PI3Kinase Inhibition + Anti-PD-1 Antibody for Colorectal Cancer

Overseen By Joann Santmyer, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Immunotherapy, PI3K inhibitors, CYP3A4

Disqualifiers: CNS metastases, Active infection, Diabetes, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

48 Participants Needed

Trial Summary

What is the purpose of this trial?

A phase I/II study of PI3Kinase inhibition (copanlisib) and anti-PD-1 antibody nivolumab in relapsed/refractory solid tumors with expansions in mismatch-repair proficient (MSS) colorectal cancer.

Do I need to stop my current medications to join the trial?

The trial requires that you stop using CYP3A4 inhibitors and inducers (types of drugs that affect how your body processes other medications) within 2 weeks of starting the study drug and throughout the treatment. If you are on these medications, you will need to stop them before joining the trial.

What data supports the effectiveness of the drug combination of Copanlisib, Nivolumab, and Opdivo for colorectal cancer?

A case report showed that a PD-1 inhibitor, similar to Nivolumab and Opdivo, combined with another drug, demonstrated good effectiveness in a specific type of colorectal cancer. Additionally, PD-1 inhibitors like Nivolumab are being developed and used for various cancers, suggesting potential benefits in colorectal cancer. ^{1 2 3 4 5}

Is the combination of PI3Kinase Inhibition and Anti-PD-1 Antibody safe for humans?

Nivolumab, an Anti-PD-1 Antibody, can cause immune-related side effects like colitis (inflammation of the colon), which is more common compared to some other treatments. However, these side effects can often be managed with proper medical care. ^{3 6 7 8 9}

What makes the drug combination of Copanlisib and Nivolumab unique for colorectal cancer?

This drug combination is unique because it combines Copanlisib, which inhibits a pathway often altered in cancer cells and enhances immune responses, with Nivolumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells. This combination aims to improve the effectiveness of immune therapies by overcoming immune suppression in tumors. ^{10 11 12 13 14}

Research Team

Nilofer Azad, MD

Principal Investigator

Johns Hopkins Medical Institution

Eligibility Criteria

Adults over 18 with advanced solid tumors, including colorectal cancer that's still growing despite treatment. They must have tried at least two other treatments and be in good physical shape (able to perform daily activities). Participants need functioning organs, measurable disease for tracking progress, and the ability to provide consent. Pregnant or breastfeeding women can't join, nor can those with recent serious health issues like heart attacks or infections.

Inclusion Criteria

I am fully active or can carry out light work.

I've completed all treatments meant to cure me and have had at least 2 types of systemic therapy.

Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

Cytomegalovirus polymerase chain reaction (CMV PCR) positive

I have been treated with a PI3K inhibitor before.

I am on medication for seizures.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Copanlisib and Nivolumab for relapsed/refractory solid tumors

6 months

Regular visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Extension

Participants may continue to be monitored for long-term outcomes such as overall survival

2 years

Treatment Details

Interventions

• Copanlisib
• Nivolumab

Trial Overview The trial is testing Copanlisib, a PI3Kinase inhibitor, alongside Nivolumab, an anti-PD-1 antibody. It aims to see how well they work together in patients whose colorectal cancer hasn't responded to standard treatments. The study will monitor safety and effectiveness of this combination therapy.

Participant Groups

Group I: Phase II/Arm B -P13K wild type /Copanlisib and Nivolumab Experimental Treatment 2 Interventions

Group II: Phase II /Arm A-P13K mutation/Copanlisib and Nivolumab Experimental Treatment 2 Interventions

Group III: Phase I - Copanlisib and Nivolumab (De-Escalation) Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

Programmed cell death 1 (PD-1) and its ligand (PD-L1) are promising targets for treating gastrointestinal cancers, which are a leading cause of cancer-related deaths, highlighting the need for new biomarkers and therapies.

Several PD-1/PD-L1 inhibitors, including pembrolizumab, have been developed and approved for use in other cancers, showing potential for improving treatment efficacy in gastrointestinal cancers, although resistance mechanisms to these therapies are still being studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed cell death 1 as prognostic marker and therapeutic target in upper gastrointestinal cancers. Khoshghamat, N., Jafari, N., Moetamani-Ahmadi, M., et al.[2021]

In a phase II trial involving 48 patients with microsatellite stable colorectal cancer, the combination of regorafenib and avelumab showed a best response of stable disease in 53.5% of patients, with a median progression-free survival of 3.6 months and overall survival of 10.8 months.

The study found that higher infiltration of CD8+ T cells in tumors was linked to better outcomes, suggesting that assessing immune cell presence could help identify patients who might benefit more from this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial. Cousin, S., Cantarel, C., Guegan, JP., et al.[2022]

PD-1/PD-L1 inhibitors used in treating non-small cell lung cancer (NSCLC) are associated with a significantly higher risk of immune-related colitis, with an overall incidence of 1.40% for all grades and 0.89% for severe cases, compared to chemotherapy.

While PD-1 inhibitors specifically increase the risk of colitis, they may also reduce the risk of all-grade diarrhea, indicating a complex safety profile that clinicians need to consider when prescribing these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The incidence and relative risk of PD-1/PD-L1 inhibitors-related colitis in non-small cell lung cancer: A meta-analysis of randomized controlled trials. Lin, LL., Lin, GF., Luo, Q., et al.[2020]

In a meta-analysis of clinical trials, PD-1 inhibitors (like nivolumab and pembrolizumab) were found to have a higher incidence of colitis compared to PD-L1 inhibitors (like atezolizumab and durvalumab), with rates of 1.49% for all grade colitis and 0.85% for grade 3-4 colitis.

The analysis indicated that the relative risk of developing colitis with PD-1 inhibitors was significantly higher (1.80 for all grade colitis and 2.52 for grade 3-4 colitis), suggesting that patients receiving PD-1 inhibitors may need closer monitoring for this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and Risk of Colitis With Programmed Death 1 Versus Programmed Death Ligand 1 Inhibitors for the Treatment of Cancer. Miyashita, H., Mikami, T., Satoi, S., et al.[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]

The PI3Kα inhibitor alpelisib demonstrated a 58.2% disease control rate in patients with solid tumors that have PIK3CA alterations, indicating its potential efficacy in this specific cancer population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PI3Kα Inhibitor Alpelisib Has Activity in PIK3CA-altered Tumors. [2019]

References

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

PD-1 inhibitor in combination with fruquintinib therapy for initial unresectable colorectal cancer: A case report. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

Programmed cell death 1 as prognostic marker and therapeutic target in upper gastrointestinal cancers. [2021]

3. Australia pubmed.ncbi.nlm.nih.gov

Risk of immune-related colitis with PD-1/PD-L1 inhibitors vs chemotherapy in solid tumors: systems assessment. [2020]

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

Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a systematic review and meta-analysis. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

The incidence and relative risk of PD-1/PD-L1 inhibitors-related colitis in non-small cell lung cancer: A meta-analysis of randomized controlled trials. [2020]

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

Incidence and Risk of Colitis With Programmed Death 1 Versus Programmed Death Ligand 1 Inhibitors for the Treatment of Cancer. [2021]

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

Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease. [2023]

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

PD-1 Pathway Inhibitors: Immuno-Oncology Agents for Restoring Antitumor Immune Responses. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors. [2019]

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

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer. [2022]

12. Italy pubmed.ncbi.nlm.nih.gov

Pan-PI3K inhibition with copanlisib overcomes Treg- and M2-TAM-mediated immune suppression and promotes anti-tumor immune responses. [2023]

13. 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]

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

The PI3Kα Inhibitor Alpelisib Has Activity in PIK3CA-altered Tumors. [2019]