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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates whether a combination of two drugs, Durvalumab and Tremelimumab (also known as Imjudo or Tremelimumab-actl), is safe and effective for individuals with surgically removable liver cancer. The trial aims to treat the cancer before surgery to determine if it improves outcomes. Participants will receive the combination treatment before surgery and continue with Durvalumab afterward. This trial suits those with early to intermediate-stage liver cancer who have not received other treatments, except for surgery or ablation performed over two years ago. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of Tremelimumab and Durvalumab has been studied for safety in treating liver cancer. One study tested this combination on patients with advanced liver cancer and found it to be generally safe. The study included 326 patients, who tolerated the treatment well over an average of about 3.7 months.

This combination has also been used to treat other types of cancer. It has improved survival rates without causing severe side effects for most patients. While some patients experienced side effects, these were usually manageable and similar to those expected with immune therapies.

Since this trial is in an early phase, the treatment is considered safe enough to test in more patients. There is reasonable confidence in its safety, but ongoing monitoring during the trial will provide more information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for liver cancer, which often rely on chemotherapy and targeted therapies, Tremelimumab combined with Durvalumab is an immunotherapy approach that works by enhancing the body's immune system to fight cancer cells. Researchers are excited about these treatments because Tremelimumab targets CTLA-4, a protein that normally helps keep the immune system in check, thereby allowing the immune cells to attack cancer more effectively. This combination therapy is unique because it not only aims to reduce the tumor before surgery but also provides ongoing treatment after surgery to help prevent the cancer from returning. By leveraging the body's natural defenses, this approach offers a promising alternative to traditional liver cancer treatments.

What evidence suggests that the combination of Durvalumab and Tremelimumab might be an effective treatment for liver cancer?

This trial will evaluate the use of Tremelimumab in combination with Durvalumab for liver cancer. Studies have shown that using these drugs together can extend the lives of people with liver cancer. The HIMALAYA trial found that this combination treatment significantly increased survival compared to sorafenib, a common drug for liver cancer. Some patients lived up to five years with this treatment. Tremelimumab and Durvalumab enhance the immune system's ability to find and attack cancer cells more effectively. This treatment is already approved for liver cancer cases that cannot be treated with surgery. ^{1 6 7 8 9}

Who Is on the Research Team?

Jennifer J. Knox, MD, MSc

Principal Investigator

Univeristy Health Network

Grainne O'Kane, MD

Principal Investigator

Univeristy Health Network

Bruno Sangro, MD

Principal Investigator

Clinica Universidad de Navarra

Gonzalo Sapisochin, MD

Principal Investigator

Univeristy Health Network

Vincenzo Mazaferro, MD

Principal Investigator

University of Milan

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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 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]

Citations

1. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2100070

Tremelimumab plus Durvalumab in Unresectable ... Conclusions. STRIDE significantly improved overall survival versus sorafenib. Durvalumab monotherapy was noninferior to sorafenib for patients ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10841291/

FDA Approval Summary: Tremelimumab in combination ... On October 21, 2022, the FDA approved tremelimumab (Imjudo) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma (uHC).

3. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/imfinzi-plus-imjudo-demonstrated-unprecedented-overall-survival-alc-with-one-in-five-patients-surviving-five-years-himalaya-phase-iii-trial.html

IMFINZI® (durvalumab) plus IMJUDO® (tremelimumab-actl ... AstraZeneca's IMFINZI (durvalumab) plus IMJUDO (tremelimumab-actl) demonstrated a sustained, clinically meaningful overall survival (OS) benefit at five years.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40222621/

Five-year overall survival update from the HIMALAYA study ... STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) vs. sorafenib in unresectable HCC and demonstrated long- ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.01462

Patient-Reported Outcomes From the Phase III HIMALAYA ... Compared with sorafenib, STRIDE and durvalumab were associated with clinically meaningful, patient-centered GHS/QoL, functioning, and symptom benefits in ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK602395/

Clinical Review - Tremelimumab (Imjudo) in Combination With ... The OS rates at 36 months were 30.7% (95% CI, 25.8 to 35.7) in the tremelimumab in combination with durvalumab group and 20.2% (95% CI,15.8 to 25.1) in the ...

7. imfinzihcp.com imfinzihcp.com/hcc/unresectable/safety.html

Safety Profile of IMFINZI® (durvalumab) & IMJUDO® ... Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the phase 3 HIMALAYA ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.20.03555

Safety, Efficacy, and Pharmacodynamics of Tremelimumab ... The safety analysis included 326 patients from parts 2 and 3. The median (range) duration of exposure was 3.7 (0.8-27.1) months for T300 + D, ...

9. journal-of-hepatology.eu journal-of-hepatology.eu/article/S0168-8278(24)02424-3/fulltext

Outcomes in the Asian subgroup of the phase III ... The global, phase III HIMALAYA study found that the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen improved overall survival ...