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A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 9, 2017 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT02821754
First received: June 29, 2016
Last updated: March 21, 2017
Last verified: March 9, 2017
  Purpose

BACKGROUND:

  • Various tumor ablative procedures and techniques have been shown to result in immunogenic cell death and induction of a peripheral immune response. The term ablative therapies applies to trans-arterial catheter chemoembolization (TACE), radiofrequency ablation (RFA) and cryoablation (CA).
  • The underlying hypothesis of this study is that the effect of immune checkpoint inhibition can be enhanced by TACE, CA and RFA in patients with advanced hepatocellular carcinoma (HCC) and biliary tract carcinomas (BTC). We have already demonstrated proof of principle as well as safety and feasibility of this approach with anti-CTLA4 therapy.
  • Based on the concept of PDL1-mediated adaptive resistance and the emerging role of PD1 therapy in HCC, we would like to evaluate the combination of tremelimumab and durvalumab (with ablative therapies) in HCC and BTC.

Objectives:

- To preliminarily evaluate the 6-month progression free survival (PFS) of combining tremelimumab and durvalumab in patients with advanced HCC (either alone or with cryoablation, TACE or RFA) and in patients with advanced biliary tract carcinoma (BTC) (either alone or with cryoablation or RFA).

ELIGIBILITY:

  • Histologically or cytologically confirmed diagnosis of HCC or biliary tract carcinoma 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 (or biliary tract carcinoma).
  • Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this limitation does not apply.
  • Patients must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation.

DESIGN:

We will evaluate the combination of tremelimumab and durvalumab (with ablative therapies) in cohorts A (HCC; N=40) and B (BTC; N=30). The first N=10 patients in both cohorts will receive tremelimumab and durvalumab only (i.e. No interventional radiologic procedures).

  • A: Advanced HCC, BCLC# Stage B/C

    • N= 1st 10 pts: No ablative procedure Cryoablation/RFA/TACE##
    • Tremelimumab 75mg flat dose q28 days for 4 doses; Durvalumab 1500mg flat dose q28 days until EOS###
    • 40 total: 10 trem+ dur alone; 10 trem+ dur + TACE; 10 trem + dur + RFA; 10 trem + dur + cryo
  • B: Intra/extra-hepatic cholangiocarcinoma

    • N= 1st 10 pts: No ablative procedure; RFA/ cryoablation
    • Tremelimumab 75mg flat dose q28 days for 4 doses; Durvalumab 1500mg flat dose q28 days until EOS###
    • 30 total: 10 trem+ dur alone; 10 trem + dur + RFA; 10 trem

      • BCLC = Barcelona clinic liver cancer staging system

        • For BCLC stage B patients TACE may be repeated as per standard of care

          • EOS = End of study treatment or meeting any of the off-treatment or off study criteria.

Condition Intervention Phase
Liver Cell Caricinoma
Liver Cancer
Hapatocellular Carcinoma
Liver Neoplasms
Drug: Durvalumab
Drug: Tremelimumab
Procedure: TACE
Procedure: RFA
Procedure: Cryoablation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To preliminarily evaluate the efficacy of combining Tremelimumab and durvalumab in patients with advanced HCC (either alone or with cryoablation, TACE or RFA) and in patients with advanced biliary tract carcinoma (BTC) (either alone or with cryo... [ Time Frame: 4 years ]

Secondary Outcome Measures:
  • To assess the safety and feasibility of combining Tremelimumab and durvalumab in (Cohort A) patients with advanced HCC (either alone or with cryoablation, TACE or RFA) and (Cohort B) in patients with advanced biliary tract carcinoma (BTC) (eithe... [ Time Frame: 4 years ]
  • To evaluate changes in immune parameters as well as pharmacokinetics in the peripheral blood of patients with advanced HCC or BTC undergoing ablative therapies in combination with combined immune checkpoint inhibition. [ Time Frame: 4 years ]

Estimated Enrollment: 90
Study Start Date: June 22, 2016
Estimated Study Completion Date: April 30, 2021
Estimated Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A
Advanced HCC, BCLC# Stage B/C
Drug: Durvalumab
Every 4 weeks for up to 9 doses.
Drug: Tremelimumab
Every 4 weeks for up to 4 doses.
Procedure: TACE
Cohort A (Advanced HCC, BCLC# Stage B/C patients): TACE will be performed once only, also on Day 36 (+/- 96hrs).
Procedure: RFA
Cohort A (Advanced HCC, BCLC# Stage B/C patients): RFA will be performed once only, also on Day 36 (+/- 96hrs).
Procedure: Cryoablation
Cohort A (Advanced HCC, BCLC# Stage B/C patients): Cryoablation will be performed once only, also on Day 36 (+/- 96hrs).
Experimental: Cohort B
Intra/extra-hepatic cholangiocarcinoma
Drug: Durvalumab
Every 4 weeks for up to 9 doses.
Drug: Tremelimumab
Every 4 weeks for up to 4 doses.
Procedure: RFA
Cohort A (Advanced HCC, BCLC# Stage B/C patients): RFA will be performed once only, also on Day 36 (+/- 96hrs).
Procedure: Cryoablation
Cohort A (Advanced HCC, BCLC# Stage B/C patients): Cryoablation will be performed once only, also on Day 36 (+/- 96hrs).

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) or biliary tract carcinoma (BTC) by the Laboratory of Pathology of the NCI prior to entering this study 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 (or biliary tract carcinoma). Fibrolamellar variant is also allowed. The term BTC includes intraor extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer.
    2. Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation. HCC patients must have progressed on, been intolerant to, or refused prior sorafenib therapy. Patients with BTC must have received, been intolerant of or refused at least one line of chemotherapy.
    3. Disease must be technically amenable to transhepatic arterial chemoembolization (TACE) (HCC patients only), radiofrequency ablation (RFA), or cryoablation. Each case will be discussed at GI tumor board with interventional radiology. Patients must have evaluable disease.
    4. If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification
    5. Age >18 years
    6. ECOG performance status 0-2
    7. Patients must have normal organ and marrow function as defined below:
  • leukocytes greater than or equal to 3,000/mcL
  • 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
  • serum albumin If cirrhosis present: Part of Child Pugh requirement; If no cirrhosis: albumin should be less than or equal to 2.5g/dl
  • patients are eligible with ALT or AST up to 5 x ULN.
  • creatinine < 1.5x institution upper limit of normal OR creatinine clearance greater than or equal to 45 mL/min/1.73 m^2, as calculated below; for patients with creatinine levels above institutional normal

    8. Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 or returned to baseline.

    9. Patients must not have other invasive malignancies within the past 5 years (with the exception of non-melanoma skin cancers, non-invasive bladder cancer or localized prostate cancer for whom systemic therapy is not required).

    10. Patient must be able to understand and willing to sign a written informed consent document.

    11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women greater than or equal to 50 years of age would be considered post-menopausal if they have been

amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

12. Body weight >30kg (for durvalumab + tremelimumab).

EXCLUSION CRITERIA:

  1. Patients who have had standard of care chemotherapy, large field radiotherapy, or major surgery must wait 2 weeks prior to entering the study. For recent experimental therapies a 28 day period of time must elapse before treatment.
  2. Patients who have undergone prior liver transplantation are ineligible.
  3. 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.
  4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations that would limit compliance with study requirements.
  5. History of chronic autoimmune disease (e.g., Addison s disease, multiple sclerosis, Graves disease, Hashimoto s thyroiditis, rheumatoid arthritis, hypophysitis, etc.) with symptomatic disease within the 3 years before randomization. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion.
  6. Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol.
  7. Diverticulitis either active or history of within the past 2 years. Note that diverticulosis is permitted.
  8. Active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener s granulomatosis. Currently receiving immunosuppressive doses of steroids or other immunosuppressive medications (inhaled and topical steroids are permitted)
  9. History of sarcoidosis syndrome
  10. Patients should not be vaccinated with live attenuated vaccines within 30 days of starting durvalumab or tremelimumab treatment.
  11. Has a known history of Human Immunodeficiency Virus (HIV). HIV-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and tremelimumab. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that tremelimumab may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events.
  12. History of hypersensitivity reaction to human or mouse antibody products.
  13. Pregnancy and breast feeding are exclusion factors. The effects of tremelimumab on the developing human fetus are unknown. Enrolled patients must agree to use adequate contraception prior to study entry, the duration of study participation and 6 months after the end of the treatment. 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.
  14. Patients with unhealed surgical wounds for more than 30 days.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02821754

Contacts
Contact: Donna E Mabry, C.R.N.P. (301) 451-4864 donna.mabry@nih.gov

Locations
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
Principal Investigator: Tim F Greten, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02821754     History of Changes
Other Study ID Numbers: 160135
16-C-0135
Study First Received: June 29, 2016
Last Updated: March 21, 2017

Keywords provided by National Institutes of Health Clinical Center (CC):
Liver Cancer
Monoclonal Antibody
CTLA-4
Ablative Therapy

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Liver Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Tremelimumab
Antineoplastic Agents

ClinicalTrials.gov processed this record on March 23, 2017