Durvalumab and Tremelimumab in Resectable HCC

NCT05440864 | Recruiting Phase 2

• 1 other identifier: 22-5353
• Study Type: interventional
• Target: 28
• Locations: 3 countries
• Sites: 3

Brief Summary

Hepatocellular Carcinoma (HCC) is the third most common cause of death from cancer world wide and the incidence is rising globally. Despite surgical resection in appropriate patients, many patients recur. The results of the IMbrave150 study have established PD-L1 inhibition in combination with VEGF inhibition as a new standard of care highlighting the role of immune checkpoint inhibition in advanced HCC. In addition, the combination of Tremelimumab and Durvalumab has demonstrated efficacy in advanced HCC; the HIMALAYA trial has now completed accrual in treatment naïve patients with advanced HCC. Furthermore the earlier use of immune checkpoint inhibitors in this disease are being explored with adjuvant combination strategies, including the EMERALD-2 trial (NCT03847428). Neoadjuvant treatment in HCC allows for delivery of treatment pre surgery and may enhance pathological responses and improve outcomes. The delivery of combination CTLA-4 and PD-L1 inhibition has demonstrated efficacy in other tumour types in the neoadjuvant setting where the impact on the tumour microenvironment has also been evaluated. The safety and feasibility of Durvalumab and Tremelimumab in resectable HCC has yet to be established. Hypotheses Pre-operative (pre-op) Durvalumab and Tremelimumab treatment is safe and feasible in pre surgical setting for upfront resectable HCC The combination of Durvalumab and Tremelimumab pre-op will result in changes in immune and molecular characteristics within the tumour microenvironment. Overall Study Design This is a phase II, open-label multi-centre study to assess safety of Durvalumab and Tremelimumab treatment in pre-op setting for upfront resectable HCC, followed by adjuvant Durvalumab. 28 patients are expected to enrol at three sites. Patients will receive pre-op: 1 dose Tremelimumab (300mg) (T300) with Durvalumab (1500mg) at cycle 1 and 1 further cycle of Durvalumab (1500mg) only. Post-surgical resection, adjuvant therapy will consist of Durvalumab Q4W for up to a maximum of 12 months in total or 13 cycles of Durvalumab (11 cycles post op). All participants will be treated until progressive disease or unacceptable toxicity or withdrawal of consent or another discontinuation criterion is met. All participants will be followed for survival until the end of study. No dose reductions of Tremelimumab and Durvalumab will be allowed. Statistics The primary objective of this study is to assess safety of pre-op treatment with Durvalumab and Tremelimumab. For safety, with the null proportion of patients who discontinue treatment due to AEs, imAEs or SAE is 30% versus the alternative proportion is 10% or less than 10%, a sample size of 28 provides 80% power to detect the proportion difference with a two-sided alpha level of 0.1. The sample size estimate is based on the two-sided exact test for binomial proportion considering Binomial Enumeration method.

Conditions

Hepatocellular Carcinoma

Keywords

hcc; resection; Durvalumab; Tremelimumab; neoadjuvant; adjuvant; phase II; perioperative; surgical; immunotherapy; hepatoma; hepatocellular carcinoma

Outcome Measures

Primary Outcomes (1)

• Number of greater than grade 3 adverse events (AEs) or immune related adverse events that leads to treatment cessation

  Null proportion of patients who discontinue treatment due to AEs, imAEs or SAE is 30% versus the alternative proportion is 10% or less than 10%, a sample size of 28 provides 80% power to detect the proportion difference with a two-sided alpha level of 0.1.

  4 years

Secondary Outcomes (4)

• Number of patients who experience a surgical delay due to treatment related adverse events (TRAEs)

  4 years

• Overall response rate (ORR)

  2 year

• Pathological response rate

  2 year

• Rates of R0 resection

  2 year

Other Outcomes (6)

• Recurrence free survival

  4 years

• Overall survival

  4 years

• Changes in immune markers in tissue collected

  4 years

Study Arms (1)

Tremelimumab in combination with Durvalumab preoperatively, followed by adjuvant Durvalumab

EXPERIMENTAL

Patients will receive 1 dose Tremelimumab (300 mg) with Durvalumab (1500mg) at cycle 1 (4W) and 1 further cycle of Durvalumab (1500mg) pre surgical resection. Post-surgical resection patients will begin adjuvant Durvalumab (1500mg Q4W) to complete 13 cycles of treatment (or 11 post operatively) in total.

