Ipilimumab + Nivolumab for Colorectal Cancer
Recruiting in Palo Alto (17 mi)
Overseen byNicholas D Klemen, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Steroids, Immunosuppressants
Disqualifiers: Autoimmune disorders, Immunodeficiency, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?Background:
People with colorectal cancer (CRC) or gastroesophageal cancer (GEC) must often have major surgery to remove tumors from the esophagus, stomach, colon, or rectum. These surgeries can have adverse effects on their quality of life. Researchers want to know if one or two approved drugs (nivolumab with or without ipilimumab) can help people with CRC or GEC delay or avoid surgery.
Objective:
To test 1 or 2 drugs in people with CRC or GEC.
Eligibility:
People aged 18 years and older with CRC or GEC. People with GEC must also have changes in a particular gene.
Design:
Participants will visit the clinic about 15 times over the first 2 years. Each visit will last 4 to 8 hours.
Participants will be screened. They will have a physical exam with blood and urine tests. They will have imaging scans. Small samples of tissue will be collected from their upper or lower digestive tract where the tumor is located.
Both ipilimumab and nivolumab are administered through a tube attached to a needle inserted into a vein in the arm. Some participants will receive both drugs. Some will receive only nivolumab. Treatment will be given once every 3 weeks for up to 8 cycles up to (24 weeks).
Participants will be evaluated every 6 weeks. Those who are responding well will continue with the drug treatments. If their disease progresses, they will go to surgery.
After treatment ends, participants will have follow-up visits every 6 months for up to 5 years....
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications, but it does exclude participants taking steroids or other immunosuppressive agents that could affect the study drugs. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug combination Ipilimumab and Nivolumab for colorectal cancer?
Research shows that the combination of nivolumab and ipilimumab has been effective in treating certain types of colorectal cancer, specifically those with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) characteristics, as demonstrated in the CheckMate 142 study.
12345What safety information is available for the combination of Ipilimumab and Nivolumab?
The combination of Ipilimumab and Nivolumab has been associated with increased risk of immune-related side effects, such as colitis (inflammation of the colon), pneumonitis (lung inflammation), and diarrhea. These side effects can be serious, with some patients experiencing high-grade adverse events, and a small percentage of treatment-related deaths have been reported. Proper management of these side effects is crucial to prevent significant health issues.
678910How is the drug combination of Ipilimumab and Nivolumab unique for colorectal cancer?
The combination of Ipilimumab and Nivolumab is unique for treating colorectal cancer with specific genetic features (MSI-H/dMMR) because it targets the immune system to fight cancer cells, offering a new option for patients whose cancer has progressed after standard treatments.
123511Eligibility Criteria
This trial is for adults with colorectal or gastroesophageal cancer. For gastroesophageal cancer, a specific gene change is required. Participants will undergo numerous clinic visits and tests including blood, urine, imaging scans, and tissue samples from the digestive tract.Inclusion Criteria
Breastfeeding participants must discontinue breastfeeding during study treatment
Participants must understand and sign a written informed consent document
My medical records show special reasons for my MMR proficient colon cancer treatment.
+10 more
Exclusion Criteria
I am not on medications that could interfere with the study treatment.
Participants receiving any other investigational agents
I do not have any serious illnesses that would prevent me from having major surgery in my abdomen.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive nivolumab every 3 weeks for up to 8 cycles, with some receiving additional ipilimumab every 6 weeks for up to 4 cycles
24 weeks
8 visits (in-person)
Evaluation
Participants are evaluated every 6 weeks for response to treatment, which dictates further management
24 weeks
4 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, with follow-up visits every 6 months for up to 5 years
5 years
10 visits (in-person)
Participant Groups
The study evaluates if nivolumab alone or combined with ipilimumab can delay or avoid surgery in patients. Treatments are given through an IV every 3 weeks for up to 24 weeks. Patients responding well may continue treatment; otherwise, they'll consider surgery.
