NK Cells + Nivolumab + Relatlimab for Melanoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Washington University School of Medicine
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is a Phase 1 open-label, study designed to characterize the safety, tolerability, and preliminary anti-tumor activity of memory-like natural killer cells (ML NK) in combination with nivolumab and relatlimab in subjects with advanced and/or metastatic melanoma. There will be two arms to test the variables of ML NK cell source. ML NK cells from an autologous source will be used for Arm 1, and ML NK cells from an allogeneic source will be used for Arm 2. The investigators hypothesize that ML NK cells from either an autologous source or allogeneic source are safe and tolerable in subjects with advanced and/or metastatic melanoma.
What data supports the idea that NK Cells + Nivolumab + Relatlimab for Melanoma is an effective treatment?
The available research shows that adding relatlimab to nivolumab more than doubled the time patients lived without their melanoma getting worse, compared to using nivolumab alone. This combination also had side effects that were relatively easy to manage. This suggests that NK Cells + Nivolumab + Relatlimab is an effective treatment for melanoma.
126810What safety data exists for NK Cells + Nivolumab + Relatlimab treatment for melanoma?
Nivolumab, an immune checkpoint inhibitor, has been associated with immune-related adverse events (irAEs) in various cancers, including melanoma. The FDA approved nivolumab for melanoma based on its objective response rate and manageable safety profile, with immune-mediated adverse reactions being a key consideration. Nivolumab plus relatlimab (Opdualag) was approved in 2022 for unresectable or metastatic melanoma, with safety data indicating that the combination targets immune checkpoints and has a manageable adverse event profile. The safety of this combination therapy is supported by clinical trials and regulatory reviews.
347910Is the drug combination of memory-like natural killer cells, Nivolumab, and Relatlimab promising for treating melanoma?
Yes, the combination of Nivolumab and Relatlimab, known as Opdualag, is a promising drug for treating melanoma. It has been approved for use in advanced melanoma and has shown better results than using Nivolumab alone. This combination targets specific proteins to help the immune system fight cancer more effectively.
1351011Do I have to stop taking my current medications to join the trial?
Yes, you will need to stop taking corticosteroids and any other immune suppressive medications for at least 14 days before apheresis or lymphodepletion and continue to avoid them until 30 days after the infusion of ML NK cells. However, small doses of corticosteroids (≤15mg prednisone or equivalent) are allowed if necessary.
Eligibility Criteria
Adults with advanced or metastatic melanoma that worsened after treatment with certain immunotherapies. Participants must be in good health, able to undergo cell harvesting, not have severe active infections like HIV or hepatitis, and cannot be pregnant. They should have stable organ function and agree to use effective contraception.Inclusion Criteria
My advanced melanoma worsened after treatment with a PD1/PDL1 therapy.
I am willing and able to undergo a procedure to collect white blood cells.
I can take care of myself but may not be able to do heavy physical work.
I am 18 years old or older.
My kidney function, measured by creatinine levels or clearance, is within the normal range.
I am 18 years old or older.
Exclusion Criteria
I do not have any untreated infections like HIV or Hepatitis B/C.
I stopped cancer immunotherapy due to a severe immune-related side effect.
I have never received TIL therapy for my cancer.
I do not have uncontrolled heart problems.
Participant Groups
The trial is testing memory-like natural killer cells combined with nivolumab and relatlimab for treating melanoma. There are two groups: one receiving NK cells from their own body (autologous) and another from a donor (allogenic). The goal is to see if these treatments are safe and can shrink tumors.
3Treatment groups
Experimental Treatment
Active Control
Group I: Arm 2: Allogeneic: Memory-like natural killer cells + nivolumab + relatilimabExperimental Treatment3 Interventions
* Subjects with a haploidentical donor will enroll into Arm 2
* Subjects will receive the IV infusion of ML NK cells on Day 0.
* Relatlimab and nivolumab will be initiated at day 29 and continue every 28 days for 11 cycles, or until unacceptable toxicity, or progression, whichever is earlier.
