
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 190094
  • SECONDARY ID: 19-C-0094
  • NCT ID: NCT03937830

Conditions

  • Heptocellular Cancer
  • Heptocellular Carcinoma
  • Metastatic Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
durvalumab1/ Arm 1
Doxorubicin-Eluting Beads2/ Arm 2
bevacizumab1/ Arm 1
Tremelimumab1/ Arm 1

Purpose

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....

Detailed Description

      Background:

        -  Worldwide, hepatocellular carcinoma (HCC) is the fourth most common cause of cancer
           related death with a median survival of 6-9 months.

        -  Biliary tract carcinoma (BTC) is relatively uncommon and includes cancers of the
           gallbladder and intra- and extra-hepatic biliary ductal system, although periampullary
           tumors are often considered part of this group as well.

        -  A class of agents that in the recent years has been at the epicenter of immunotherapy
           approaches in gastrointestinal malignancies are the monoclonal antibodies (mAbs) against
           the immune checkpoint inhibitors CTLA4, PD-1 and PD-L1.

        -  Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1 )
           subclass. Durvalumab inhibits binding of programmed cell death ligand 1 (PD-L1) to
           programmed cell death 1 (PD-1) and CD80. Anti-PD-L1 antibodies directly target tumor
           cells and are expected to have less adverse events in comparison with anti-PD-1
           antibodies that target effector T-cells in the tumor microenvironment.

        -  Tremelimumab is a-uman IgG2 mAb directed against CTLA-4. Tremelimumab blocks the
           inhibitory effect of CTLA-4, and therefore enhances T cell activation.

        -  Angiogenesis is defined as the formation of new blood capillaries, which is a complex
           process that promotes vascular endothelial growth factor (VEGF) and other proangiogenic
           factor expression, thus enhancing metastasis. Inhibition of VEGF function by bevacizumab
           can lead to the inhibition of the new blood vessels formation surrounding a tumor, and
           consequently arrest the tumor growth by depriving essential nutrients and oxygen.

        -  TACE has been shown to induce anti-tumor immunity.

        -  Early phase studies have shown that anti-VEGF treatment with bevacizumab in combination
           with TACE decreases neovascular formation.

        -  We have previously shown that locoregional therapies can be safely combined with immune
           checkpoint blockade. There are also preclinical data suggesting that anti-VEGF therapy
           may target myeloid cells with suppressor activity.

      Objectives:

        -  To evaluate the 6-month progression free survival (PFS) in patients with advanced HCC
           BCLC stage B treated with bevacizumab, durvalumab, tremelimumab and TACE.

        -  To evaluate the 6-month PFS in patients with BTC and HCC BCLC stage C treated with
           bevacizumab, durvalumab and tremelimumab.

      Eligibility:

        -  Histopathological confirmation of HCC or BTC or histopathological confirmation of
           carcinoma in the setting of clinical and radiological characteristics which, together
           with the pathology, are highly suggestive of a diagnosis of BTC.

        -  Patients must have evaluable or measurable disease per RECIST 1.1.

        -  Patients must have disease that is not amenable to potentially curative resection,

      radiofrequency ablation, or liver transplantation.

      Design:

      -This is an open label Phase II trial conducted to evaluate efficacy of

      durvalumab, bevacizumab and tremelimumab combined treatment in patients with advanced HCC
      BCLC stage C or BTC and efficacy of durvalumab, bevacizumab, tremelimumab and TACE combined
      treatment in patients with advanced HCC BCLC stage B.

        -  Initially 3-6 patients with HCC BCLC Stage C or BTC will be enrolled into safety run-in
           of Arm

           1 to determine the safety of combined treatment of durvalumab, bevacizumab and
           tremelimumab.

        -  Once safety has been determined, subsequent patients with HCC BCLC Stage C and BTC will
           be enrolled in Arm 1 and patients with HCC BCLC Stage B will start enrollment into Arm
           2,

      consistent of durvalumab, bevacizumab, tremelimumab and multiple TACE procedures.

      -Treatment will continue until progression or unbearable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
1/ Arm 1ExperimentalDurvalumab, bevacizumab and tremelimumab
  • durvalumab
  • bevacizumab
  • Tremelimumab
2/ Arm 2ExperimentalDurvalumab, bevacizumab, tremelimumab and TACE
  • durvalumab
  • Doxorubicin-Eluting Beads
  • bevacizumab
  • Tremelimumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Proportion of patients with advanced HCC BCLC stage B that have progressive disease after 6 months

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Proportion of patients whose tumors shrunk after therapy
Measure:To characterize overall survival (OS) in patients with advanced HCC and BTC treated on this study
Time Frame:death
Safety Issue:
Description:Median amount of time subject survives after therapy
Measure:To determine the safety and feasibility of bevacizumab, durvalumab, tremelimumab and TACE in patients with advanced HCC
Time Frame:every visit to clinical center
Safety Issue:
Description:List of adverse event type, grade and frequency
Measure:To determine the safety and feasibility of bevacizumab, durvalumab, tremelimumab in patients with advanced BTC
Time Frame:every visit to clinical center
Safety Issue:
Description:List of adverse event type, grade and frequency

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Immune Checkpoint Blockade
  • Combined Treatment
  • Immunotherapy
  • Anti-Tumor Immunity
  • Inhinition of the Blood Vessels Surrounding a Tumor

Last Updated

October 13, 2020