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

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ClinicalTrials.gov Identifier: NCT03937830
Recruitment Status : Not yet recruiting
First Posted : May 6, 2019
Last Update Posted : October 11, 2019
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 want to see if a combination of drugs can stop HCC from getting worse. This could 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 a CT and/or MRI scan. They will have heart tests. They will give blood, urine, and tumor samples. If no tumor sample is available, they will have a biopsy. They may have an endoscopy of their esophagus and stomach.

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

  • Two drugs will be injected into a vein every 3 weeks.
  • One drug will be given under sedation. Medicine beads will be infused into artery branches. Participants may be kept overnight so they can be observed. This drug may be given once during the study, or more than one time.

Participants will repeat some of the screening tests throughout the study.

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

Participants will stay in the study until their cancer gets worse or they can no longer tolerate the side effects of the drugs.

...


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

Detailed Description:

Background:

  • Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a median survival of 6-9 months.
  • A class of agents that in the recent years has been at the epicenter of immunotherapy approaches in HCC 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.
  • 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 consequenly arrest the tumor growth by depriving essential nutrients and oxygen.
  • TACE has been shown to induce anti-tumor immunity.
  • Early phase study has showed anti-VEGF bevacizumab with TACE diminishes

neovascular formation.

-We have previously shown that the 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.

Objective:

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

Eligibility:

  • Histopathological confirmation of HCC 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 HCC
  • HCC of intermediate (B) or advanced (C) stage per Barcelona Clinic Liver Cancer (BCLC) classification.
  • 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 efficiency of durvalumab,

bevacizumab and TACE combined treatment in patients with advanced HCC.

  • Initially 6 patients with BCLC Stage C will be enrolled into safety run-in of Arm 1 to determine the safety of combined treatment, including one TACE.
  • Once safety has been determined, subsequent patients will be enrolled in Arm 1 (patients with BCLC Stage C) and Arm 2, including more than one TACE (patients with BCLC Stage B).
  • Treatment will continue until progression or unbearable toxicity.

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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 and Transarterial Chemoembolization (TACE) in Subjects With Hepatocellular Carcinoma (HCC)
Estimated Study Start Date : October 16, 2019
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/ Arm 1
Durvalumab, bevacizumab and one TACE procedure
Drug: durvalumab
1,150 mg flat dose every 21 days

Drug: Doxorubicin-Eluting Beads
used for TACE

Procedure: TACE
TACE with Doxorubicin-Eluting Beads

Drug: bevacizumab
7.5 mg/kg dose every 21 days

Experimental: 2/ Arm 2
Durvalumab, bevacizumab and one TACE procedure with possibility to perform subsequent TACE if and when is clinically necessary
Drug: durvalumab
1,150 mg flat dose every 21 days

Drug: Doxorubicin-Eluting Beads
used for TACE

Procedure: TACE
TACE with Doxorubicin-Eluting Beads

Drug: bevacizumab
7.5 mg/kg dose every 21 days




Primary Outcome Measures :
  1. To evaluate 6-month progression free survival (PFS [ Time Frame: 6 months ]
    Proportion of patients that have progressive disease after 6 months



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

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 HCC.

    • Patients should have received at least one line of systemic therapy including but not limited to sorafenib, lenvatinib, regorafenib and/or immune checkpoint inhibitor therapy with evidence of disease progression clinically or radiographically as deemed by investigator or refused standard-of-care therapy.
    • 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
    • Patients must have lesions accessible for biopsy and be willing to undergo pre- and posttreatment biopsies
    • Patients with cirrhosis must have had esophagogastric endoscopy within the previous 6 months prior to enrollment for the assessment of varices. If participants have not had this done, they must be willing to undergo this procedure prior to study enrollment. Varices must be reviewed and managed by the gastroenterologist performing endoscopy and deemed as not high risk for bleeding.
    • ECOG performance status of 0 to 1
    • If liver cirrhosis is present, patient must have a Child-Pugh score <7
    • BCLC C (Cohort 1) or BCLC B (Cohort 2)
    • 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 (Isolated prolonged aPTT with positive LAC will have hematologist clearance before enrollment)

    • 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 participation 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

EXCLUSION CRITERIA:

  • Systemic anti-cancer treatment or radiotherapy within 4 weeks of enrollment.
  • Major surgery within 6 weeks of enrollment. Minor procedures (e.g. port placement, endoscopy with intervention) within 4 weeks of enrollment.
  • Active central nervous system metastases and/or carcinomatous meningitis. Patients with known 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).
  • Patients with a history of bleeding varices within 1 year of enrollment.
  • Thromboembolic event within 6 months of enrollment (including cerebrovascular accident (CVA) and myocardial infarction (MI).
  • Evidence of bleeding diathesis or significant coagulopathy (with or without current therapeutic anticoagulation).
  • History of hemoptysis (>1/2 teaspoon of bright red blood per episode) within 1 month of enrollment.
  • 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 another monoclonal antibody.
  • Congestive heart failure, baseline LVEF <50%, transmural myocardial infarction, uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg), angina pectoris requiring medication, clinically significant valvular disease, high-risk arrhythmia within 12 months of enrollment. Prior history of hypertensive crisis or hypertensive encephalopathy.
  • Prior invasive malignancies within the past 5 years of enrollment (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 enrollment.
  • 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 enrollment. 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 enrollment. Note that diverticulosis is permitted.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 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 Not yet 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     History of Changes
Other Study ID Numbers: 190094
19-C-0094
First Posted: May 6, 2019    Key Record Dates
Last Update Posted: October 11, 2019
Last Verified: September 25, 2019

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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) ):
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
Liposomal doxorubicin
Antibodies, Monoclonal
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
Immunologic Factors