Zimberelimab + Domvanalimab for Melanoma

Overseen By Amy Rose, RN, BSN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Diwakar Davar

Must be taking: Anti-PD-1/L1 mAb

Must not be taking: Immunosuppressants, Steroids, Chemotherapy, others

Disqualifiers: Non-cutaneous melanoma, Immunodeficiency, Autoimmune, 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: 4

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two treatments, zimberelimab and domvanalimab, for individuals with melanoma unresponsive to previous PD-1 treatments. The goal is to determine how many patients show a measurable response to this treatment combination. It suits adults with cutaneous melanoma who have experienced disease progression after at least two doses of PD-1 treatment. Participants should also have a measurable tumor suitable for biopsy and meet health criteria for participation. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain immunosuppressive therapies or have recently received chemotherapy, targeted therapy, or small molecule therapy within 2 weeks before the study starts.

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

Research has shown that zimberelimab and domvanalimab are generally safe for people. In earlier studies, some patients experienced side effects, but most were mild or moderate. Common issues included tiredness and nausea, typical with many cancer treatments. Serious side effects were rare.

These findings suggest that using zimberelimab and domvanalimab together is safe so far. However, individual experiences can vary. It is important to consult a doctor to understand the risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for melanoma, which often involve checkpoint inhibitors like pembrolizumab or nivolumab, Zimberelimab and Domvanalimab offer a fresh approach by combining two distinct immune pathway targets. Zimberelimab blocks the PD-1 pathway, a common target in cancer therapy, while Domvanalimab inhibits the TIGIT pathway, a less explored but promising avenue in enhancing anti-tumor immune response. This dual-target mechanism could potentially boost the immune system's ability to fight melanoma more effectively than existing treatments. Researchers are excited about this combination because it might improve patient outcomes by overcoming resistance mechanisms that limit the efficacy of current therapies.

What evidence suggests that zimberelimab and domvanalimab might be effective treatments for melanoma?

In this trial, participants will receive a combination of zimberelimab and domvanalimab. Research has shown that these drugs may help treat certain cancers by enabling the immune system to find and fight cancer cells more effectively. Patients with difficult-to-treat cancers have shown positive responses to this combination. It has also been tested in other cancers, such as lung cancer, where it effectively shrank tumors and slowed disease progression. While results for melanoma are still being collected, early findings appear promising. ^{1 2 6 7 8}

Who Is on the Research Team?

Diwakar Davar, MD

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with a confirmed diagnosis of cutaneous melanoma who have previously not responded to anti-PD-1/L1 mAb treatments. They must have measurable disease, be able to provide a biopsy, and have good organ function and performance status. Women can't be pregnant or breastfeeding and must use contraception; men also need to use contraception.

Inclusion Criteria

My organs are functioning well.

My condition worsened despite treatment with an anti-PD-1/L1 medication.

I agree to use contraception and not donate sperm during the treatment.

Exclusion Criteria

I have not had another type of cancer besides blood cancer in the last 3 years.

I have or had lung inflammation that needed steroids.

I have been treated for an autoimmune disease in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment Phase 1

Participants receive zimberelimab 360 mg and domvanalimab 15 mg/kg every 3 weeks for 3 cycles, followed by restaging scans

9 weeks

3 visits (in-person)

Treatment Phase 2

Participants continue to receive zimberelimab and domvanalimab every 3 weeks until disease progression, intolerable toxicity, or up to 24 months

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Domvanalimab
• Zimberelimab

Trial Overview The study tests the combination of Zimberelimab (AB122) with Domvanalimab (AB154) in patients whose melanoma has not improved after PD-1 inhibitor therapy. The main goal is to see how many patients experience a reduction in their cancer size as a response to this treatment combo.

How Is the Trial Designed?

Group I: Zimberelimab plus Domvanalimab Experimental Treatment 2 Interventions

Treatment Phase 1: Zimberelimab, 360mg, IV, every 3 weeks for 3 cycles. Domvanalimab, 15mg/kg, IV, every 3 weeks for 3 cycles. After 3 cycles, scans will be performed. If it is determined that the cancer is stable or responding patients will continue with Treatment Phase 2. Treatment Phase 2: Zimberelimab, 360mg, IV, every 3 weeks for 3 cycles. Domvanalimab, 15mg/kg, IV, every 3 weeks, for up to 24 months.

Who Is Running the Clinical Trial?

