Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Central Nervous System Depressants

All Drugs and Chemicals

Hematinics

Anti-Infective Agents

Anesthetics

Liver Extracts

Ethanol

The Combined Treatment: patients undergo a surgical operation of ipsilateral liver lobe devascularization and four weeks later after the operation percutaneous alcohol injection sessions.

This modality of palliative treatment includes initial surgical operation where arterial vascular supply of the tumor carrying liver lobe of the corresponding hepatic artery as well as the extrahepatic collateral arteries (EHCAs) feeding the large HCC (\> 5 cms size) under general anesthesia. Four weeks after the operation the tumor is injeted (intralesionally and intravascularly) with absolute ethanol alcohol injections on regular weekly percutaneous sessions until the tumor become saturated and its vascularity rendered inactive.

Combined Treatment

Osama M Elsanousi, MD

Assessment of the long-term outcome of combined ipsilateral liver lobe devascularization (ILAD) and alcohol injection of the large hepatocellular carcinoma (HCC): single center non-randomized trial.

Assessment of the overall (OS); one year; two years and three years' survival rates; the disease free survival (DFS) and the tumor response rate in the patients undergoing Combined Ipsilateral Liver Lobe Devascularization and Alcohol Treatment (CILDAT) of the Large HCC. This is a prospective non randomized trial carried out at the Ribat University Hospital between May 2017 to April 2020.

Prospective, non-randomized and time series clinical trial.

Combined Ipsilateral Liver Lobe Devascularization and Alcohol Treatment of the Large Hepatocellular Carcinoma

Long Term Outcome of Combined Ipsilateral Liver Lobe Devascularization and Alcohol Treatment (CILDAT) of the Large Hepatocellular Carcinoma (HCC)

The percentage of patients who are still alive for three years after they started CILDAT for their large HCC.

Percentage of HCC patients who are alive and well (without a recurrence of their HCC) 3 years after CILDAT

Incidence of post CILDAT Clavien-Dindo comlicatins grade 3b or more.

Incidence of post CILDAT Common Terminology Criteria for Adverse Events (CTCAE v4.03) grade

Mean percentage reduction in the sizes of the patients' tumors

The National Ribat University

General Surgeon

Antineoplastic Agents

Bevacizumab

Doxorubicin

Liposomal doxorubicin

Immunomodulating Agents

Durvalumab

Chlorotrianisene

Tremelimumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Durvalumab, bevacizumab, tremelimumab and TACE

1,150 mg flat dose every 21 days, starting on day 1 of cycle 1

durvalumab

used for TACE (only in patients with HCC BCLC stage B)

Doxorubicin-Eluting Beads

TACE with Doxorubicin-Eluting Beads (only in patients with HCC BCLC stage B) on Cycle 2. More TACE can be done if clinically necessary.

TACE

7.5 mg/kg dose every 21 days, starting on day 1 of cycle 2

bevacizumab

300, 150 or 75 mg once on day 1 of cycle 1

Donna M Hrones, C.R.N.P.

Tim F Greten, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

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.

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 (IgG1k ) 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 human 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 3-18 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.

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

A Phase II Study of Combined Treatment of Durvalumab, Bevacizumab, Tremelimumab and Transarterial Chemoembolization (TACE) in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinoma (BTC)

.All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP

Proportion of patients with advanced HCC BCLC stage B that have progressive disease after 6 months

Proportion of patients with BTC and HCC BCLC stage C that have progressive disease after 6 months

Proportion of patients whose tumors shrunk after therapy

Median amount of time subject survives after therapy

List of adverse event type, grade and frequency

National Cancer Institute (NCI)

Rare Diseases

Cholangiocarcinoma

Bile Duct Cancer

Intrahepatic Cholangiocarcinoma

Gemcitabine

Cisplatin

Antimetabolites

Radioembolization with Y-90 will be performed in nominal day 0

radioembolization with Y-90

Following radioembolization, for 6 cycles -intravenous infusion on day 1 of each cycle

Following radioembolization, for 6 cycles -intravenous infusion on day 1 and 8 of each cycle

Francesco De Cobelli, MD

Stephanie Steidler, PhD

Francesca Ratti, MD

Underlying disease mechanisms are fundamental for correct treatment selection and patient management in highly invasive and debilitating non-transmissible diseases. Even though overall disease burden of cancer may have decreased due to a higher degree of awareness, the availability of high-quality healthcare and early diagnosis may become challenging in certain neoplasms. Cholangiocarcinoma is usually diagnosed at advanced stages due to non-specific presentation and is frequently refractory to chemotherapy, causing a massive impact on patients and their families. Surgery is currently the only curative treatment but is available to only approximately 30% of patients. The combination of interventional- and immune-oncology to standard of care creates the perfect substrate for synergistic mechanisms to fight tumor growth; in situ cell death following transarterial embolization(TARE) elicits immune mediated response, inflammatory response and biomarkers of oxidative stress and increases antigen presenting T-cells which an anti-anti progam death ligand (PD-L)1 can bind to; standard of care can then add on with its known effects.The rationale of a combined- locoregional and systemic - treatment lies in the synergistic effects of each of the treatments.