Drug: Tremelimumab

Interventions

Tremelimumab DRUG

Pre-operatively Tremelimumab will be administered first for 1 hour; the Durvalumab infusion (1hr) will start approximately 1 hour (maximum 2 hours) after the end of the Tremelimumab infusion. Post-operatively patients will receive Durvalumab Q4W to complete up to 12 months of treatment or a maximum of 11 cycles of adjuvant Durvalumab

Also known as: Durvalumab

Tremelimumab in combination with Durvalumab preoperatively, followed by adjuvant Durvalumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must be capable of providing written informed consent.
• Age \>18 years at time of study entry
• Histologically proven resectable HCC (early and intermediate stage HCC)\*
• Must consent to provide biopsy sample prior to treatment
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• Childs Pugh score of 5 or 6
• ALBI grade 1†
• Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL) prior to study entry. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (\<10 IU/ml or under limit of detection per local lab standard) do not require anti-viral therapy prior to study entry. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml or above the limit of detection per local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication.
• Patients with HCV infection must have management of this disease per local institutional practice throughout the study. HCV diagnosis is characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment.
• Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients.
• Adequate normal organ and marrow function as defined below within screening period:
• Haemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC ≥1.0 × 109 /L)
• Platelet count ≥65 × 109/L
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). \<\<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.

You may not qualify if:

• \. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• \. Any prior therapy for HCC - except liver resection or ablation on one occasion only which was given with curative intent and that occurred at least two years prior to study enrolment.
• \. Evidence of distant metastasis co-existing malignant disease or macrovascular invasion on baseline imaging.
• \. History of hepatic encephalopathy within 12 months prior to enrolment or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• \. Evidence of portal vein thrombosis, visible on baseline/eligibility imaging, and patients with Vp1, Vp2, Vp3 and Vp4.
• \. Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first dose of study treatment.
• (a) Patients with ascites who have required pharmacologic intervention (eg, diuretics) and who have been on stable doses of diuretics for ascites for ≥2 months before enrolment are eligible.
• \. Any history of nephrotic or nephritic syndrome. 8. Evidence of symptomatic congestive heart failure (New York Heart Association II to IV) or symptomatic or poorly controlled cardiac arrhythmia.
• \. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[except for diverticulosis\], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome \[e.g., granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, and uveitis\]). The following are exceptions to this criterion:
• (a) Patients with vitiligo or alopecia (b) Patients with hypothyroidism (e.g., following Hashimoto syndrome), stable on hormone replacement (c) Any chronic skin condition that does not require systemic therapy (d) Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician (e) Patients with celiac disease controlled by diet alone 10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease (ILD), serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• \. History of another primary malignancy except for the following:
• Prostate cancer of pathologic stage less than or equal to T2cN0M0 determined from a prior prostatectomy without biochemical recurrence and who, in the opinion of the Investigator, are not deemed to require active intervention, or patients with incidental histologic findings of prostate cancer that has not been treated prior to the study and who do not require specific therapy for prostate cancer beyond the surgery described in the Clinical Study Protocol and also are considered to be at low risk for recurrence per the Investigator
• Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study treatment and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo malignant without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease 12. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Clinica Universidad de Navarra, Universidad de Navarra: collaborator
• University of Milan: collaborator

Study Sites (3)

University Health Network

Toronto, Ontario, M5G 2M9, Canada

RECRUITING

University of Milan

Milan, 20122, Italy

NOT YET RECRUITING

Clinica Universidad De Navarra

Pamplona, 31008, Spain

NOT YET RECRUITING

Related Publications (23)

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MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

tremelimumab; durvalumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Study Officials

• Gonzalo Sapisochin, MD

  Univeristy Health Network

  STUDY CHAIR

• Grainne O'Kane, MD

  Univeristy Health Network

  STUDY CHAIR

• Jennifer Knox, MD

  Univeristy Health Network

  PRINCIPAL INVESTIGATOR

• Bruno Sangro, MD

  Clinica Universidad de Navarra

  PRINCIPAL INVESTIGATOR

• Vincenzo Mazaferro, MD

  University of Milan

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Claudia Sweeney

CONTACT

416-634-8300; claudia.sweeney@ozmosisresearch.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a phase II, open label single arm, multicentre study of single dose Tremelimumab (T300) in combination with Durvalumab preoperatively in patients with upfront resectable HCC followed by adjuvant Durvalumab. This study will enroll 28 patients at three academic institutions in Canada and Europe. Patients will receive 1 dose Tremelimumab (300 mg) with Durvalumab (1500mg) at cycle 1 (4W) and 1 further cycle of Durvalumab (1500mg) pre surgical resection. Post-surgical resection patients will begin adjuvant Durvalumab (1500mg Q4W) to complete 13 cycles of treatment (or 11 post operatively) in total.

Study Record Dates

• First Submitted: June 21, 2022
• First Posted: July 1, 2022
• Study Start: October 26, 2023
• Primary Completion: November 1, 2025
• Study Completion (Estimated): November 1, 2026
• Last Updated: October 10, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1); CA (1); IT (1)