Copanlisib + Nivolumab for Lymphoma

Recruiting at 3 trial locations

Overseen By Alexey Danilov, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inhibitors, Corticosteroids

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

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

Compensation: Varies

Number of Visits: 6

Duration: 48 weeks

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial studies how well copanlisib and nivolumab work together in treating patients with aggressive forms of lymphoma. Copanlisib stops cancer cell growth by blocking certain enzymes, and nivolumab helps the immune system attack the cancer. The goal is to find the best dose and see how effective this combination is.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use strong CYP3A4 inhibitors or inducers within 2 weeks before starting the study therapy, and you should not be on chronic corticosteroids exceeding 15 mg of prednisone per day.

What data supports the effectiveness of the drug combination Copanlisib and Nivolumab for treating lymphoma?

Research shows that Copanlisib, when combined with other drugs like rituximab, significantly reduces the risk of disease progression in patients with relapsed indolent non-Hodgkin lymphoma. Additionally, Copanlisib has shown effectiveness in combination with other agents in various lymphoma models, suggesting potential benefits when used with Nivolumab. ^{1 2 3 4 5}

What safety data exists for Copanlisib + Nivolumab treatment in humans?

Nivolumab, used in combination with other drugs, has been associated with some side effects like rash, fatigue, and immune-related adverse events in various cancers. In lymphoma patients, nivolumab showed a 74% incidence of any grade side effects, with common ones being fatigue, rash, and hypothyroidism. However, these side effects are generally considered manageable. ^{6 7 8 9 10}

How is the drug combination of Copanlisib and Nivolumab unique for treating lymphoma?

The combination of Copanlisib and Nivolumab is unique because it combines a PI3K inhibitor (Copanlisib) with a PD-1 inhibitor (Nivolumab), potentially enhancing the immune system's ability to fight lymphoma by targeting different pathways involved in cancer cell survival and immune evasion. ^{11 12 13 14 15}

Research Team

Alexey V Danilov

Principal Investigator

City of Hope Comprehensive Cancer Center

Eligibility Criteria

This trial is for patients with Richter's transformation or transformed indolent non-Hodgkin lymphoma who've had at least one prior treatment. Participants must have measurable disease, acceptable organ function, and agree to contraception if applicable. Exclusions include pregnancy, uncontrolled health conditions like hypertension or bleeding disorders, recent major surgery, live vaccines, certain heart issues, and previous treatments with similar drugs.

Inclusion Criteria

I have lymphoma, have tried at least one treatment without success, and am not planning or eligible for a stem cell transplant.

I have had at least 2 treatments for my Richter's Syndrome or CLL.

Your AST and ALT levels are lower than 2.5 times the normal limit at the medical facility where you are being treated.

Exclusion Criteria

I haven't had cancer treatments like antibodies, radiation, or chemotherapy recently.

My cancer has spread to my brain or spinal cord.

I have had a bone marrow or organ transplant from another person.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive copanlisib IV on days 1, 8, and 15 and nivolumab IV on days 1 and 15, repeating every 28 days for up to 12 cycles

48 weeks

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

12 months

Every 3 months

Treatment Details

Interventions

• Copanlisib
• Nivolumab

Trial Overview The trial tests the combination of copanlisib (blocks enzymes for cell growth) and nivolumab (boosts immune system against cancer). It aims to find the best dose and see how well these drugs work together in treating specific types of lymphoma by stopping tumor growth and helping the body attack cancer cells.

Participant Groups

Group I: Treatment (copanlisib and nivolumab) Experimental Treatment 2 Interventions

Patients receive copanlisib IV over 60 minutes on days 1, 8, and 15 and nivolumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The phase III CHRONOS-3 trial demonstrated that adding copanlisib, a pan-PI3K inhibitor, to standard rituximab significantly benefits patients with relapsed indolent non-Hodgkin lymphoma.

This combination therapy was found to be safe and reduced the risk of disease progression or death by nearly 50% compared to the placebo plus rituximab group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NHL Progression Risk Cut with Copanlisib-Rituximab Combo. [2021]

Copanlisib is effective in treating relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL), with an overall response rate of 57% and a complete response rate of 13% based on a meta-analysis of 652 patients across 8 studies.

Combination therapy with copanlisib and rituximab showed significantly higher efficacy compared to copanlisib alone, with complete response rates of 34% versus 6%, while treatment-related adverse events were manageable, with common side effects including hyperglycemia and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of copanlisib in relapsed/refractory B-cell non-Hodgkin lymphoma: A meta-analysis of prospective clinical trials. Wang, J., Zhou, H., Mu, M., et al.[2022]

A review of 29 articles identified specific dermatological adverse events (AEs) associated with various immunotherapy combinations, highlighting that combinations like nivolumab/ipilimumab and lenvatinib/pembrolizumab had the highest incidence of rash.

Understanding these dermatological AEs, such as pruritus and alopecia, is crucial for optimizing treatment plans and improving patient monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. Salloum, A., Habre, M., Chebl, JA., et al.[2022]

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 311 patients treated with nivolumab or pembrolizumab for advanced melanoma or lung cancer, 37.3% experienced immune-related adverse events, which were linked to improved overall survival rates.

Patients who had immune-related adverse events showed a significantly higher overall response rate (53.9%) compared to those without such events (12.9%), suggesting that these adverse effects may indicate better treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non-small-cell lung cancer: a real-life retrospective study. Dupont, R., Bérard, E., Puisset, F., et al.[2021]

Monoclonal antibodies like nivolumab and pembrolizumab, which target PD-1, have shown a survival benefit and better tolerability compared to standard second-line chemotherapy in non-small cell lung cancer, as demonstrated in three phase III trials.

Patients receiving PD-1 inhibitors may experience unique immune-related adverse events that require early recognition and a multidisciplinary management approach, highlighting the need for ongoing education among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. O'Kane, GM., Labbé, C., Doherty, MK., et al.[2018]

Nivolumab and pembrolizumab, both anti-PD-1 therapies, show promising efficacy in treating relapsed or refractory lymphoma, with an overall response rate of 58% and a 6-month overall survival rate of 96% across 10 studies involving 718 patients.

While both treatments have tolerable adverse effects, pembrolizumab is associated with fewer instances of fatigue and rash compared to nivolumab, and patients with Hodgkin lymphoma respond better to treatment than those with non-Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Anti-PD-1 Monoclonal Antibodies in Patients With Relapsed or Refractory Lymphoma: A Meta-Analysis of Prospective Clinic Trails. Zhou, H., Fu, X., Li, Q., et al.[2020]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

Nivolumab, an immune checkpoint inhibitor targeting PD-1, has shown effectiveness in treating various cancers, including Hodgkin lymphoma, as evidenced by a partial response in a 75-year-old patient after multiple treatments.

The case highlights a potential risk where discontinuation of nivolumab led to the emergence and progression of new malignancies, suggesting that while ICIs can be effective, they may also uncover or allow the growth of other cancers in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two primary cancers appeared after discontinuation of nivolumab in the course of treating Hodgkin lymphoma: a case report. Potluri, LB., Nanjareddy, S., Al Sbihi, A., et al.[2023]

In a phase 1b trial involving 137 patients with relapsed/refractory lymphoid malignancies, the combination of nivolumab with ipilimumab or lirilumab showed significant activity in classical Hodgkin lymphoma, with overall response rates of 74% and 76%, respectively.

However, the combination therapies did not demonstrate a meaningful improvement in efficacy compared to single-agent nivolumab, and the combination with ipilimumab resulted in higher rates of severe treatment-related adverse events (29%) compared to lirilumab (15%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies. Armand, P., Lesokhin, A., Borrello, I., et al.[2021]

Checkpoint inhibitors like nivolumab and pembrolizumab are effective treatment options for patients with relapsed or refractory classic Hodgkin lymphoma, particularly for those who cannot undergo autologous stem-cell transplantation due to health issues.

These treatments not only improve overall survival rates but also have a manageable side effect profile, making them a safer alternative for patients with comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint Inhibition Therapy in Transplant-Ineligible Relapsed or Refractory Classic Hodgkin Lymphoma. Al-Hadidi, SA., Lee, HJ.[2022]

References

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

NHL Progression Risk Cut with Copanlisib-Rituximab Combo. [2021]

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

Copanlisib synergizes with conventional and targeted agents including venetoclax in B- and T-cell lymphoma models. [2022]

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

First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of copanlisib in relapsed/refractory B-cell non-Hodgkin lymphoma: A meta-analysis of prospective clinical trials. [2022]

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

Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. [2022]

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

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

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

The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non-small-cell lung cancer: a real-life retrospective study. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. [2018]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Anti-PD-1 Monoclonal Antibodies in Patients With Relapsed or Refractory Lymphoma: A Meta-Analysis of Prospective Clinic Trails. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]

12. China pubmed.ncbi.nlm.nih.gov

Two primary cancers appeared after discontinuation of nivolumab in the course of treating Hodgkin lymphoma: a case report. [2023]

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

A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies. [2021]

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

Clinical PD-1/PD-L1 Blockades in Combination Therapies for Lymphomas. [2023]

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

Checkpoint Inhibition Therapy in Transplant-Ineligible Relapsed or Refractory Classic Hodgkin Lymphoma. [2022]