CBL0137 + Immunotherapy for Melanoma

Overseen By Tanu Singh, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Fox Chase Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Prior CTLA-4/PD1, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 8 weeks

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a new drug, CBL0137 (an experimental treatment), combined with the standard cancer treatments ipilimumab and nivolumab, is safe and effective for individuals with metastatic melanoma. Melanoma is a type of skin cancer, and this study targets those with advanced cancer for whom immune system-boosting treatments are viable. Participants should have melanoma that can be easily biopsied and must be willing to undergo multiple biopsies and blood tests during the study. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop your current medications, but you cannot be on other investigational drugs or need immunosuppressive medications.

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

Research is exploring the use of CBL0137 with ipilimumab and nivolumab to treat melanoma. This trial is in its early stages, so researchers are still gathering detailed safety information about CBL0137. However, ipilimumab and nivolumab have previously been used together to treat melanoma. Studies have shown that this combination can be effective, though it may cause side effects like tiredness, skin rash, or diarrhea. Importantly, no new safety issues or treatment-related deaths have been reported with these drugs.

Since this trial is in an early phase, its primary aim is to determine the right dose and identify any safety concerns. This stage is crucial for understanding how well participants tolerate the new combination with CBL0137. Prospective participants should be aware that while the existing treatments have known side effects, the effects of adding CBL0137 are still under investigation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of CBL0137 with immunotherapy for melanoma because it brings a fresh approach to treatment. While most treatments for melanoma, like targeted therapies and standard immunotherapies such as Ipilimumab and Nivolumab, aim to boost the immune response or target specific mutations, CBL0137 works differently. It targets chromatin remodeling, a process that affects how DNA is packaged and expressed in cancer cells, potentially making them more vulnerable to attack by the immune system. This novel mechanism, combined with established immunotherapies, could enhance the overall effectiveness against melanoma and overcome resistance seen with current treatments.

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

Research has shown that using CBL0137 with the drugs ipilimumab and nivolumab might be more effective at killing melanoma cells. In this trial, participants will receive different dose levels of CBL0137 combined with nivolumab and ipilimumab. Studies have found that the combination of nivolumab and ipilimumab, common treatments for melanoma, can greatly improve survival rates. Specifically, about 59% of patients with advanced melanoma lived longer with these two drugs. This trial tests CBL0137 to see if it can enhance this effect by better targeting cancer cells. While researchers continue to study this combination, early results suggest it could make melanoma treatment more effective. ^{2 4 6 7 8}

Who Is on the Research Team?

Anthony Olszanski, MD

Principal Investigator

Fox Chase Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with advanced melanoma, either stage III with lymph node metastases or stage IV, who can undergo biopsies. They must have good performance status and normal organ/marrow function. Not eligible if they're on other trials, have active autoimmune diseases, previous CTLA-4 or PD1/PD-L1 treatments, unresolved diarrhea, or need immunosuppressants.

Inclusion Criteria

I am older than 18 years.

I am fully active or can carry out light work.

I have stage III or IV melanoma with lymph node metastases that can be biopsied or surgically treated.

Exclusion Criteria

I have had diarrhea for over two weeks that hasn't improved with treatment.

I am taking medication that weakens my immune system.

You have a current autoimmune disease that is not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CBL0137 in combination with Ipilimumab and Nivolumab in 8-week treatment cycles

8 weeks

Visits on Days 1, 8, and 29

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CBL0137
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing CBL0137 combined with standard melanoma drugs Ipilimumab and Nivolumab. It's a phase I study to check safety and how the body responds to this mix of drugs in adults with serious melanoma that can be biopsied.

How Is the Trial Designed?

Group I: CBL0137 (Dose level 1) +Ipilimumab + Nivolumab Experimental Treatment 3 Interventions

Dose level 1 CBL0137 on Days 1 and 8, Nivolumab and Ipilimumab on days 8 and 29 administrated IV of 8 weeks treatment cycles.

Group II: CBL0137 ( Dose level 2) +Ipilimumab + Nivolumab Experimental Treatment 3 Interventions

Dose level 2 CBL0137 on Days 1 and 8, Nivolumab and Ipilimumab on days 8 and 29 administrated IV of 8 weeks treatment cycles.

Group III: CBL0137 ( Dose level -1) +Ipilimumab + Nivolumab Experimental Treatment 3 Interventions

Dose level -1 CBL0137 on Days 1 and 8, Nivolumab and Ipilimumab on days 8 and 29 administrated IV of 8 weeks treatment cycles.

Who Is Running the Clinical Trial?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

Incuron

Industry Sponsor

Trials

4

Recruited

110+

Published Research Related to This Trial

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

In a phase 3 study involving 582 patients with advanced nonsquamous non-small-cell lung cancer (NSCLC), nivolumab significantly improved overall survival compared to docetaxel, with a median survival of 12.2 months versus 9.4 months, respectively.

