Copanlisib + Immunotherapy for Advanced Solid Cancers

Recruiting at 5 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Pregnancy, Hepatitis B/C, Autoimmune, others

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

Compensation: Varies

Number of Visits: 32

Duration: Up to 2 years

102 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of copanlisib when given together with nivolumab and ipilimumab and to see how well they work in treating patients with solid cancers that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and have changes in PIK3CA and PTEN genes. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for 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. The addition of copanlisib to usual immunotherapy may work better in treating patients with solid cancers compared to usual immunotherapy alone.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take certain medications that strongly affect liver enzymes (CYP3A4) or herbal medications. You should discuss your current medications with the trial team to see if any adjustments are needed.

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

Research shows that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) can prolong survival in patients with advanced non-small cell lung cancer and advanced melanoma, compared to chemotherapy. These drugs have shown durable and long-term efficacy, suggesting potential benefits when used in combination with other treatments like Copanlisib Hydrochloride for advanced solid cancers. ^{1 2 3 4 5}

What is known about the safety of Copanlisib and immune checkpoint inhibitors like Ipilimumab and Nivolumab?

Immune checkpoint inhibitors, including Ipilimumab and Nivolumab, have been associated with immune-related side effects, such as colitis (inflammation of the colon) and skin rash. These treatments can cause serious immune-related adverse reactions, which are important to consider when evaluating their safety. ^{6 7 8 9 10}

How is the drug combination of Copanlisib, Ipilimumab, and Nivolumab unique for treating advanced solid cancers?

This drug combination is unique because it combines Copanlisib, a PI3K inhibitor, with two immune checkpoint inhibitors, Ipilimumab and Nivolumab, which target CTLA-4 and PD-1 pathways, respectively. This approach aims to enhance the immune system's ability to fight cancer by blocking different pathways that tumors use to evade immune detection, offering a novel strategy compared to traditional chemotherapy or single-agent immunotherapy. ^{2 3 5 11 12}

Research Team

Timothy A Yap

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Eligibility Criteria

Adults with advanced solid cancers and specific gene changes (PIK3CA/PTEN) can join this trial. They must have a good performance status, controlled diabetes, measurable disease by certain criteria, and no recent other treatments. Pregnant or breastfeeding women, those with active infections or CNS metastases, and individuals on strong CYP3A4 inhibitors/inducers are excluded.

Inclusion Criteria

Absolute neutrophil count (ANC) >= 1,500 /mcL

My cancer has spread, cannot be surgically removed, and standard treatments are not effective.

Platelets >= 100,000 / mcL

Exclusion Criteria

You are currently using any experimental drugs.

I have no severe allergies to copanlisib, PI3K inhibitors, nivolumab, or ipilimumab.

I am not taking strong drugs that affect how Copanlisib works.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive copanlisib hydrochloride IV on days 1, 8, and 15 of cycle 1. Beginning in cycle 2, patients also receive nivolumab IV on day 1. In Trial II, ipilimumab is added every 8 weeks for 4 doses. Cycles repeat every 28 days.

Up to 2 years

Visits every 28 days, with additional visits for scans and biopsies

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3-6 months for up to 2 years.

Up to 2 years

Follow-up visits every 3-6 months

Treatment Details

Interventions

• Copanlisib Hydrochloride
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing the effectiveness of adding Copanlisib to standard immunotherapy (Nivolumab with/without Ipilimumab) in treating advanced solid tumors with PIK3CA and PTEN mutations. It's a phase I/II study aiming to find the best dose while monitoring how well patients respond compared to usual treatment.

Participant Groups

Group I: Trial II (copanlisib, nivolumab, ipilimumab) Experimental Treatment 8 Interventions

Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 of cycle 1. Beginning in cycle 2, patients also receive nivolumab IV over 60 minutes on day 1 and ipilimumab IV over 90 minutes every 8 weeks for 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray and/or CT scan during screening and every 8 weeks, as well as a tumor biopsy at baseline, cycle 1 day 15, cycle 2 day 15, and every 3 weeks thereafter, and at disease progression. Patients also undergo blood sample collection at baseline, cycle 1 days 8 and 15, cycle 2 day 15, cycle 4 day 1 and disease progression. Patients undergo ECHO during screening and as clinically indicated on study.

