Copanlisib + Nivolumab + Ipilimumab for Advanced Cancers

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of drugs to determine their effectiveness in treating advanced cancers, such as solid tumors and lymphoma, that have spread and resisted other treatments. The trial tests copanlisib, which aims to stop cancer cell growth, alongside two immunotherapy drugs, nivolumab and ipilimumab, which help the immune system fight cancer. Participants may receive either copanlisib and nivolumab or all three drugs to identify the most effective combination. This trial may suit those with advanced cancer or lymphoma who have not succeeded with other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

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

Research has shown that the combination of copanlisib and nivolumab is generally well tolerated by patients with advanced solid tumors. Studies have demonstrated that this pair can affect tumors without introducing new safety concerns, meaning participants managed the treatment well while it helped fight the cancer.

However, adding ipilimumab might increase the risk of serious side effects. In one study involving people with advanced melanoma who used both ipilimumab and nivolumab, about 51% experienced severe treatment-related issues. This suggests that while using copanlisib, nivolumab, and ipilimumab together might be effective, it could also lead to more serious side effects compared to using only copanlisib and nivolumab.

These findings come from earlier studies. Since this trial is in an early phase, the main goal is to ensure the treatments are safe and to determine the best dose. Safety remains a top priority, and researchers closely monitor any potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about copanlisib, nivolumab, and ipilimumab for advanced cancers because these drugs offer a novel approach by harnessing the body's immune system to fight cancer. Unlike standard chemotherapy, which attacks rapidly dividing cells indiscriminately, these treatments are designed to target specific pathways involved in cancer growth and immune response. Copanlisib is a PI3K inhibitor, blocking signals that help cancer cells survive and grow. Nivolumab and ipilimumab are immune checkpoint inhibitors that unleash the immune system to recognize and destroy cancer cells more effectively. This combination holds the promise of improved effectiveness against advanced cancers with potentially fewer side effects than traditional treatments.

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

Research has shown that using copanlisib and nivolumab together can help fight tumors in patients with advanced cancers. This drug combination is usually well tolerated and has shown promising results in early studies. In this trial, some participants will receive this combination, while others will receive an additional treatment with ipilimumab to further boost the immune system's ability to attack cancer cells. Although data collection on using all three drugs together is ongoing, each drug has shown potential individually. Previous findings suggest that these treatments, especially when combined, could effectively target and treat advanced cancers. ^{1 2 3 6 7}

Who Is on the Research Team?

A P Chen

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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]

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, 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39927513/

A Phase Ib Study in Patients with Advanced Solid Tumors The combination of copanlisib and nivolumab was well tolerated and showed antitumor effects in patients with advanced solid tumors.

2. aacrjournals.org aacrjournals.org/cancerrescommun/article/5/3/444/754187/Safety-and-Efficacy-of-Copanlisib-in-Combination

Safety and Efficacy of Copanlisib in Combination with ... Copanlisib in combination with immune checkpoint inhibitors demonstrated synergy and favorable antitumor immune responses in preclinical models.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03735628

NCT03735628 | An Study to Evaluate the Safety and ... An Study to Evaluate the Safety and Efficacy of Copanlisib in Combination With Nivolumab in Patients With Advanced Solid Tumors · Study Overview · Contacts and ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(23)02724-2/fulltext

701P NCI10221: Phase II multicenter biomarker driven ... The combination of copanlisib and nivolumab is well tolerated with antitumor activity in pts with PIK3CA hotspot and PTEN mutations including PD-1/L1i-exposed ...

5. onclive.com onclive.com/view/early-data-with-copanlisib-nivolumab-combo-support-further-exploration-in-mss-crc

Early Data With Copanlisib/Nivolumab Combo Support ... Eric S. Christenson, MD, discusses the potential benefit of copanlisib plus nivolumab in PIK3CA-mutant microsatellite stable colorectal cancer.

6. aacrjournals.org aacrjournals.org/cancerrescommun/article/doi/10.1158/2767-9764.CRC-24-0407/751678/am/Safety-and-efficacy-of-copanlisib-in-combination

Safety and efficacy of copanlisib in combination with nivolumab Conclusions: No new safety concerns were identified with this combination, and preliminary efficacy indicated an anti-tumor effect. Data supported an ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40605718/

Safety and efficacyof the combination of copanlisib and ... Overall, treatment with copanlisib and nivolumab demonstrated manageable toxicity and promising clinical efficacy in tNHL patients.