Pomalidomide + Nivolumab for Viral Associated Cancers

Overseen By Kathryn A Lurain, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Antiretrovirals, Aspirin

Must not be taking: Systemic steroids

Disqualifiers: Pregnancy, Severe illness, Cirrhosis, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

Duration: 24 months

58 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Less toxic and more effective treatments are needed for cancers caused by viruses. These cancers include Hodgkin and non-Hodgkin lymphoma, hepatocellular carcinoma, head and neck cancer, nasopharyngeal carcinoma, gastric cancer, anal cancer, cervical cancer, vaginal cancer, vulvar cancer, penile cancer, Merkel cell carcinoma, Kaposi sarcoma, and leiomyosarcoma. Researchers want to see if a combination of drugs can help. Objective: To find a safe dose of pomalidomide plus nivolumab in people with cancers caused by viruses. Eligibility: Adults ages 18 or older who have cancers caused by Epstein Barr virus (EBV), human herpes virus 8/Kaposi sarcoma herpesvirus (HHV8/KSHV), human papilloma virus (HPV), hepatitis B or C virus (HBV/HCV), and Merkel cell polyomavirus (MCPyV) that have not responded to previous treatments or have relapsed, or in adults who do not want to have surgery because of disfigurement or other risks. Adults who have HIV with any CD4 T cell count are eligible. Design: Participants will be screened with blood and urine tests, scans, and heart tests. They will have a physical exam. Their ability to perform normal daily activities will be assessed. They may have a tumor biopsy. Treatment will be given in 28-day cycles. Participants will take pomalidomide as a tablet by mouth for 21 days of each cycle, for up to 24 cycles. They will get nivolumab by intravenous infusion once each cycle. They will take an aspirin each day until 30 days after their last dose of the study drugs. Participants will keep a pill diary. They will bring it to their study visit at the end of each cycle. At these visits, some screening tests will be repeated. Participants with Kaposi sarcoma will have pictures taken of their lesions. Participants will give blood and saliva samples for research. They may have optional anal and/or cervical swabs. They may have optional biopsies. Participants will have a follow-up visit 30 days after they stop taking the study drugs, then every month for 100 days. Some screening tests will be repeated. Then they may by contacted by phone every 3 months for 9 months, and then every 6 months thereafter....

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 have had anticancer treatment within the last 2 weeks, and you should not be on systemic steroid therapy that cannot be discontinued, except for low-dose replacement therapy. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Pomalidomide and Nivolumab for viral associated cancers?

Research shows that Pomalidomide, when combined with other drugs, can enhance immune responses and inhibit tumor growth in various cancers, such as multiple myeloma and pancreatic cancer. Additionally, Pomalidomide has been shown to work well with immune-modulating drugs, suggesting potential benefits when combined with Nivolumab, an immune checkpoint inhibitor. ^{1 2 3 4 5}

Is the combination of Pomalidomide and Nivolumab safe for humans?

Nivolumab, used in various cancers, can cause immune-related side effects, but it is generally considered safe when monitored. Pomalidomide, used for multiple myeloma, also has known side effects like low blood counts and blood clots, but is generally safe under medical supervision. ^{6 7 8 9 10}

How is the drug combination of Pomalidomide and Nivolumab unique for treating viral-associated cancers?

The combination of Pomalidomide and Nivolumab is unique because it combines an immune-modulating drug (Pomalidomide) with a PD-1 inhibitor (Nivolumab), which helps the immune system recognize and attack cancer cells. This approach is novel for viral-associated cancers, as it leverages the immune system in a way that is different from traditional chemotherapy or surgery. ^{7 11 12 13 14}

Research Team

Kathryn A Lurain, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults 18+ with virus-related cancers (like Kaposi sarcoma, lymphoma) that are advanced, not curable by surgery or have come back after treatment. This includes people with HIV and any CD4 count. Must be able to take daily aspirin, have good organ function, and use birth control if needed. Can't join if on strong immune system drugs, severe health issues, pregnant/nursing, had certain treatments recently or allergic to the trial drugs.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

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

I do not have an autoimmune disease that needs strong immune system-suppressing drugs.

Exclusion Criteria

Participants who are receiving any other investigational agents

I have had an organ or stem cell transplant from a donor.

I haven't had cancer treatment in the last 2 weeks, or it was for a cancer that won't affect this trial.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive pomalidomide orally for 21 days and nivolumab intravenously once per 28-day cycle, for up to 24 cycles

24 months

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with some screening tests repeated

100 days

Monthly visits (in-person)

Long-term Follow-up

Participants are contacted by phone every 3 months for 9 months, then every 6 months thereafter

1 year

Treatment Details

Interventions

• Nivolumab
• Pomalidomide

Trial Overview The trial is testing a combo of two drugs: Pomalidomide taken orally for 21 days in a cycle and Nivolumab given via IV once each cycle for up to 24 cycles. The goal is to find a safe dose for people whose cancer is caused by viruses like EBV or HPV.

Participant Groups

Group I: 3/Dose Expansion Experimental Treatment 2 Interventions

Nivolumab + pomalidomide (at optimal dose determined in dose escalation portion of the study) for up to 30 participants

Group II: 2/Dose Escalation Experimental Treatment 2 Interventions

Treatment with pomalidomide at escalating doses and nivolumab at a fixed dose

Group III: 1/Dose De-Escalation Experimental Treatment 2 Interventions

Treatment with pomalidomide at de-escalating doses if necessary and nivolumab at a fixed dose - CLOSED

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Durvalumab, a PD-L1 inhibitor, showed enhanced immune cell activation when combined with pomalidomide in patients with relapsed/refractory multiple myeloma, leading to significant changes in immune cell populations and gene expression in the tumor microenvironment.

While durvalumab alone did not induce immunologic changes, the combination therapy increased levels of monocytes, neutrophils, and natural killer cells, suggesting that combining these treatments may improve immune responses in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation by durvalumab and pomalidomide in patients with relapsed/refractory multiple myeloma. Young, MH., Pietz, G., Whalen, E., et al.[2021]

In a phase I/IIA study involving 22 treatment-naive patients with extensive-stage small-cell lung cancer, the maximum-tolerated dose of pomalidomide was determined to be 4 mg/day, with common side effects including fatigue, nausea, and neutropenia.

While the combination of pomalidomide with cisplatin and etoposide was found to be safe, it did not enhance the effectiveness of chemotherapy alone, as indicated by an overall response rate of only 31.8% and a median overall survival of 49.6 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of pomalidomide (CC-4047) in combination with cisplatin and etoposide in patients with extensive-stage small-cell lung cancer. Ellis, PM., Jungnelius, U., Zhang, J., et al.[2022]

In a phase I study involving 23 patients with metastatic pancreatic cancer, the combination of pomalidomide and gemcitabine was found to be feasible and safe, with a maximum tolerated dose of 10 mg/day for pomalidomide.

While not the primary focus, the treatment showed promising signs of efficacy, with 15% of patients achieving partial responses and 50% experiencing significant decreases in CA 19-9 levels, a marker for pancreatic cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer. Infante, JR., Jones, SF., Bendell, JC., et al.[2022]

New biphenyl-based chimeric compounds containing pomalidomide effectively inhibit the PD-1/PD-L1 complex, with compound 3 showing strong activity at an IC50 value of 60 nM.

Compounds 4 and 5 were able to significantly restore immune function in a cell line model, indicating their potential as immunotherapy agents, although they did not reduce PD-L1 protein levels as shown by Western blot analysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction. Shaabani, S., Gadina, L., Surmiak, E., et al.[2022]

Pomalidomide combined with dexamethasone (PomDex) shows strong anti-cancer effects in both lenalidomide-sensitive and resistant multiple myeloma cell lines, indicating its potential as an effective treatment option for patients who have not responded to other therapies.

The combination therapy not only inhibits tumor growth more effectively than single-agent treatments but also induces apoptosis through specific molecular mechanisms, such as the degradation of IKZF3 and modulation of pro-apoptotic pathways, particularly in lenalidomide-resistant cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma. Rychak, E., Mendy, D., Shi, T., et al.[2018]

In a study of 71 melanoma patients, the incidence of immune-related adverse events (IrAEs) was similar between those receiving nivolumab every 2 weeks (40%) and those receiving it every 4 weeks (50%), indicating that extended dosing is as safe as the original regimen.

Patients on the Q4W dosing experienced a potentially later onset of IrAEs, and most adverse events were mild (grade 1-2), suggesting that Q4W dosing not only maintains safety but also reduces the frequency of clinic visits and patient exposure to viruses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilization and toxicity patterns of 2-weekly (Q2W) versus 4-weekly (Q4W) nivolumab for treatment of adjuvant and metastatic melanoma at BC cancer. Truong, J., Yeung, SST., Kletas, V., et al.[2023]

Nivolumab and pembrolizumab are FDA-approved monoclonal antibodies that target PD-1, helping to enhance T cell activity against cancer by blocking the PD-1/PD-L1 interaction, which allows cancer cells to escape immune detection.

Both drugs have shown efficacy across multiple cancer types, including melanoma and non-small cell lung cancer, and are considered interchangeable options for treating these conditions, which may help manage the rising costs of cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Prasad, V., Kaestner, V.[2022]

In a phase II study involving 45 patients with MSI-H/dMMR metastatic colorectal cancer, the combination of nivolumab and low-dose ipilimumab showed a high objective response rate of 69% and a disease control rate of 84%, indicating strong efficacy as a first-line treatment.

The treatment was well tolerated, with only 22% of patients experiencing grade 3-4 treatment-related adverse events, and 74% of responders maintained their response at the time of data cutoff, suggesting durability of the treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. Lenz, HJ., Van Cutsem, E., Luisa Limon, M., et al.[2022]

In a study of 355 patients with metastatic melanoma resistant to anti-PD-(L)1 therapy, combining ipilimumab with anti-PD-1 (either pembrolizumab or nivolumab) resulted in a significantly higher objective response rate (31%) compared to ipilimumab alone (13%).

Patients receiving the combination therapy also experienced longer overall survival (20.4 months vs. 8.8 months) and longer progression-free survival (3.0 months vs. 2.6 months), while the rates of severe adverse events were similar between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. Pires da Silva, I., Ahmed, T., Reijers, ILM., et al.[2021]

In a phase II clinical trial involving 55 patients with melanoma, a one-year regimen of low-dose nivolumab resulted in an 85.7% relapse-free survival rate, suggesting it could be an effective treatment option.

The combination of a shorter low-dose nivolumab with ipilimumab was found to be less effective and more prone to adverse events, indicating that longer treatment with nivolumab alone may be preferable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial. Schwarze, JK., Garaud, S., Jansen, YJL., et al.[2022]

In the CheckMate 358 trial, nivolumab showed promising efficacy in patients with recurrent/metastatic cervical cancer, achieving an objective response rate of 26.3% and a median overall survival of 21.9 months, indicating its potential as a treatment option.

The treatment was generally well-tolerated, with 63.2% of cervical cancer patients experiencing any-grade treatment-related adverse events, but no treatment-related deaths were reported, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. Naumann, RW., Hollebecque, A., Meyer, T., et al.[2021]

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

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 (Opdivo) monotherapy led to complete regression of local recurrence and multiple lung metastases in a patient with recurrent skin melanoma and a positive BRAF mutation, demonstrating its efficacy as a treatment option.

After 5 courses of nivolumab, the patient experienced significant improvement in her condition, achieving an ECOG performance status of 0, indicating a return to an active lifestyle without pain, and normal serum LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. Samsonia, M., Kandelaki, M., Gibradze, O., et al.[2021]

References

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

Immunomodulation by durvalumab and pomalidomide in patients with relapsed/refractory multiple myeloma. [2021]

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

A phase I study of pomalidomide (CC-4047) in combination with cisplatin and etoposide in patients with extensive-stage small-cell lung cancer. [2022]

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

A phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction. [2022]

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

Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma. [2018]

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

Utilization and toxicity patterns of 2-weekly (Q2W) versus 4-weekly (Q4W) nivolumab for treatment of adjuvant and metastatic melanoma at BC cancer. [2023]

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

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. [2022]

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

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. [2022]

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

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. [2021]

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

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial. [2022]

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

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. [2021]

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

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

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

14. Georgia (Republic) pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. [2021]