2Treatment groups
Experimental Treatment
Group I: 2: nivolumabExperimental Treatment1 Intervention
Nivolumab (3 mg/kg) every 3 weeks for up to an initial 4 cycles (an additional 4 cycles may be given depending on response, for a total of 8 cycles).
Group II: 1: nivolumab and ipilimumabExperimental Treatment2 Interventions
Nivolumab (3 mg/kg) every 3 weeks for up to an initial 4 cycles (an additional 4 cycles may be given depending on response, for a total of 8 cycles); low-dose ipilimumab at 1 mg/kg every other cycle (every 6 weeks) for up to an initial 2 doses (an additional 2 doses may be given depending on response, for a maximum of 4 doses).
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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]Frontline treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) induced durable and long-term efficacy, compared with chemotherapy, in patients with advanced non-small cell lung cancer (NSCLC) and tumor PD-L1 expression greater than 1% or less than 1%, according to updated results from part 1 of the phase 3 CheckMate 227 (NCT02477826)trial presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program.
Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]Nivolumab plus ipilimumab achieves higher response rates than previously reported for nivolumab alone.
First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. [2022]Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study.
Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. [2023]First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival.
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]On the 15 November 2018, the Committee for Medicinal Products for Human Use adopted an extension to an existing indication for the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). The approval was based on results from the Pivotal CA209214 study, a randomised, open-label, phase III study, comparing nivolumab +ipilimumab with sunitinib in subjects≥18 years of age with previously untreated advanced RCC (not amenable for surgery or radiotherapy) or metastatic RCC, with a clear-cell component. A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab (n=425) in combination with ipilimumab administered every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) administered orally for 4 weeks followed by 2 weeks off, every cycle. A statistically significant difference in overall survival (OS) was observed in the nivolumab + ipilimumab group compared with the sunitinib group in intermediate/poor-risk subjects (HR 0.63 (99.8% CI 0.44 to 0.89); stratified log-rank 2-sided p-value
Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]Recent studies suggest that combining nivolumab with ipilimumab is a more effective treatment for melanoma patients, compared to using ipilimumab or nivolumab alone. However, treatment with these immunotherapeutic agents is frequently associated with increased risk of toxicity, and (auto-) immune-related adverse events. The precise pathophysiologic mechanisms of these events are not yet clear, and evidence from clinical trials and translational studies remains limited. Our retrospective analysis of ~7700 metastatic melanoma patients treated with ipilimumab and/or nivolumab from the FDA Adverse Event Reporting System (FAERS) demonstrates that the identified immune-related reactions are specific to ipilimumab and/or nivolumab, and that when the two agents are administered together, their safety profile combines reactions from each drug alone. While more prospective studies are needed to characterize the safety of ipilimumab and nivolumab, the present work constitutes perhaps the first effort to examine the safety of these drugs and their combination based on computational evidence from real world post marketing data.
Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. [2022]A systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to examine treatment-related adverse events (TRAEs) for combination of nivolumab (NIVO) and ipilimumab (IPI) compared to NIVO monotherapy among cancer patients. We searched several databases to identify relevant RCTs. Meta-analysis was performed using random-effects model. In fourteen RCTs included in the study, we found that compared to NIVO monotherapy, combination NIVO + IPI increased the risk of any grade (Risk Ratio (RR) = 1.11), and grade 3 or 4 (RR = 1.95) TRAEs. Compared to NIVO, NIVO + IPI had higher risk for any grade colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68).
Antitumor Activity and Treatment-Related Toxicity Associated With Nivolumab Plus Ipilimumab in Advanced Malignancies: A Systematic Review and Meta-Analysis. [2023]Combining immune checkpoint inhibitors has shown its efficacy compared to monotherapy in advanced malignancies. We conducted this meta-analysis to provide latest evidence on the objective response rate (ORR) and incidence of treatment-related high-grade adverse events (AEs) during nivolumab and ipilimumab combination treatment and further explore from different drug dose level. PubMed and the 2019 American Society of Clinical Oncology (ASCO) annual meeting abstracts were searched for qualified clinical trials up to June 2019. Of the 23 clinical trials (13 from publications and 11 from ASCO abstracts) included, 2,114 and 2,674 patients were eligible for efficacy and safety analysis, respectively. Pooled analysis suggested that the overall ORR was achieved in 34.5% [95% confidence interval (CI), 29.1-40.4%] of patients. There was no significant difference between nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks (N3I1-Q3W) and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (N1I3-Q3W) arms in ORR [30.8% vs 41%; odds ratio (OR), 0.72; 95% CI, 0.39-1.30; P = 0.275]. Grade 3-4 AEs related to combination therapy occurred in 39.9% (95% CI, 33.5-46.7%) of patients; the most commonly reported grade 3-4 treatment-related AEs were diarrhea (5.28%), colitis (3.96%) and increased alanine aminotransferase (3.51%). Incidence of grade 3-4 AEs were significant lower in N3I1-Q3W arm than in N1I3-Q3W arm (31.3% vs 55.9%; OR 0.52; 95% CI, 0.32-0.87; P = 0.012). Treatment-related death was rare and occurred in 2.0% (95% CI, 1.5-2.7%) of patients. Our comprehensive study provides more precise data on the incidence of treatment-related high-grade AEs and ORR among patients receiving nivolumab and ipilimumab combination regimens. Patients on the N3I1-Q3W arm had comparable ORR and significantly occurred less grade 3-4 AEs than patients on the N1I3-Q3W arm. Our finding is of great importance in assisting clinical trial design and clinical medication choice.
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]The use of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) therapy (ipilimumab) and anti-programmed cell-death 1 (anti-PD1) agents (nivolumab and pembrolizumab) in advanced melanoma have been associated with immune-related adverse events (irAEs) including colitis. We aimed to estimate the incidence and the risk of colitis in elderly patients with advanced melanoma treated with anti-CTLA4 and anti-PD1 in the real-world setting.
Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. [2022]Immune checkpoint inhibitors (ICIs) affect immunologic homeostasis, leading to immune-related adverse events (irAEs). Early irAE detection and management can prevent significant morbidity and mortality. A retrospective chart review was performed to characterize irAEs associated with nivolumab, ipilimumab, and nivolumab plus ipilimumab in adult medical oncology patients in Nova Scotia Health-Central Zone from 2013-2020, and to describe adherence to toxicity management guidelines. Diarrhea/colitis, hepatitis, pneumonitis, nephrotoxicity, and cardiotoxicity were studied. Of 129 charts reviewed, 67 patients (51.9%) experienced at least one irAE for a total of 98 irAEs and a 1.5% fatality rate. Of these irAEs, 33.7% led to an emergency room visit. Patients were admitted to hospital and steroids were used in 24.5% and 35.7% of cases, respectively. In 17.3% of irAEs, ICIs were permanently discontinued. In 20.4% of irAEs, ICIs were held, and patients were monitored; while in 18.4%, ICIs were held until the irAE was Grade 0-1 (and until steroids were tapered). Almost 47% of irAEs were managed according to guidelines (14.3% were not), and 38.8% had no documented management. Patients receiving immunotherapy frequently experience irAEs with half of irAEs having documented management adhering to guidelines. As immunotherapy indications expand, it is important to ensure irAEs are documented and managed appropriately.
Nivolumab Plus Ipilimumab vs Nivolumab Alone in Advanced Cancers Other Than Melanoma: A Meta-Analysis. [2023]Although the combination of nivolumab plus ipilimumab has unquestionable benefit over nivolumab monotherapy in advanced melanoma, currently no summative analyses have compared the combination with nivolumab monotherapy for advanced cancers other than melanoma.