Nivolumab also had a much lower rate of severe treatment-related adverse events (10%) compared to docetaxel (54%), indicating a better safety profile while maintaining efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. Borghaei, H., Paz-Ares, L., Horn, L., et al.[2022]

Ipilimumab, a monoclonal antibody targeting CTLA-4, has been shown to significantly improve overall survival in patients with metastatic melanoma, with a median survival of 10.1 months compared to 6.4 months for those receiving a vaccine alone in a phase III trial involving previously treated patients.

While ipilimumab offers a clear survival benefit, it is associated with serious immune-related adverse events in 10% to 15% of patients, necessitating careful monitoring and potential use of immune-suppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Lipson, EJ., Drake, CG.[2022]

Combined immune checkpoint blockade (ICB) using nivolumab and ipilimumab shows significant efficacy in treating advanced melanoma, but it also leads to a higher frequency and severity of adverse drug reactions (ADRs) compared to single-agent therapies, based on pooled safety data from 1551 patients.

Most immune-related ADRs are reversible with glucocorticoids, but due to the increased risk and rapid onset of these toxicities, clinicians must be well-trained to monitor and manage these side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Hassel, JC., Heinzerling, L., Aberle, J., et al.[2022]

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

In a study of 655 patients with advanced melanoma, pembrolizumab showed an overall objective response rate of 33%, indicating its efficacy in treating this type of cancer.

The median overall survival for patients receiving pembrolizumab was 23 months, with a 12-month survival rate of 66%, while 14% of patients experienced severe treatment-related adverse events, highlighting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. Ribas, A., Hamid, O., Daud, A., et al.[2022]

In a study of 37 patients with stage IV metastatic melanoma, high levels of soluble CD73 (sCD73) enzyme activity in the serum were linked to significantly poorer overall survival and progression-free survival when treated with nivolumab.

Patients with high sCD73 activity had a median progression-free survival of only 2.6 months compared to 14.2 months for those with lower activity, suggesting that measuring sCD73 could help predict how well patients will respond to nivolumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. Morello, S., Capone, M., Sorrentino, C., et al.[2018]

In a retrospective analysis of 40 advanced melanoma patients, a treatment regimen combining short-term CTLA-4 blockade (ipilimumab) followed by PD-1 blockade (nivolumab or pembrolizumab) achieved a best overall response rate of 55% and a disease control rate of 75%, indicating promising efficacy.

The combination therapy resulted in grade 3 and 4 adverse events in 38% of patients, suggesting that this approach may offer similar effectiveness to concurrent therapies but with potentially lower toxicity, warranting further investigation in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience. Meerveld-Eggink, A., Rozeman, EA., Lalezari, F., et al.[2020]

Citations

1. cancer.gov cancer.gov/clinicaltrials/NCI-2022-10371

CBL0137 in Combination with Ipilimumab and Nivolumab ... Giving CBL0137 in combination with ipilimumab and nivolumab may kill more cancer cells in patients with melanoma. ... Trial Objectives and Outline. PRIMARY ...

2. opdivo.com opdivo.com/melanoma/clinical-trial-results/advanced-immunotherapy-combination

Advanced Melanoma Skin Cancer | Clinical Trial Results 59% of those given OPDIVO® + YERVOY® for advanced melanoma survived, versus. In the clinical trial, people given OPDIVO + YERVOY had a 45% lower risk of ...

3. careacross.com careacross.com/clinical-trials/trial/NCT05498792

Study of CBL0137 in Combination With Ipilimumab and ... Detailed description: The primary objectives will be Initial assessment of safety and tolerability of the combination of CBL0137 with Nivolumab and Ipilimumab.

4. opdivohcp.com opdivohcp.com/efficacy/melanoma/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Efficacy in ... 10-Year survival outcomes from the phase 3 CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma. Oral presentation at: ESMO Congress 2024; ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11895829/

Pooled Long-Term Outcomes With Nivolumab Plus ... Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/ ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05498792

Study of CBL0137 in Combination With Ipilimumab and ... Phase I, open label, dose-escalation, and safety study designed to assess the safety and biologic activity of the investigational agent CBL0137 in combination ...

7. ancora.ai ancora.ai/en/details/NCT05498792

Study of CBL0137 in Combination With Ipilimumab and ... Phase I, open label, dose-escalation, and safety study designed to assess the safety and biologic activity of the investigational agent CBL0137 in combinat.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8718224/

Long-Term Outcomes With Nivolumab Plus Ipilimumab or ... Higher incidences of AEs of all types were reported with the combination regimen, but no new safety signals or treatment-related deaths were ...