Tumors are highly selective and well defined abnormal cellular proliferations in which microenvironment plays an important role in response to treatment. Intrahepatic Cholangiocarcinoma (iCCA), a tumor derived from the epithelia cells of the bile duct, is particularly invasive and malignant. Personalized treatment options with documented efficacy in patients with iCCA are still not available due to the complex and heterogenous molecular pathogenesis which has not been holistically described. Disease models have limited reproducibility; underlying chronic cholestatic disease, chronic inflammation and risk factors contribute to the complexity and diversity of tumor microenvironment. Although novel systemic therapeutic agents show improvement compared to standard of care chemotherapy, a significant percentage of patients still does not respond to treatment, maybe due to molecular/immunologic features which confer resistance. Local treatment prior to systemic therapy has shown to induce subtle changes in the tumor microenvironment and a systemic immune response: engagement of the immune system may therefore lead to enhanced and long term immunosurveillance and therefore, lasting benefits for cancer patients.

Combined systemic treatment with an anti PD-L1, that binds to the programmed cell death protein 1, and the standard of care (SOC) protein kinase inhibitor sorafenib and gemcitabine (which inhibits DNA synthesis), have been used in clinical trials for other primary liver indications and in patients with biliary tract cancers (TOPAZ trial).

Radioembolization (TARE) combines the embolization properties of microspheres with the radiant effect of Yttrium-90 (Y-90). The locally treated tumor tissue is left in place and releases tumor-associated antigens and danger-associated molecular peptides originating from dead or dying cancer cells which promote the activation of antigen presenting cells and anti-tumor CD8+T cells. The resulting development of a systemic immune response following local treatment may lead to tumor regression at different sites than the one treated locally, leading to the so-called abscopal effect.

Comprehensive evaluations in patients undergoing combined treatment may allow a better understanding of tumor pathophysiology as well as the optimization of combined treatment schemes.

This study will investigate the efficacy, primary endpoint overall response rate according to mRECIST (modified Response Evaluation Criteria in Solid Tumors) , and safety of the association of locoregional radioembolization followed by the combination of standard of care (SOC) chemotherapy with Cisplatin and Gemcitabine and durvalumab in patients with liver predominant unresectable intrahepatic cholangiocarcinoma. The biological profile of patients prior to and following locoregional treatment and the effect of systemic therapy will be characterized in terms of potential biomarkers such as quantitative non-invasive radiological based parameters, tumor tissue profiling and evaluation of biological substrates to help define and stratify patients with higher response and better outcome.

Precision Medicine in Patients With Unresectable CholAngiocarcinoma: RadioEmbolization and Combined Biological Therapy

Single Arm, Multicenter Phase II Study Investigating the Efficacy and Safety of a Novel Therapeutic Scheme in Patients With Unresectable CholAngiocarcinoma: RadioEmbolization in Combination With CisGem and Durvalumab (MEDI4736)

mRECIST criteria on imaging (modified Response Evaluation Criteria in Solid Tumors criteria)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combined Ipsilateral Liver Lobe Devascularization and Alcohol Treatment of the Large Hepatocellular Carcinoma	NCT03138044	Hepatocellular ...	Combined Treatm...	15 Years - 75 Years	The National Ribat University
Combined Treatment of Durvalumab, Bevacizumab, Tremelimumab and Transarterial Chemoembolization (TACE) in Subjects With Hepatocellular Carcinoma or Biliary Tract Carcinoma	NCT03937830	Hepatocellular ... Hepatocellular ... Metastatic Hepa...	durvalumab Doxorubicin-Elu... TACE bevacizumab Tremelimumab	18 Years -	National Institutes of Health Clinical Center (CC)
Precision Medicine in Patients With Unresectable CholAngiocarcinoma: RadioEmbolization and Combined Biological Therapy	NCT06375915	Intrahepatic Ch...	radioembolizati... Durvalumab Cisplatin Gemcitabine	18 Years - 80 Years	IRCCS San Raffaele
Combined Ipsilateral Liver Lobe Devascularization and Alcohol Treatment of the Large Hepatocellular Carcinoma	NCT03138044	Hepatocellular ...	Combined Treatm...	15 Years - 75 Years	The National Ribat University
Precision Medicine in Patients With Unresectable CholAngiocarcinoma: RadioEmbolization and Combined Biological Therapy	NCT06375915	Intrahepatic Ch...	radioembolizati... Durvalumab Cisplatin Gemcitabine	18 Years - 80 Years	IRCCS San Raffaele

Spots Global Cancer Trial Database for combined treatment