Durvalumab + Tremelimumab for Solid Tumors

Overseen By Heather Heath

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: John L. Villano, MD, PhD

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune disorders, Active infection, Organ transplant, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

14 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will examine whether patients with relapsed/refractory solid tumors harboring evidence of somatic hypermutation (intermediate versus high tumor mutational burden) will exhibit improvement in disease progression-free survival with dual Tremelimumab and Durvalumab treatment.

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, it mentions that you should not have received any anticancer therapy 30 days before starting the study drug. It's best to discuss your current medications with the study team to ensure they don't interfere with the trial.

What data supports the effectiveness of the drug combination of Durvalumab and Tremelimumab for solid tumors?

Research shows that the combination of Durvalumab and Tremelimumab provides clinical benefits and is generally safe for patients with solid tumors. This combination may offer better anti-tumor activity than using either drug alone, as seen in studies involving non-small cell lung cancer. ^{1 2 3 4 5}

Is the combination of Durvalumab and Tremelimumab generally safe for humans?

The combination of Durvalumab and Tremelimumab has been found to have a tolerable safety profile in patients with solid tumors, although it may lead to more severe side effects compared to Durvalumab alone, such as increased rates of reduced appetite and diarrhea. ^{1 2 6 7 8}

How is the combination of durvalumab and tremelimumab unique for treating solid tumors?

The combination of durvalumab and tremelimumab is unique because it uses two immune checkpoint inhibitors to enhance the body's immune response against tumors, potentially offering greater antitumor activity than using either drug alone. ^{1 2 3 6 9}

Research Team

John Villano, MD, PhD

Principal Investigator

University of Kentucky

Eligibility Criteria

Adults over 18 with relapsed/refractory solid tumors and a high or moderate tumor mutational burden, who haven't had prior anti-PD-1/PD-L1 or anti-CTLA-4 therapy. Participants must have good organ function, not be pregnant or breastfeeding, use effective contraception, and have no history of certain autoimmune diseases or uncontrolled illnesses.

Inclusion Criteria

I am older than 18 years.

I am not pregnant and am post-menopausal or have had a negative pregnancy test if pre-menopausal.

I am a man who will use approved birth control methods if I have sex, or I won't have sex.

Exclusion Criteria

I have nerve damage that affects my daily activities.

I have side effects from past treatments that won't worsen with durvalumab or tremelimumab.

You have received an organ transplant from someone else in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Durvalumab and Tremelimumab combination therapy for treatment of relapse/refractory solid tumors with moderate to high tumor mutational burden

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Durvalumab and Tremelimumab Combination

Trial Overview The trial is testing the combination of Durvalumab and Tremelimumab to see if they improve progression-free survival in patients with solid tumors that show somatic hypermutation. It's for those whose cancer has returned after treatment.

Participant Groups

Group I: Patients with moderate to high tumor mutational burden Experimental Treatment 1 Intervention

Patients with recurrent or refractory disease in solid tumors naïve to anti-PD-1/PD-L1 or anti-CTLA-4 immunotherapy and have moderate to high tumor mutational burden (TMB)

Who Is Running the Clinical Trial?

John L. Villano, MD, PhD

Lead Sponsor

Trials

3

Recruited

90+

Findings from Research

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 combination of durvalumab and tremelimumab was studied in 19 articles involving 2052 patients with solid tumors, showing some benefits over traditional chemotherapy in certain tumor types.

However, this combination did not consistently outperform durvalumab alone, indicating that while it may have potential, further research with larger and better-designed studies is needed to clarify its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. Arru, C., De Miglio, MR., Cossu, A., et al.[2023]

In a phase 1b study involving 102 patients with advanced non-small cell lung cancer, the combination of durvalumab and tremelimumab demonstrated manageable safety, although 36% of patients experienced serious treatment-related adverse events, including three treatment-related deaths.

The treatment showed evidence of antitumor activity in both PD-L1-positive and PD-L1-negative tumors, with a confirmed objective response rate of 23% in the cohort receiving tremelimumab 1 mg/kg, indicating potential effectiveness regardless of PD-L1 status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Antonia, S., Goldberg, SB., Balmanoukian, A., et al.[2022]

In the NEPTUNE phase 3 study involving 823 patients with metastatic non-small cell lung cancer (mNSCLC), the combination of durvalumab and tremelimumab did not significantly improve overall survival compared to standard chemotherapy in patients with a blood tumor mutational burden (bTMB) of 20 mutations per megabase or more.

However, the combination therapy showed a lower incidence of severe treatment-related adverse events (20.7%) compared to chemotherapy (33.6%), suggesting a potentially better safety profile for durvalumab plus tremelimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NEPTUNE: Phase 3 Study of First-Line Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC. de Castro, G., Rizvi, NA., Schmid, P., et al.[2023]

This phase II study aims to evaluate the effectiveness of combining durvalumab and tremelimumab with neoadjuvant chemotherapy in improving progression-free survival (PFS) in patients with advanced-stage ovarian cancer, specifically those with stage IIIC/IV epithelial ovarian cancer.

The study will involve 24 patients and will assess immune biomarkers and changes in the tumor microenvironment through serial biopsies, with the primary goal of achieving a 12-month PFS rate, while also monitoring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of neoadjuvant chemotherapy plus durvalumab and tremelimumab in advanced-stage ovarian cancer: a Korean Gynecologic Oncology Group Study (KGOG 3046), TRU-D. Lee, JY., Kim, JW., Lim, MC., et al.[2020]

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]

In a phase I trial involving Japanese patients with advanced cancer, tremelimumab was found to be safe and well-tolerated, with no dose-limiting toxicities observed in the initial dosing phase, although 75% of patients reported treatment-related adverse events.

When combined with durvalumab, tremelimumab showed a manageable safety profile, with only two instances of serious adverse events (Grade 4 myasthenia gravis and hyperglycemia), indicating that the combination therapy can be administered with careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma. Fujiwara, Y., Takahashi, Y., Okada, M., 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]

In the phase III POSEIDON study involving 1,013 patients with metastatic non-small-cell lung cancer (mNSCLC), the combination of durvalumab plus chemotherapy significantly improved progression-free survival (PFS) compared to chemotherapy alone, with a median PFS of 5.5 months versus 4.8 months.

The addition of tremelimumab to durvalumab and chemotherapy further enhanced both PFS and overall survival (OS) compared to chemotherapy alone, with a median OS of 14.0 months versus 11.7 months, while maintaining a similar safety profile to chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. Johnson, ML., Cho, BC., Luft, A., et al.[2023]

References

1. 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]

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

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. [2022]

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

NEPTUNE: Phase 3 Study of First-Line Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC. [2023]

5. Korea (South) pubmed.ncbi.nlm.nih.gov

A phase II study of neoadjuvant chemotherapy plus durvalumab and tremelimumab in advanced-stage ovarian cancer: a Korean Gynecologic Oncology Group Study (KGOG 3046), TRU-D. [2020]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma. [2022]

8. 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]

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

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. [2023]