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Protocol Details

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 NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

16-C-0135

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Completed Study; data analyses ongoing
Gender: Male & Female
Min Age: 18 Years
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

Pregnant Women;
Fetuses;
Children

Keywords

PDL1-Mediated Adaptive Resistance;
Monoclonal Antibody;
CTLA-4;
Ablative Therapy;
Combination of Tremelimumab and Durvalumab

Recruitment Keyword(s)

None

Condition(s)

Biliary Tract Neoplasms;
Liver Cancer;
Hepatocellular Carcinoma;
Cholangiocarcinoma;
Bile Duct Cancer

Investigational Drug(s)

Tremelimumab
Durvalumab

Investigational Device(s)

None

Intervention(s)

Drug: Durvalumab
Drug: Tremelimumab
Procedure/Surgery: Trans-arterial Catheter Chemoembolization (TACE)
Procedure/Surgery: Radiofrequency Ablation (RFA)
Procedure/Surgery: Cryoablation

Supporting Site

National Cancer Institute

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 (PDL 1)-mediated adaptive resistance and the emerging role of programmed cell death protein 1 (PD 1) 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.

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Eligibility

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. Patients must have multiple tumor lesions (at least 2): one for the ablation procedure and another for evaluation located outside the proposal ablation zone.

4. 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.

5. If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification

6. Age 18 years or older

7. ECOG performance status 0-2

8. 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 for patients with creatinine levels above institutional normal

9. 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.

10. 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).

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

12. 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.

13. Body weight greater than 30kg

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.


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Citations:

Duffy AG, Greten TF. Immunological off-target effects of standard treatments in gastrointestinal cancers. Ann Oncol. 2014 Jan;25(1):24-32. doi: 10.1093/annonc/mdt349. Epub 2013 Nov 7.

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2.

Sangro B, Gomez-Martin C, de la Mata M, I(SqrRoot) arrairaegui M, Garralda E, Barrera P, Riezu-Boj JI, Larrea E, Alfaro C, Sarobe P, Lasarte JJ, P(SqrRoot)(Copyright)rez-Gracia JL, Melero I, Prieto J. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013 Jul;59(1):81-8. doi: 10.1016/j.jhep.2013.02.022. Epub 2013 Mar 4.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Tim F. Greten, M.D.
National Cancer Institute (NCI)
NIHBC 10 - CLINICAL CENTER BG RM 2B38B
10 CENTER DR
BETHESDA MD 20892
(240) 760-6114
gretentf@mail.nih.gov

Donna M. Hrones, C.R.N.P.
National Cancer Institute (NCI)
BG 10 RM 5B40
10 CENTER DR
BETHESDA MD 20814
(240) 858-3155
donna.mabry@nih.gov

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
1-888-NCI-1937

Clinical Trials Number:

NCT02821754

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