PD-1 Inhibitor vs. PD-1 + TIM-3 Inhibitors for Melanoma

Recruiting at4 trial locations

Overseen by Diwakar Davar, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Diwakar Davar

Must not be taking: Immunosuppressants, Corticosteroids, Anti-PD-1, others

Disqualifiers: Uveal melanoma, Active CNS metastases, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests Dostarlimab alone or with TSR-022 in patients with advanced but operable melanoma. These drugs help the immune system attack cancer by preventing cancer cells from hiding. The goal is to see if these treatments improve outcomes before and after surgery.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic immunosuppressive medications or have recently received certain cancer treatments, you may need to stop or adjust those before participating.

What data supports the effectiveness of the drug Dostarlimab (TSR-042) combined with TIM-3 inhibitors for treating melanoma?

Research shows that combining different types of treatments, like MEK inhibitors and immune checkpoint inhibitors, can enhance the body's ability to fight melanoma. For example, combining trametinib (a MEK inhibitor) with an anti-TIM-3 antibody improved the immune response against melanoma in mice, suggesting that similar combinations could be effective in humans. ^{1 2 3 4 5}

What makes the drug Dostarlimab combined with TIM-3 inhibitors unique for treating melanoma?

This treatment is unique because it combines Dostarlimab, a PD-1 inhibitor, with TIM-3 inhibitors to enhance the immune system's ability to fight melanoma by reversing T cell exhaustion, which is a state where immune cells become less effective at attacking cancer cells. ^{3 4 6 7 8}

Research Team

Diwakar Davar, MD

Principal Investigator

UPMC Hillman Cancer Center

Eligibility Criteria

Adults with operable melanoma, including primary melanoma with regional metastasis or recurrence, are eligible for this trial. They must have adequate organ function and provide a recent tumor biopsy. Pregnant women and individuals on systemic immunosuppression or with certain autoimmune diseases, other active cancers, or severe psychiatric issues cannot participate.

Inclusion Criteria

I agree to use birth control during the study.

My melanoma is not related to the eye or mucous membranes but confirmed by a lab test.

My cancer has spread to nearby lymph nodes or distant parts of my body.

Exclusion Criteria

I have another cancer that is getting worse or needs treatment.

My invasive cancer was diagnosed and treated within the last 2 years.

You have a history of hepatitis B or C, or a positive test for these viruses.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-Operative Treatment

Participants receive neoadjuvant therapy with Dostarlimab (TSR-042) or Dostarlimab (TSR-042)/TSR-022 combination for 6 weeks prior to planned surgery

6 weeks

2 visits (in-person)

Surgery

Surgery occurs 1-4 weeks after completion of pre-operative therapy

1-4 weeks

1 visit (in-person)

Post-Operative Treatment

Participants receive Dostarlimab (TSR-042) for approximately 48 weeks post-surgery

48 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dostarlimab (TSR-042) (PD-1 Inhibitor)
• Dostarlimab (TSR-042) and TSR-022 (PD-1 Inhibitor and TIM-3 Inhibitor)

Trial Overview The study is testing the effectiveness of Dostarlimab (TSR-042) alone versus its combination with Cobolimab (TSR-022) in treating melanoma before surgery. Participants will be randomly assigned to receive one of these two treatment options.

Participant Groups

Group I: Dostarlimab (TSR-042) and Cobolimab TSR-022 (combination) Experimental Treatment 1 Intervention

Pre-Operative Phase: Dostarlimab (TSR-042) 500mg and Cobolimab TSR-022 300mg will be administered through an IV over 30 minutes, on Cycle 1 Day 1 and then again on Cycle 2 Day 1. Post-Operative Phase: Dostarlimab (TSR-042) will be administered through an IV over 30 minutes for 4 doses every 3 weeks (Cycles 3-4), and then 1000mg will be administered through an IV over 30 minutes every 6 weeks for 6 doses (Cycles 5-10) for approximately 48 weeks. TSR-022 will not be administered.

Group II: Dostarlimab (TSR-042) (singly) Experimental Treatment 1 Intervention

Pre-Operative Phase: Dostarlimab (TSR-042) 500mg will be administered through an IV over 30 minutes, on Cycle 1 Day 1, and then again on Cycle 2 Day 1. Post-Operative Phase: Dostarlimab (TSR-042) 500mg will be administered through an IV over 30 minutes for 4 doses every 3 weeks (Cycles 3-4) and then 1000mg will be administered through an IV over 30 minutes every 6 weeks for 6 doses (Cycles 5-10) for approximately 48 weeks.

Who Is Running the Clinical Trial?

Diwakar Davar

Lead Sponsor

Trials

12

Recruited

420+

Tesaro, Inc.

Industry Sponsor

Trials

57

Recruited

10,600+

Findings from Research

In a compassionate-use setting involving 271 patients with BRAF V600-mutant unresectable or metastatic melanoma, the combination of dabrafenib and trametinib demonstrated a high overall response rate of 67.3% and a median overall survival of 20.0 months for BRAFi-naive patients.

The treatment was well tolerated with no new safety concerns, showing significant clinical activity even in patients with brain metastases, indicating its effectiveness across different treatment lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II). Atkinson, V., Sandhu, S., Hospers, G., et al.[2023]

Nivolumab combined with ipilimumab demonstrated significantly better overall survival compared to BRAF + MEK inhibitors, with hazard ratios indicating a 36% to 44% reduction in the risk of death after 12 months.

While nivolumab + ipilimumab had improved survival outcomes, it also resulted in a higher rate of grade 3/4 adverse events (54.1%) compared to dabrafenib + trametinib (31.6%) and similar rates to vemurafenib + cobimetinib (59.5%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison. Atkins, MB., Tarhini, A., Rael, M., et al.[2020]

Combining targeted therapies (dabrafenib and trametinib) with anti-PD-1 or anti-PD-L1 antibodies significantly enhances antitumor activity in a mouse model of BRAF (V600E) mutant melanoma, leading to increased tumor-infiltrating lymphocytes and macrophages.

Adding immunostimulatory antibodies targeting CD137 or CD134 to the combination therapy further improves antitumor effects, suggesting that these combinations could be promising treatment options for patients with metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma. Homet Moreno, B., Mok, S., Comin-Anduix, B., et al.[2021]

The combination of trametinib, a MEK inhibitor, and anti-Tim-3 monoclonal antibody significantly enhances antitumor effects in B16-F10 melanoma mice by promoting apoptosis and inhibiting tumor cell proliferation while also stimulating CD8+ T cells.

This study highlights the potential of combining targeted therapy with immunotherapy, suggesting that trametinib can improve the effectiveness of anti-Tim-3 treatment, making it a promising strategy for melanoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma. Liu, Y., Cai, P., Wang, N., et al.[2018]

In a phase III study involving patients with BRAF V600 mutation-positive melanoma, trametinib significantly improved quality of life (QOL) compared to chemotherapy, with patients reporting better global health status and less functional impairment.

Patients treated with trametinib experienced improvements in symptoms like pain and insomnia, while chemotherapy led to worsening symptoms and a decline in overall health, highlighting trametinib's potential as a more tolerable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. Schadendorf, D., Amonkar, MM., Milhem, M., et al.[2023]

Tim-3 is not only an immune checkpoint receptor that inhibits T-cell function but also acts as a growth-suppressive receptor in melanoma cells, where its blockade can promote tumor growth in both immunocompetent and immunocompromised mice.

Inhibiting Tim-3 in melanoma cells enhances MAPK signaling, leading to increased tumor growth, but combining Tim-3 blockade with MAPK inhibitors can reverse this effect and improve the antitumor efficacy of T-cell-directed therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of Melanoma Cell-Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis. Schatton, T., Itoh, Y., Martins, C., et al.[2023]

In patients with advanced melanoma, NY-ESO-1-specific CD8(+) T cells expressing PD-1 also express Tim-3, and these Tim-3(+)PD-1(+) T cells are more dysfunctional, producing lower levels of important cytokines like IFN-γ, TNF, and IL-2.

Blocking the Tim-3-Tim-3L pathway enhances the function of NY-ESO-1-specific CD8(+) T cells, especially when combined with PD-1-PD-L1 blockade, suggesting a potential therapeutic strategy to overcome T cell exhaustion in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. Fourcade, J., Sun, Z., Benallaoua, M., et al.[2022]

The small molecule SMI402 effectively binds to the TIM-3 immune checkpoint, preventing its interaction with other molecules that contribute to T cell dysfunction, which is crucial in the tumor microenvironment.

In mouse models of cancer, SMI402 not only inhibited tumor growth but also enhanced the infiltration and function of CD8+ T cells and natural killer (NK) cells, suggesting its potential as a promising candidate for cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a novel small-molecule inhibitor targeting TIM-3 for cancer immunotherapy. Wu, M., Wu, A., Zhang, X., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II). [2023]

2. England pubmed.ncbi.nlm.nih.gov

Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison. [2020]

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

Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma. [2021]

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

Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. [2023]

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

Inhibition of Melanoma Cell-Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis. [2023]

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

Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Identification of a novel small-molecule inhibitor targeting TIM-3 for cancer immunotherapy. [2023]