Group II: Trial I (copanlisib, nivolumab) Experimental Treatment 7 Interventions

Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 of cycle 1. Beginning in cycle 2, patients also receive nivolumab IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray and/or CT scan during screening and every 8 weeks, as well as a tumor biopsy at baseline, cycle 1 day 15, cycle 2 day 15, and every 3 weeks thereafter, and at disease progression. Patients also undergo blood sample collection at baseline, cycle 1 days 8 and 15, cycle 2 day 15, cycle 4 day 1 and disease progression. Patients undergo 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 pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

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]

In a real-world study of 709 patients with advanced melanoma treated with ipilimumab plus nivolumab, 50.7% experienced severe treatment-related adverse events, highlighting the need for careful monitoring during therapy.

Despite the high rate of adverse events, the combination therapy showed promising long-term survival outcomes, with a median overall survival of 28.7 months and a 4-year overall survival rate of 50% for patients similar to those in the CheckMate-067 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. van Zeijl, MCT., van Breeschoten, J., de Wreede, LC., et al.[2023]

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]

A review of 2217 adverse drug reaction reports related to immune checkpoint inhibitors (ICIs) from 2011 to 2018 revealed that these drugs, particularly nivolumab, are associated with a higher frequency of serious immune-related adverse events, including gastrointestinal and respiratory disorders.

Emerging safety signals, such as ischaemic heart disease and cardiac failure, were identified, indicating the need for further investigation into the long-term safety profile of ICIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. Cutroneo, PM., Isgrò, V., Ientile, V., et al.[2021]

In a study of 184 patients with non-small cell lung cancer treated with immune checkpoint inhibitors, 26.6% developed immune-related adverse events (IRAEs), with certain factors like statin use and previous corticosteroid therapy increasing the risk of IRAEs.

Interestingly, patients who experienced IRAEs had significantly better progression-free survival (41 weeks vs. 9 weeks) and overall survival (89 weeks vs. 28 weeks), suggesting that the occurrence of IRAEs may be linked to improved treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. Serino, M., Freitas, C., Martins, M., et al.[2022]

In a study analyzing 2,088 individual case safety reports (ICSRs) related to immune checkpoint inhibitors (ICIs) in Italy, 801 reports documented serious immune-related adverse drug reactions (irADRs), primarily affecting male patients with gastrointestinal and skin toxicities.

Among the ICIs, nivolumab and pembrolizumab were most frequently associated with irADRs, with significant risks identified for pembrolizumab and ipilimumab, highlighting the need for oncologists to recognize and manage these serious side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. Ruggiero, R., Fraenza, F., Scavone, C., 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 phase 3 trial involving 1096 patients with untreated advanced renal-cell carcinoma, nivolumab plus ipilimumab significantly improved overall survival rates (75% at 18 months) compared to sunitinib (60% at 18 months), indicating a more effective treatment option for patients with intermediate or poor prognostic risk.

The objective response rate was also higher with nivolumab plus ipilimumab (42%) compared to sunitinib (27%), although both treatments had a high incidence of treatment-related adverse events, with nivolumab plus ipilimumab showing a slightly lower rate of severe (grade 3 or 4) events (46% vs. 63%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. Motzer, RJ., Tannir, NM., McDermott, DF., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. [2023]

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

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

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

A Multicenter, Randomized Phase III Study Comparing Platinum Combination Chemotherapy Plus Pembrolizumab With Platinum Combination Chemotherapy Plus Nivolumab and Ipilimumab for Treatment-Naive Advanced Non-Small Cell Lung Cancer Without Driver Gene Alterations: JCOG2007 (NIPPON Study). [2022]

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

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. [2023]

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

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

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

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Development of Skin Rash Predicts Outcome of Anti-PD-1- and Anti-CTLA4-Based Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer or Squamous Cell Carcinoma of the Head and Neck: A Single-Center Analysis. [2021]

8. Spain pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. [2022]

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

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. [2022]

10. 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]

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

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. [2022]

12. Japan pubmed.ncbi.nlm.nih.gov

Combination therapy with PD-1 or PD-L1 inhibitors for cancer. [2020]