Group II: Arm 1: Autologous: Memory-like natural killer cells + nivolumab + relatilimabExperimental Treatment3 Interventions
* Subjects enrolled into arm 1 will receive autologous ML NK cells on Day 0.
* Relatlimab and nivolumab will be initiated at day 29 and continue every 28 days for 11 cycles, or until unacceptable toxicity, or progression, whichever is earlier.
Group III: Allogeneic DonorsActive Control1 Intervention
Memory-like natural killer cells is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Opdualag for:
- Advanced melanoma (unresectable or metastatic) in patients aged 12 years and older
🇪🇺 Approved in European Union as Opdualag for:
- Advanced melanoma (unresectable or metastatic) in patients aged 12 years and older
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
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Who is running the clinical trial?
Washington University School of MedicineLead Sponsor
Melanoma Research AllianceCollaborator
Rising Tide FoundationCollaborator
References
Nivolumab plus ipilimumab in advanced melanoma. [2022]In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.
Anti-PD-1 therapy in melanoma. [2020]Immune-regulatory mechanisms are used by cancer to hide from the immune system. Advances and in-depth understanding of the biology of melanoma and its interaction with the immune system have led to the development of some of antagonistic antibodies to the programmed death 1 pathway (PD-1) and one of its ligands, programmed death ligand 1 (PD-L1), which are demonstrating high clinical benefit rates and tolerability. Blocking the immune-regulatory checkpoints that limit T-cell responses to melanoma upon PD-1/PD-L1 modulation has provided clinically validated targets for cancer immunotherapy. Combinations with other anti-melanoma agents may result in additional benefits. Nivolumab, pembrolizumab (formerly known as MK-3475 and lambrolizumab), and pidilizumab are anti-PD-1 antibodies in clinical development for melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers, lymphoma, and several other cancers. Long-term survivors already have been reported with these therapies. In this review, we discuss the current state of anti-PD-1 agents, the evidence in the literature to support the combination of anti-PD-1 antibodies with other anti-cancer agents and discuss the future directions for rational design of clinical trials that keep on increasing the number of long-term survivors.
Nivolumab: a review in advanced squamous non-small cell lung cancer. [2022]Nivolumab (Opdivo(®); Nivolumab BMS™) was the first programmed death (PD)-1 immune checkpoint inhibitor to be approved for use in advanced, squamous non-small cell lung cancer (NSCLC) following prior chemotherapy. In the pivotal CheckMate 017 trial, intravenous nivolumab 3 mg/kg every 2 weeks was associated with significantly better overall survival and progression-free survival and a significantly higher overall response rate than intravenous docetaxel in the second-line treatment of advanced, squamous NSCLC. Nivolumab was also better tolerated than docetaxel in CheckMate 017, and its adverse event profile (which included immune-mediated adverse events) was manageable. In conclusion, nivolumab represents an important advance in previously-treated, advanced, squamous NSCLC.
U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. [2023]On December 22, 2014, the FDA granted accelerated approval to nivolumab (OPDIVO; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received 3 mg/kg of nivolumab intravenously every 2 weeks with at least 6-month follow-up in an ongoing, randomized, open-label, active-controlled clinical trial. The ORR as assessed by a blinded independent review committee per RECIST v1.1 was 31.7% (95% confidence interval, 23.5-40.8). Ongoing responses were observed in 87% of responding patients, ranging from 2.6+ to 10+ months. In 13 patients, the response duration was 6 months or longer. The risks of nivolumab, including clinically significant immune-mediated adverse reactions (imARs), were assessed in 268 patients who received at least one dose of nivolumab. The FDA review considered whether the ORR and durations of responses were reasonably likely to predict clinical benefit, the adequacy of the safety database, and systematic approaches to the identification, description, and patient management for imARs in product labeling. Clin Cancer Res; 23(14); 3484-8. ©2017 AACR.
Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. [2020]Nivolumab plus ipilimumab combined therapy is one of the promising drugs that enhance the anti- immune response in patients with advanced melanoma. Therefore, to increase its response rate is of great interest to dermatologists. Recent reports suggested that, since CD8+ T cells after the administration of ICIs increase the RANKL expression to induce an immunosuppressive tumor microenvironment in melanoma, denosumab might enhance the anti-tumor effects of immune checkpoint inhibitors, such as nivolumab and ipilimumab. In this report, we present a case of multiple metastatic melanoma with nivolumab, ipilimumab plus denosumab combined therapy.
Nivolumab and ipilimumab are associated with distinct immune landscape changes and response-associated immunophenotypes. [2021]BACKGROUNDThe reshaping of the immune landscape by nivolumab (NIVO) and ipilimumab (IPI) and its relation to patient outcomes is not well described.METHODSWe used high-parameter flow cytometry and a computational platform, CytoBrute, to define immunophenotypes of up to 15 markers to assess peripheral blood samples from metastatic melanoma patients receiving sequential NIVO > IPI or IPI > NIVO (Checkmate-064).RESULTSThe 2 treatments were associated with distinct immunophenotypic changes and had differing profiles associated with response. Only 2 immunophenotypes were shared but had opposing relationships to response/survival. To understand the impact of sequential treatment on response/survival, phenotypes that changed after the initial treatment and differentiated response in the other cohort were identified. Immunophenotypic changes occurring after NIVO were predominately associated with response to IPI > NIVO, but changes occurring after IPI were predominately associated with progression after NIVO > IPI. Among these changes, CD4+CD38+CD39+CD127-GARP- T cell subsets were increased after IPI treatment and were negatively associated with response/survival for the NIVO > IPI cohort.CONCLUSIONCollectively, these data suggest that the impact of IPI and NIVO on the immunophenotypic landscape of patients is distinct and that the impact of IPI may be associated with resistance to subsequent NIVO therapy, consistent with poor outcomes in the IPI > NIVO cohort of Checkmate-064.
Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. [2021]Immune-related adverse events (irAEs) are associated with the efficacy of immune-checkpoint inhibitors in patients with melanoma and non-small cell lung cancer. We therefore evaluated the relationship between irAEs and nivolumab efficacy against metastatic renal cell carcinoma.
LAG3-PD-1 Combo Impresses in Melanoma. [2021]Immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA4 have dramatically improved melanoma treatment-and the LAG3 immune checkpoint inhibitor relatlimab may soon be added to the mix. In a phase III trial, adding relatlimab to the PD-1 inhibitor nivolumab more than doubled progression-free survival, and the combination had relatively manageable side effects.
Side effects of immune-checkpoint inhibitors: Can multiple side effects be seen in a patient? [2022]Nivolumab is a human immunoglobulin G4 monoclonal antibody that inhibits programmed cell death-1 activity by binding to the programmed cell death-1 receptors. Cancer cells express increased number of programmed cell death-1 ligands and this allows them to escape the cytotoxic effects of the T cells. Therefore, the negative programmed cell death-1 receptor signal regulates T-cell proliferation and activation is disrupted. However, this change in the activity of the T cells can cause them to lose their ability to recognize host cells. The immune response enabled by these agents has led to side effects, commonly known as "immune-related adverse events."
Nivolumab Plus Relatlimab: First Approval. [2022]Nivolumab plus relatlimab (nivolumab and relatlimab-rmbw; Opdualag™) is a fixed-dose, combination immunotherapy treatment being developed by Bristol Myers Squibb for the treatment of multiple types of advanced cancers. Both drugs are immunoglobulin G4 (IgG4) monoclonal antibodies developed to target immune checkpoints, with nivolumab targeting the programmed cell death protein 1 (PD-1) receptor and relatlimab being a newly developed, first-in-class drug targeting the lymphocyte-activation gene 3 (LAG-3) protein. In March 2022, nivolumab plus relatlimab received its first approval in the USA for the treatment of unresectable or metastatic melanoma in adult patients and paediatric patients aged ≥ 12 years who weigh ≥ 40 kg. This article summarizes the milestones in the development of this combination therapy leading to this first approval for unresectable or metastatic melanoma.
The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. [2023]The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes.