Phase 2
N=54
A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)
Biliary Tract Neoplasms · Liver Cancer · Hepatocellular Carcinoma · Cholangiocarcinoma · Bile Duct Cancer
Bottom Line
View on ClinicalTrials.gov: NCT02821754 ↗Enrolled (actual)
54
Serious AEs
51.9%
Results posted
Mar 2022
Primary outcome: Primary: 6 Month Progression Free Survival (PFS) — 2.8; NA Months
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Durvalumab (Drug); Tremelimumab (Drug); Trans-arterial Catheter Chemoembolization (TACE) (Procedure); Radiofrequency Ablation (RFA) (Procedure); Cryoablation (Procedure)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- National Cancer Institute (NCI)
- Primary completion
- Feb 2021
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 6 Month Progression Free Survival (PFS) |
2.8; NA | — |
| SECONDARY Number of Grades 1-5 Adverse Events Related to Tremelimumab and Durvalumab |
355; 233; 125; 133; 62; 50 | — |
Summary
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-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) therapy.
* Based on the concept of programmed death-ligand 1 (PDL1)-mediated adaptive resistance and the emerging role of programmed cell death protein 1 (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 every (q)28 days for 4 doses; Durvalumab 1500mg flat dose q28 days until end of study (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 patients (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.
Eligibility Criteria
- INCLUSION CRITERIA:
- Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) or biliary tract carcinoma (BTC) by the Laboratory of Pathology of the National Cancer Institute (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 intra or extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer.
- 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.
- Patients must have multiple tumor lesions (at least 2): one for the ablation procedure and another for evaluation located outside the proposal ablation zone.
- Disease must be technically amenable to transhepatic arterial chemoembolization (TACE) (HCC patients only), radiofrequency ablation (RFA), or cryoablation. Each case will be discussed at gastrointestinal (GI) tumor board with interventional radiology. Patients must have evaluable disease.
- If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification
- Age 18 years or older
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- 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 x upper limit of normal (ULN)
- 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 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) up to 5 x ULN.
- creatinine 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.
- Body weight greater than 30kg
EXCLUSION CRITERIA
- 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.
- Patients who have undergone prior liver transplantation are ineligible.
- 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.
- 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.
- 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.
- Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requ
Data sourced from ClinicalTrials.gov (NCT02821754). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.