Durvalumab + Tremelimumab for Liver Cancer

((NEOTOMA) Trial)

Recruiting at 2 trial locations

Overseen By Claudia Sweeney

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must be taking: Antivirals

Must not be taking: Immunosuppressants

Disqualifiers: Metastasis, Autoimmune disorders, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

28 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you have hepatitis B, you must continue antiviral therapy during the study and for 6 months after. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug combination of Durvalumab and Tremelimumab for liver cancer?

The combination of Durvalumab and Tremelimumab was shown to improve overall survival in patients with inoperable liver cancer compared to the drug sorafenib, as demonstrated in the HIMALAYA study. Patients receiving this combination lived a median of 16.4 months, compared to 13.8 months for those on sorafenib. ^{1 2 3 4 5}

Is the combination of Durvalumab and Tremelimumab safe for humans?

The combination of Durvalumab and Tremelimumab has been studied in various cancers and is generally considered to have a tolerable safety profile, though it can cause side effects like rash, fatigue, diarrhea, and abdominal pain. In studies, serious side effects occurred in about 32.6% of patients, which is higher than when using Durvalumab alone. ^{1 3 4 6 7}

How is the drug combination of durvalumab and tremelimumab unique for liver cancer?

The combination of durvalumab and tremelimumab is unique for liver cancer because it involves a novel regimen with a single priming dose of tremelimumab followed by monthly durvalumab, which has shown better overall survival compared to the standard treatment sorafenib for patients with inoperable liver cancer. ^{1 2 3 4 5}

Research Team

Jennifer J. Knox, MD, MSc

Principal Investigator

Univeristy Health Network

Grainne O'Kane, MD

Principal Investigator

Univeristy Health Network

Gonzalo Sapisochin, MD

Principal Investigator

Univeristy Health Network

Bruno Sangro, MD

Principal Investigator

Clinica Universidad de Navarra

Vincenzo Mazaferro, MD

Principal Investigator

University of Milan

Eligibility Criteria

This trial is for adults over 18 with early to intermediate stage resectable liver cancer (HCC). They must be in good health, have a specific liver function score (Childs Pugh 5 or 6), and agree to use effective contraception. Excluded are those with certain types of HCC, previous HCC therapies except one curative surgery/ablation, active infections like TB or HIV, recent major surgeries, heart issues, other cancers or autoimmune diseases.

Inclusion Criteria

Body weight > 30kg

My organs and bone marrow are functioning well.

Must consent to provide biopsy sample prior to treatment

Exclusion Criteria

I have had significant fluid buildup in my abdomen within the last 6 months.

My cancer has spread to distant parts of my body.

I have both hepatitis B and either hepatitis C or D.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-operative Treatment

Participants receive 1 dose of Tremelimumab (300 mg) with Durvalumab (1500 mg) at cycle 1 and 1 further cycle of Durvalumab (1500 mg) before surgical resection

8 weeks

Surgical Resection

Participants undergo surgical resection of the tumor

Adjuvant Treatment

Post-surgical resection, participants receive adjuvant Durvalumab (1500 mg Q4W) for up to 11 cycles

44 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Treatment Details

Interventions

• Tremelimumab

Trial Overview The study tests the safety and effects of Durvalumab combined with Tremelimumab before surgery in patients with resectable liver cancer. Participants will receive these drugs pre-surgery followed by up to 13 cycles of Durvalumab post-surgery. The goal is to see if this treatment can improve outcomes by affecting the tumor environment.

Participant Groups

Group I: Tremelimumab in combination with Durvalumab preoperatively, followed by adjuvant Durvalumab Experimental Treatment 1 Intervention

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.

Tremelimumab is already approved in United States for the following indications:

Approved in United States as Imjudo for:

• Unresectable hepatocellular carcinoma

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

University of Milan

Collaborator

Trials

268

Recruited

307,000+

Clinica Universidad de Navarra, Universidad de Navarra

Collaborator

Trials

154

Recruited

74,800+

Findings from Research

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

The combination of tremelimumab and durvalumab (T300 + D) showed the highest overall survival rate (18.7 months) and objective response rate (24.0%) among patients with unresectable hepatocellular carcinoma, indicating its potential as an effective treatment option.

All treatment regimens were generally well-tolerated, but T300 + D had the most favorable safety profile, with a significant association between early CD8+ lymphocyte expansion and treatment response, suggesting a promising mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. Kelley, RK., Sangro, B., Harris, W., et al.[2022]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

The FDA approved tremelimumab in combination with durvalumab for treating unresectable hepatocellular carcinoma based on the HIMALAYA study, which showed a significant improvement in overall survival (OS) compared to sorafenib, with a median OS of 16.4 months versus 13.8 months.

Common adverse reactions in patients receiving the combination treatment included rash, fatigue, diarrhea, and abdominal pain, occurring in 20% or more of patients, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. Patel, TH., Brewer, JR., Fan, J., et al.[2023]

In the phase III HIMALAYA trial, patients with inoperable hepatocellular carcinoma who received a single dose of tremelimumab combined with monthly durvalumab showed improved overall survival compared to those treated with sorafenib.

This suggests that the combination therapy may be a more effective first-line treatment option for this type of liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Immunotherapy Makes Strides against HCC. [2022]

The single-dose regimen of 300 mg tremelimumab combined with durvalumab (STRIDE) shows a favorable benefit-risk profile for patients with unresectable hepatocellular carcinoma (uHCC), as demonstrated in phase I/II and phase III studies.

Higher exposure to tremelimumab is associated with longer overall survival in patients, with those having minimum serum drug concentrations above the median living significantly longer (18.99 months) compared to those below the median (10.97 months), although this relationship may be influenced by other patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma. Song, X., Kelley, RK., Khan, AA., et al.[2023]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Dual Immunotherapy Makes Strides against HCC. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]