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

Trial Summary

What is the purpose of this trial?

Phase I, open label, dose-escalation, and safety study designed to assess the safety and biologic activity of the investigational agent CBL0137 in combination with standard of care drugs, ipilimumab and nivolumab in sequential cohorts of adult patients with locally advanced and metastatic melanoma who are candidates for immune checkpoint blockade and have tumors accessible for serial biopsies.

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.

What data supports the effectiveness of the drug combination of CBL0137, ipilimumab, and nivolumab for treating melanoma?

Research shows that the combination of nivolumab and ipilimumab significantly improves survival and tumor response in patients with advanced melanoma compared to ipilimumab alone. Nivolumab, as a single agent, is also effective in treating advanced melanoma by blocking the PD-1 pathway, which helps the immune system attack cancer cells. ^{1 2 3 4 5}

Is the combination of CBL0137 and immunotherapy safe for treating melanoma?

Ipilimumab and nivolumab, used in combination for melanoma, can cause serious immune-related side effects in 10% to 15% of patients, such as inflammation in the colon, liver, thyroid, and other organs. These side effects are often reversible with treatment, but require careful monitoring and management by experienced healthcare providers. ^{6 7 8 9 10}

What makes the drug combination of CBL0137, Ipilimumab, and Nivolumab unique for treating melanoma?

This drug combination is unique because it combines CBL0137, a novel agent targeting the FACT complex, with established immune checkpoint inhibitors Ipilimumab and Nivolumab, which block CTLA-4 and PD-1 pathways. This approach aims to enhance the immune response against melanoma by targeting multiple mechanisms of tumor resistance. ^{11 12 13 14 15}

Research Team

Anthony Olszanski, MD

Principal Investigator

Fox Chase Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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 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]

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 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]

References

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

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

Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. [2018]

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

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. [2022]

5. England 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. [2022]

6. England pubmed.ncbi.nlm.nih.gov

What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? [2020]

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

Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. [2022]

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

Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. [2022]

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

BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis. [2016]

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

A Pilot Study of Short-course Nivolumab and Low-dose Ipilimumab for Adjuvant Treatment of Melanoma: Brown University Oncology Research Group Trial, BrUOG 324. [2021]

13. England pubmed.ncbi.nlm.nih.gov

ABT-737 synergizes with Bortezomib to kill melanoma cells. [2021]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment. [2023]

15. England pubmed.ncbi.nlm.nih.gov

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience. [2020]