Copanlisib + Nivolumab + Ipilimumab for Advanced Cancers

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Uncontrolled infection, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 6 years

64 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial studies the side effects and best dose of copanlisib and nivolumab and side effects of copanlisib given together with nivolumab and ipilimumab in treating patients with solid tumors that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or lymphoma. Copanlisib stops tumors from growing by blocking proteins that are known to be important for tumor cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving copanlisib together with nivolumab or with nivolumab and ipilimumab may work better in treating patients with solid tumors or lymphoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong CYP3A4 inhibitors or inducers, and herbal medications while on copanlisib treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Copanlisib, Nivolumab, and Ipilimumab for advanced cancers?

Research shows that the combination of nivolumab and ipilimumab has been effective in treating advanced melanoma and non-small cell lung cancer, with improved response rates and survival compared to using ipilimumab alone. This suggests potential effectiveness when combined with other treatments like copanlisib for advanced cancers. ^{1 2 3 4 5}

Is the combination of Copanlisib, Nivolumab, and Ipilimumab generally safe for humans?

The combination of Nivolumab and Ipilimumab has been associated with immune-related side effects, which can range from mild to severe. These side effects are due to the immune system being activated and can include conditions like colitis (inflammation of the colon). While most side effects are manageable, some can be serious, so close monitoring and early treatment are important. ^{6 7 8 9 10}

What makes the drug combination of Copanlisib, Nivolumab, and Ipilimumab unique for advanced cancers?

This drug combination is unique because it combines Copanlisib, a PI3K inhibitor, with Nivolumab and Ipilimumab, which are immune checkpoint inhibitors. This approach aims to enhance the immune system's ability to fight cancer by targeting different pathways, potentially offering a more effective treatment for advanced cancers compared to using these drugs individually. ^{1 2 3 4 11}

Research Team

A P Chen

Principal Investigator

National Cancer Institute LAO

Eligibility Criteria

Adults with advanced solid tumors or lymphoma, who have tried at least one line of therapy without a cure available. They must have acceptable organ function and blood counts, not be on certain medications, agree to use contraception, and provide tissue samples for research. Excluded are those with significant illnesses or conditions like brain metastases, uncontrolled hypertension or diabetes, recent immunosuppressants use, known allergies to trial drugs, active autoimmune diseases requiring treatment within the past 3 months.

Inclusion Criteria

I agree to use birth control during and after the study for the required time.

Willingness to provide blood for research purposes (all patients, apart from patients enrolled onto triplet safety run-in phase) and willingness to provide new tumor biopsy samples for research purposes (doublet and triplet expansion cohorts)

Absolute neutrophil count >= 1,500/mcL

Exclusion Criteria

I am HIV-positive, on stable HAART without CYP3A4 inhibitors, and have an undetectable viral load.

I do not have any major health issues that would stop me from participating in the study.

My blood oxygen level is above 90% at rest, and I don't have lung diseases like ILD, pneumonitis, or fibrosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive copanlisib, nivolumab, and ipilimumab in various combinations depending on cohort, with cycles repeating every 28 days

Up to 6 years

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

Monthly visits (in-person)

Treatment Details

Interventions

• Copanlisib
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing how well patients tolerate the combination of Copanlisib (blocks tumor growth proteins) and Nivolumab (boosts immune system against cancer), as well as this duo plus Ipilimumab (another immune booster). It aims to find the best dose for Copanlisib when used with these immunotherapies in treating advanced cancers and lymphomas.

Participant Groups

Group I: Cohort III (Triplet) (copanlisib, nivolumab, ipilmumab) Experimental Treatment 7 Interventions

Patients receive copanlisib IV over 1 hour on days 1, 8, and 15 of each cycle, nivolumab IV over 30 minutes on day 15 of cycle 1 and then day 1 of each subsequent cycles, and ipilimumab IV over 90 minutes on day 1 for cycles 2-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan and/or MRI throughout the trial. Patients undergo blood sample collection on study and during follow-up, as well as tumor biopsy on study. Patients also undergo an ECHO during screening and as clinically indicated on study.

Group II: Cohort II (Triplet Safety) (copanlisib, nivolumab, ipilimumab) Experimental Treatment 8 Interventions

Patients receive copanlisib IV over 1 hour on days 1, 8, and 15 of each cycle, nivolumab IV over 30 minutes on day 1 of each cycle, and ipilimumab IV over 90 minutes on day 1 for cycles 1-4. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan and/or MRI throughout the trial. Patients undergo an ECHO during screening and as clinically indicated on study.

Group III: Cohort I (Doublet) (copanlisib, nivolumab) Experimental Treatment 7 Interventions

Patients receive copanlisib IV over 1 hour on days 1 and 15 or days 1, 8, and 15 of each cycle and nivolumab IV over 30 minutes on day 1 or days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan and/or MRI throughout the trial. Patients undergo blood sample collection on study and during follow-up, as well as tumor biopsy on study. Patients also undergo an ECHO during screening and as clinically indicated on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 study of 84 advanced melanoma patients who had previously failed anti-PD-1 therapy, ipilimumab alone showed a 16% overall response rate, while the combination of ipilimumab and nivolumab had a slightly higher response rate of 21%.

Despite the combination therapy showing a higher response rate, both treatments had similar one-year overall survival rates of around 54-55%, suggesting that ipilimumab alone remains a viable option for patients who did not respond to prior anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma. Zimmer, L., Apuri, S., Eroglu, Z., et al.[2021]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Nivolumab (Opdivo) is an effective immune checkpoint inhibitor that enhances the immune system's ability to fight advanced cancers, showing impressive durability of response compared to traditional therapies.

It is well tolerated and approved for several types of cancer, including non-small cell lung cancer, melanoma, and renal cell carcinoma, with ongoing research to identify biomarkers for response and explore combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers. Rajan, A., Kim, C., Heery, CR., et al.[2023]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

In a study of 274 elderly patients with advanced melanoma, the risk of developing colitis was similar for those treated with anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab or pembrolizumab) therapies.

However, when considering patients across all stages of melanoma, anti-PD1 treatment was associated with a significantly lower risk of colitis compared to anti-CTLA4, suggesting a safer profile for anti-PD1 in this broader patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. Almutairi, AR., Slack, M., Erstad, BL., et al.[2022]

In a meta-analysis of 2,946 cancer patients, the combination therapy of nivolumab and ipilimumab was found to significantly increase the risk of immune-related adverse events (irAEs) compared to nivolumab alone.

Patients receiving the combination therapy experienced higher rates of various irAEs, including skin reactions, gastrointestinal issues, and liver enzyme elevation, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients. Zhou, S., Khanal, S., Zhang, H.[2022]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

Ipilimumab, the first drug to improve survival in advanced melanoma, works by inhibiting CTLA-4 on T cells, but newer PD-1 inhibitors like nivolumab and pembrolizumab have shown better efficacy and safety.

The combination of ipilimumab and nivolumab enhances response rates and progression-free survival in advanced melanoma patients, but it also increases the risk of immune-related toxicities, leading to its FDA approval in 2015 for BRAF wild-type cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? Carlino, MS., Long, GV.[2018]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma. [2021]

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

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

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

Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers. [2023]

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

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

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

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Risk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

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

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. [2022]

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

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? [2018]