Combination Immunotherapy for Refractory Cancers

Overseen By Jibran Ahmed, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Anticancer therapy

Disqualifiers: Active CNS metastases, HIV, Autoimmune disease, 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: 4

Duration: 24 weeks

31 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: The drug IL-15 activates the immune system. The drugs nivolumab and ipilimumab unblock immune cells. The drugs together may allow immune cells to recognize and attack cancer cells, causing tumors to shrink. Objective: To test the effects and maximum dose of IL-15, nivolumab, and ipilimumab. Eligibility: People ages 18 and older who have cancer that does not respond to treatment Design: Participants will be screened with: * Medical history * Physical exam * Heart, blood, and urine tests * Scans Tumor biopsy: A small needle removes a tumor sample. Participants will be in 1 of 3 treatment groups: * IL-15 with nivolumab * IL-15 with ipilimumab * IL-15 with nivolumab and ipilimumab Participants will take the drugs in four 6-week cycles. IL-15 is injected under the skin. The other two drugs are injected into an arm vein over 60-90 minutes. Participants may need to stay at the hospital 2-3 hours after the first dose of any drug to watch for side effects. Each cycle will include: * Weekly blood and urine tests * 5 IL-15 injections * 1 ipilimumab injection if applicable * 3 nivolumab injections if applicable * Scans and a tumor biopsy on day 42 After cycle 4, participants will stop taking IL-15. They will continue the other drugs until they can no longer tolerate the side effects or their cancer gets worse. Those cycles will include: * Blood tests on 3-4 days * Urine tests on 1 day * 1 ipilimumab injection if applicable * 3 nivolumab injections if applicable * Scans every other cycle After participants stop treatment, their doctor will monitor their side effects for 4 months or until they go away.

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 can continue hormone therapy for prostate cancer and bisphosphonates/denosumab for any cancer. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Ipilimumab, Yervoy, Nivolumab, Opdivo, and rhIL-15 for refractory cancers?

Research shows that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has been effective in treating advanced non-small cell lung cancer and certain colorectal cancers, providing longer survival and better response rates compared to traditional chemotherapy. ^{1 2 3 4 5}

What safety data exists for combination immunotherapy with nivolumab and ipilimumab?

Combination immunotherapy with nivolumab and ipilimumab can cause immune-related side effects like diarrhea, liver inflammation, lung inflammation, kidney issues, and heart problems. In a study, about 52% of patients experienced at least one side effect, with some requiring hospital visits or stopping treatment. Proper management of these side effects is crucial to prevent serious health issues. ^{6 7 8 9 10}

What makes the combination immunotherapy drug unique for refractory cancers?

This treatment combines three drugs: Ipilimumab, Nivolumab, and rhIL-15, which work together to boost the immune system's ability to fight cancer cells. This combination is unique because it uses two immune checkpoint inhibitors (Ipilimumab and Nivolumab) along with rhIL-15, potentially enhancing the immune response more effectively than other treatments. ^{1 11 12 13 14}

Research Team

Jibran Ahmed, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults (18+) with cancers that have spread and don't respond to treatment can join. They must be able to sign consent, not pregnant or breastfeeding, agree to use contraception, and have no severe illnesses or mental health issues that could interfere with the trial. Prior treatments are okay if recovered from side effects.

Inclusion Criteria

I've had treatment with a trial drug or similar before but have recovered from its side effects.

My organ and bone marrow functions are normal.

I have recovered from side effects of my last cancer treatment.

Exclusion Criteria

I haven't had cancer treatments or major surgery in the last 4 weeks.

I have brain cancer or cancer that has spread to my brain.

I am not on any cancer treatment except hormone therapy for breast or prostate cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive IL-15 with nivolumab, IL-15 with ipilimumab, or IL-15 with both nivolumab and ipilimumab in four 6-week cycles

24 weeks

Weekly visits for blood and urine tests, drug administration, and scans

Extended Treatment

Participants continue with nivolumab and ipilimumab until they can no longer tolerate side effects or their cancer progresses

Variable

Blood tests on 3-4 days, urine tests on 1 day, scans every other cycle

Follow-up

Participants are monitored for side effects for 4 months or until they resolve after stopping treatment

4 months

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• rhIL-15

Trial Overview The trial tests a combination of immune-activating drugs: IL-15 plus nivolumab and/or ipilimumab in patients whose cancer hasn't responded to other treatments. It aims to find the highest safe dose by dividing participants into three groups receiving different drug combinations over four cycles.