Diwakar Davar

Lead Sponsor

Trials

12

Recruited

420+

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Published Research Related to This Trial

In a phase III trial involving 655 patients with advanced melanoma, tremelimumab did not show a statistically significant improvement in overall survival compared to standard chemotherapy, with median survival times of 12.6 months for tremelimumab versus 10.7 months for chemotherapy.

Although the objective response rates were similar between the two treatments, patients receiving tremelimumab experienced a significantly longer duration of response (35.8 months) compared to those on chemotherapy (13.7 months), indicating potential benefits in long-term treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. Ribas, A., Kefford, R., Marshall, MA., et al.[2022]

Tremelimumab, a monoclonal antibody, has shown the ability to induce durable tumor regressions in 7% to 10% of patients with metastatic melanoma, with effects lasting up to 8 years, primarily through the activation of cytotoxic T lymphocytes.

While tremelimumab can lead to significant tumor responses, it also carries a risk of severe toxicities (20% to 25% of patients), mainly due to inflammatory or autoimmune reactions from its mechanism of action, which involves inhibiting CTLA-4 to enhance immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of the anti-CTLA-4 antibody tremelimumab. Ribas, A.[2021]

In a phase II study involving 251 patients with refractory melanoma, tremelimumab demonstrated an objective response rate of 6.6%, with responses lasting between 8.9 to 29.8 months, indicating its potential effectiveness in treating this type of cancer.

The treatment was generally well-tolerated, with most adverse events being mild to moderate; however, there were some serious side effects, including grade 3/4 diarrhea and colitis, and 2 treatment-related deaths, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Kirkwood, JM., Lorigan, P., Hersey, P., et al.[2022]

In a review of 143 patients with advanced melanoma treated with tremelimumab, a CTLA-4 antibody, the median overall survival was 13 months, with some patients surviving over 12 years, indicating potential for long-term benefits from this treatment.

The study found an objective response rate of 15.6% with a median duration of response lasting 6.5 years, suggesting that tremelimumab can provide sustained anti-tumor effects in a subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab. Eroglu, Z., Kim, DW., Wang, X., et al.[2023]

In a phase 2 trial involving 40 patients with malignant mesothelioma, the combination of tremelimumab and durvalumab resulted in an immune-related objective response in 28% of patients, with a median response duration of 16.1 months, indicating promising efficacy for this treatment approach.

The treatment was generally well-tolerated, with 75% of patients experiencing treatment-related adverse events, mostly manageable and reversible, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study. Calabrò, L., Morra, A., Giannarelli, D., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05130177

NCT05130177 | Zimberelimab (AB122) With TIGIT Inhibitor ... The main goal of this study is to establish the proportion of patients with objective response to zimberelimab/domvanalimab in PD-1 R/R melanoma patients.

2. clinicaltrial.be clinicaltrial.be/en/details/48030?per_page=20&only_recruiting=0&only_eligible=0&only_active=0

Study Evaluating Effectiveness and Safety of Zimberelimab... This is a phase 2 study to evaluate zimberelimab (AB122) combined with domvanalimab (AB154) in front-line, PD-L1-high, locally advanced or ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04791839

Study Details | NCT04791839 | Safety and Efficacy of ... Safety and Efficacy of Zimberelimab (AB122) in Combination With Domvanalimab (AB154) and Etrumadenant (AB928) in Patients With Previously Treated Non-Small ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-04927

Study to Evaluate Monotherapy and Combination ... This randomized phase 2 open-label study will evaluate the safety and efficacy of zimberelimab (AB122) monotherapy, domvanalimab (AB154) in combination with ...

5. cancertherapyadvisor.com cancertherapyadvisor.com/home/cancer-topics/lung-cancer/zimberelimab-domvanalimab-etrumadenant-metastatic-nsclc/

Zimberelimab, Domvanalimab, and Etrumadenant for ... Title: A pilot study to evaluate the safety and efficacy of zimberelimab (AB122) in combination with domvanalimab (AB154) and etrumadenant ...

6. trials.braintumor.org trials.braintumor.org/trials/NCT05130177

Zimberelimab (AB122) With TIGIT Inhibitor Domvanalimab ... The main goal of this study is to establish the proportion of patients with objective response to zimberelimab/domvanalimab in PD-1 R/R melanoma patients.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03628677

NCT03628677 | A Study to Evaluate the Safety and ... This is a Phase 1, multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, PK, PD, and clinical activity of domvanalimab (AB154)

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03628677/

Clinical Trial: NCT03628677 This is a Phase 1, multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, PK, PD, and clinical activity of ...