What side effects are associated with this type of intervention?

Common treatments for colorectal cancer, such as Nivolumab (a PD-1 inhibitor), Trametinib (a MEK inhibitor), and Ipilimumab (a CTLA-4 inhibitor), have distinct side effect profiles. Nivolumab often causes fatigue, rash, diarrhea, and immune-related adverse events like pneumonitis and colitis. Trametinib is associated with rash, diarrhea, peripheral edema, and cardiomyopathy. Ipilimumab can lead to severe immune-mediated reactions including colitis, dermatitis, hepatitis, and endocrinopathies. Combining these therapies may increase the risk and severity of these side effects.

What prior FDA approvals exist?

Nivolumab, a PD-1 inhibitor, has been approved by the FDA for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Ipilimumab, a CTLA-4 inhibitor, has also been approved in combination with Nivolumab for the same indication. However, Trametinib, a MEK inhibitor, is not currently approved for colorectal cancer treatment. These approvals highlight the use of immune checkpoint inhibitors in specific genetic subtypes of colorectal cancer.

What other types of research exist?

Promising novel alternatives for colorectal cancer treatment in 2024 include: <ol> <li>Pembrolizumab (PD-1 Inhibitor): Effective for patients with dMMR or high TMB.</li> <li>Dostarlimab (PD-1 Inhibitor): Another option for dMMR colorectal cancer.</li> <li>Combination of PD-1/PD-L1 inhibitors with chemotherapy: This approach has shown higher response rates and progression-free survival in other cancers and is being explored in colorectal cancer.</li> <li>Emerging biomarkers and personalized medicine: Genomic testing to identify actionable mutations can guide the use of targeted therapies and immunotherapies tailored to individual patient profiles.</li> </ol>

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Checkpoint Inhibitor

Nivolumab + Trametinib (+/- Ipilimumab) for Colorectal Cancer (CheckMate 9N9 Trial)

Phase 1 & 2

Waitlist Available

Research Sponsored by Bristol-Myers Squibb

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 at screening and on cycle 1 day 1 (C1D1)

Histologically or cytologically confirmed previously treated metastatic colorectal cancer with adenocarcinoma histology and in Stage IV per American Joint Committee on Cancer (version 4.0) at study entry

Must not have

History of interstitial lung disease or pneumonitis

BRAF V600 mutant colorectal cancer

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of drugs to treat patients with advanced colon or rectal cancer who have already tried other treatments. The drugs help the immune system fight cancer and block proteins that help cancer grow. One of the drugs being tested has shown promise in treating advanced colorectal cancer.

Who is the study for?

This trial is for individuals with Stage IV colorectal cancer that has spread and was previously treated. They must have measurable disease, be in good physical condition (ECOG 0-1), and not have certain genetic mutations (BRAF V600). People can't join if they've had brain metastases, need systemic steroids or immunosuppressants, are allergic to the drugs being tested, or have used checkpoint inhibitors/MEK inhibitors before.

What is being tested?

The study tests nivolumab combined with trametinib, with some participants also receiving ipilimumab. It aims to see how well these drugs work together in treating colorectal cancer that's spread after previous treatment. Participants will be randomly assigned to different drug combinations.

What are the potential side effects?

Possible side effects include immune-related reactions affecting organs like the lungs (pneumonitis), skin issues, fatigue, digestive problems such as diarrhea or colitis, liver inflammation (hepatitis), hormonal gland issues like thyroid disorders and adrenal insufficiency.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am fully active or restricted in physically strenuous activity but can do light work.

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My colorectal cancer is confirmed to be in stage IV and has been previously treated.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

I have had interstitial lung disease or pneumonitis.

Select...

My colorectal cancer has a BRAF V600 mutation.

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I have an autoimmune disease.

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I have been treated with drugs targeting the immune system and MEK enzymes.