Participant Groups

Group I: triplet Experimental Treatment 3 Interventions

triplet combination

Group II: lead-in doublet B Experimental Treatment 2 Interventions

lead-in doublet for initial safety evaluation: rhIL-15 given SC days 1-8 and 22- 29 + nivolumab (anti-PD1) given IV on days 8, 22, and 36 (IL-15 doses are limited to first 4 cycles only)

Group III: lead-in doublet A Experimental Treatment 2 Interventions

lead-in doublet for initial safety evaluation: rhIL-15 given SC days 1-8 and 22- 29 + ipilimumab (anti- CTLA-4) given IV on day 8 (IL-15 doses are limited to first 4 cycles only)

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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 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]

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 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 46 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, 72% experienced immune-related adverse events (irAEs), which were linked to significantly longer progression-free survival (PFS) compared to those without irAEs.

While irAE development was an independent predictor of longer PFS, it did not affect overall survival (OS), suggesting that irAEs could serve as a useful prognostic marker for treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Ikeda, T., Ishihara, H., Nemoto, Y., et al.[2022]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

In a study of 129 advanced renal cell carcinoma patients treated with nivolumab and ipilimumab, the occurrence of immune-related adverse events (irAEs) was linked to improved overall survival (OS) and progression-free survival (PFS), with significant hazard ratios indicating a strong positive association.

Patients who experienced multiple irAEs had even better survival outcomes, suggesting that the presence of these adverse events may be a marker for a more favorable response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis. Washino, S., Shirotake, S., Takeshita, H., et al.[2023]

In a review of 129 oncology patients treated with immune checkpoint inhibitors, 51.9% experienced at least one immune-related adverse event (irAE), highlighting the common occurrence of these side effects.

Nearly half of the irAEs were managed according to established guidelines, but there was significant variability in documentation and management practices, indicating a need for improved adherence as immunotherapy use increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. Teimouri, A., Minard, LV., Scott, SN., et al.[2022]

In a meta-analysis of 11,465 patients from 18 clinical trials, PD-1/PD-L1 inhibitors were found to significantly increase the risk of developing dermatologic adverse effects like rash and pruritus compared to chemotherapy, with relative risks of 1.84 and 3.74, respectively.

PD-1/PD-L1 inhibitors showed a lower risk of mucosal inflammation and alopecia compared to chemotherapy, indicating a distinct safety profile that differs from traditional cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of dermatologic and mucosal adverse events associated with PD-1/PD-L1 inhibitors in cancer patients: A meta-analysis of randomized controlled trials. Yang, W., Li, S., Yang, Q.[2021]

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

In a phase 1 study involving 78 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab as first-line therapy demonstrated a tolerable safety profile with no treatment-related deaths and manageable adverse events, such as increased lipase and pneumonitis.

The treatment showed promising efficacy, with confirmed objective response rates of 47% in the ipilimumab every-12-weeks cohort and 38% in the every-6-weeks cohort, suggesting potential benefits over anti-PD-1 monotherapy and warranting further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Hellmann, MD., Rizvi, NA., Goldman, JW., et al.[2022]

In a study of 47 patients with advanced melanoma who experienced acquired resistance to initial combination immunotherapy, reinduction with ipilimumab (with or without anti-PD-1) resulted in a modest response rate of 26% and a disease control rate of 45%.

While reinduction therapy showed some clinical activity, it also carried a significant risk of immune-related adverse events (irAEs), with 58% of patients experiencing them, including severe cases, and many patients experiencing recurrence of previously observed irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy. Hepner, A., Atkinson, VG., Larkin, J., et al.[2021]

In a study of 45 Japanese patients with untreated metastatic renal cell carcinoma, the combination therapy of nivolumab and ipilimumab showed a 41.5% objective response rate and a median progression-free survival of 17.8 months over a 2-year follow-up period.

The 2-year analysis indicated that nivolumab plus ipilimumab therapy's effectiveness aligns with previous studies, and second-line therapy following this combination also demonstrated a 20% objective response rate with a median progression-free survival of 9.8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study). Kojima, T., Kato, R., Sazuka, T., et al.[2022]

References

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

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

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

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

3. 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]

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

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

5. 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]

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

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. [2022]

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

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. [2023]

8. Japan pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis. [2023]

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

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. [2022]

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

Risk of dermatologic and mucosal adverse events associated with PD-1/PD-L1 inhibitors in cancer patients: A meta-analysis of randomized controlled trials. [2021]

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

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. [2022]

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

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study). [2022]