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

Not currently recruiting at 5 trial locations

Overseen By Danielle J Bednarz

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Diwakar Davar

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

Disqualifiers: Uveal melanoma, Active CNS metastases, 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

Compensation: Varies

Number of Visits: 14

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments for melanoma, a skin cancer that can spread to other body parts. Researchers compare the effects of a single drug, Dostarlimab (a PD-1 inhibitor), with a combination of Dostarlimab and TSR-022 (a TIM-3 inhibitor) to determine which option is more effective. Suitable participants have operable melanoma with regional lymph node involvement or limited spread and have not received certain prior treatments like anti-PD-1 therapy. The trial aims to determine if adding TSR-022 to Dostarlimab improves patient outcomes. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group.

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.

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

Studies have shown that Dostarlimab (TSR-042), whether used alone or with Cobolimab (TSR-022), is generally well-tolerated by patients. Research indicates that patients using Dostarlimab alone have experienced significant positive outcomes. Specifically, one study found that patients with advanced rectal cancer had a 100% remission rate without major side effects.

When combined with Cobolimab, early findings suggest Dostarlimab is also safe for patients. This combination has shown promising results, such as improving response rates in patients with high-risk melanoma. These findings indicate that while both treatments are still under investigation, they have been safe enough for continued research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they introduce a novel approach to tackling melanoma. Unlike the standard of care, which typically involves PD-1 inhibitors like pembrolizumab or nivolumab, the combination of Dostarlimab (TSR-042) with Cobolimab (TSR-022) targets both the PD-1 and TIM-3 pathways. This dual inhibition strategy could potentially enhance the immune system's ability to fight cancer cells more effectively. Additionally, Dostarlimab alone offers a promising alternative with its unique formulation, which may improve patient outcomes by providing a different immune modulation profile. These innovative approaches might offer new hope for patients with melanoma, aiming to improve response rates and extend survival.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that dostarlimab, a drug that aids the immune system in fighting cancer, effectively treats melanoma, a type of skin cancer. In this trial, some participants will receive dostarlimab alone, which previous studies have shown significantly reduces tumor size in patients with certain genetic traits. Other participants will receive a combination of dostarlimab and cobolimab, which works differently. Studies suggest that this combination improves the body's response to high-risk melanoma more effectively than dostarlimab alone. Early results are promising, indicating potential for these treatments in managing surgically removable melanoma. ^{2 3 4 5 6}

Who Is on the Research Team?

Diwakar Davar, MD

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Dostarlimab (TSR-042)
• Dostarlimab (TSR-042) and TSR-022

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.

How Is the Trial Designed?

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.

Dostarlimab (TSR-042) is already approved in European Union, United States for the following indications:

Approved in European Union as Jemperli for:

• Endometrial cancer

Approved in United States as Jemperli for:

• Mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer
• Solid tumors with dMMR

Who Is Running the Clinical Trial?

Diwakar Davar

Lead Sponsor

Trials

12

Recruited

420+

Tesaro, Inc.

Industry Sponsor

Trials

57

Recruited

10,600+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. onclive.com onclive.com/view/dostarlimab-plus-cobolimab-improves-mpr-rate-vs-dostarlimab-in-high-risk-resectable-melanoma

Dostarlimab Plus Cobolimab Improves MPR Rate vs ... Cobolimab addition to dostarlimab improved major pathological response rates in high-risk resectable melanoma compared to monotherapy. The ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10493167/

Outcomes for Dostarlimab and Real-World Treatments in ... Response rates as low as 10% to 15% have been observed with available 2L options. There is, therefore, a clear need for access to effective ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1040842824001173

Dostarlimab: Review on success story and clinical trials A recently published clinical trial reported 100 % remission of advanced rectal cancer without significant side effects in the participants.

4. gsk.com gsk.com/en-gb/media/press-releases/jemperli-dostarlimab-trial-continues-to-show-unprecedented-results/

Jemperli (dostarlimab) trial continues to show ... The trial showed an unprecedented 100% clinical complete response rate (cCR) in 42 patients who completed treatment with dostarlimab.

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2216334

Dostarlimab for Primary Advanced or Recurrent ... Dostarlimab plus carboplatin–paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04139902

NCT04139902 | Neoadjuvant PD-1 Inhibitor Dostarlimab ... This is a randomized phase II neoadjuvant study comparing neoadjuvant therapy with PD-1 inhibitor Dostarlimab (TSR-042) to the PD-1/TIM-3 inhibitor combination ...