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I have active cancer spread to my brain or its coverings.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Side effects data

From 2024 Phase 3 trial • 529 Patients • NCT02017717

80%

Fatigue

70%

Diarrhoea

70%

Headache

40%

Vomiting

40%

Aspartate aminotransferase increased

40%

Rash maculo-papular

40%

Alanine aminotransferase increased

40%

Lipase increased

30%

Partial seizures

30%

Hemiparesis

30%

Gait disturbance

30%

Fall

30%

Cough

30%

Dry skin

30%

Amylase increased

30%

Nausea

30%

Confusional state

20%

Malignant neoplasm progression

20%

Pyrexia

20%

Candida infection

20%

Mucosal infection

20%

Decreased appetite

20%

Back pain

20%

Dysphonia

20%

Hypotension

20%

Colitis

20%

Hyperthyroidism

20%

Oedema peripheral

20%

Muscular weakness

20%

Hypothyroidism

10%

Tinnitus

10%

Cushingoid

10%

Diabetic ketoacidosis

10%

Procedural haemorrhage

10%

Blood bilirubin increased

10%

Bradycardia

10%

Sinus tachycardia

10%

Hyperglycaemia

10%

Hypocalcaemia

10%

Neck pain

10%

Brain oedema

10%

Hydrocephalus

10%

Lethargy

10%

Seizure

10%

Hypertension

10%

Palpitations

10%

Cheilitis

10%

Presyncope

10%

Face oedema

10%

Oedema

10%

Conjunctivitis

10%

Enterocolitis infectious

10%

Oral candidiasis

10%

Pneumonia

10%

Sinusitis

10%

Staphylococcal infection

10%

Blood alkaline phosphatase increased

10%

Spinal pain

10%

Tremor

10%

Dizziness

10%

Dysarthria

10%

Urinary retention

10%

Dyspnoea exertional

10%

Nasal congestion

10%

Pneumonitis

10%

Dermatitis

10%

Erythema

10%

Rash

10%

Klebsiella infection

10%

Hypomagnesaemia

10%

Syncope

10%

Haemorrhage intracranial

10%

Pancreatitis

10%

Cholecystitis

10%

Upper respiratory tract infection

10%

Acute kidney injury

10%

Dermatitis bullous

10%

Lymphopenia

10%

Optic nerve disorder

10%

Visual impairment

10%

Dehydration

10%

Hypokalaemia

10%

Scoliosis

10%

Cognitive disorder

10%

Memory impairment

10%

Hallucination

10%

Insomnia

10%

Irritability

10%

Urinary incontinence

10%

Dyspnoea

10%

Dermatitis acneiform

10%

Pelvic venous thrombosis

10%

Sepsis

100%

80%

60%

40%

20%

Study treatment Arm

Cohort 1: Arm N1+I3

Cohort 2: Arm B

Part A Cohort 1c: Arm N3+RT+TMZ

Part A Cohort 1d: Arm N3+RT

Part B Cohort 1c: Arm N3+RT+TMZ

Part B Cohort 1d: Arm N3+RT

Cohort 1: Arm N3

Cohort 1b: Arm N3+I1

Cohort 2: Arm N3

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

6Treatment groups

Experimental Treatment

Group I: Part 2 Cohort 5 (3L): RegorafenibExperimental Treatment1 Intervention

Group II: Part 2 Cohort 4 (3L): nivolumab + ipilimumab + trametinibExperimental Treatment3 Interventions

Group III: Part 1B Cohort 6 (2L): nivolumab + ipilimumab + trametinibExperimental Treatment3 Interventions

Group IV: Part 1A Cohort 3 (2L): nivolumab + ipilimumab + trametinibExperimental Treatment3 Interventions

Group V: Part 1A Cohort 2 2nd Line (2L): nivolumab + ipilimumab + trametinibExperimental Treatment3 Interventions

Group VI: Part 1 Cohort 1 3rd Line (3L): nivolumab + trametinibExperimental Treatment2 Interventions

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Trametinib

2014

Completed Phase 2

~1630

Regorafenib

2014

Completed Phase 2

~1630

Ipilimumab

2014

Completed Phase 3

~3140

Nivolumab

2014

Completed Phase 3

~5220

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for colorectal cancer include immune checkpoint inhibitors and targeted therapies. Nivolumab, a PD-1 inhibitor, works by blocking the programmed cell death protein 1 (PD-1) pathway, thereby enhancing the immune system's ability to attack cancer cells. Trametinib, a MEK inhibitor, targets the MEK enzyme in the MAPK/ERK pathway, which is often overactive in cancer cells, leading to reduced tumor growth. Ipilimumab, a CTLA-4 inhibitor, blocks the CTLA-4 protein on T cells, boosting the immune response against cancer cells. These mechanisms are crucial for colorectal cancer patients as they offer a way to target cancer cells more precisely and enhance the body's immune response, potentially leading to better outcomes.

Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer.