What side effects are associated with this type of intervention?

Common treatments for colorectal cancer, such as chemotherapy and biologic therapies, often come with a range of side effects. Chemotherapy agents like 5-fluorouracil (5-FU) and oxaliplatin can cause neuropathy, diarrhea, nausea, vomiting, and fatigue. Biologic therapies, including immune modulators like bevacizumab, can lead to hypertension, proteinuria, and increased risk of bleeding and thromboembolism. Treatments involving enzyme inhibition, such as Selumetinib, may cause skin rash, diarrhea, and fatigue. Cyclosporine, an immune modulator, can result in nephrotoxicity, hypertension, and increased susceptibility to infections. These side effects vary in severity and frequency among patients.

What prior FDA approvals exist?

FDA-approved treatments for colorectal cancer that involve enzyme inhibition include cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR). Additionally, regorafenib and encorafenib are kinase inhibitors used in specific genetic contexts. For immune modulation, pembrolizumab and nivolumab are immune checkpoint inhibitors approved for colorectal cancers with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). These treatments reflect the strategies of enzyme inhibition and immune modulation similar to those being studied with Selumetinib and Cyclosporine.

What other types of research exist?

Promising novel alternatives for colorectal cancer treatment include: <ol> <li>Immunotherapy agents such as pembrolizumab and nivolumab, particularly for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors.</li> <li></li> </ol> Combination therapies involving mTOR inhibitors like everolimus with other agents such as letrozole. 3. New chemotherapeutic agents like irinotecan and raltitrexed, which are being evaluated in clinical trials. 4. Targeted therapies such as PI3K inhibitors and AKT inhibitors, which are under investigation for their potential efficacy in colorectal cancer.

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Immunosuppressant

Selumetinib + Cyclosporine for Colorectal Cancer

Phase 1

Waitlist Available

Led By Christopher H Lieu

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

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

Must have

DOSE ESCALATION PHASE: Histological or cytopathological diagnosis of an advanced cancer that is refractory to standard therapy or for which no standard therapy exists

Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Must not have

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris (Canadian Cardiovascular Society grade II-IV despite medical therapy), cardiac arrhythmia, active bleeding diatheses, or psychiatric illness/social situations that would limit compliance with study requirements

Known ophthalmological conditions as follows: intra-ocular pressure > 21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure); current or past history of central serous retinopathy or retinal vein occlusion

Timeline

Screening 3 weeks

Treatment Varies

Follow Up pre-dose, 0.5, 1, 2, 4, 8, and 24 hours on days -7, -3, and 1 of course 1

Awards & highlights

No Placebo-Only Group

Summary

This trial studies the combination of Selumetinib and Cyclosporine in patients with advanced cancers that do not respond to standard treatments. Selumetinib blocks growth signals in cancer cells, while Cyclosporine helps by modifying the immune system. Cyclosporine is an immunosuppressive drug that has been used in human transplants and autoimmune diseases, and it has been approved for use in dermatology for many years.

Who is the study for?

This trial is for adults with advanced solid tumors or colorectal cancer that's spread and can't be treated or controlled. They must have had certain treatments, not have specific mutations, and be healthy enough overall (good organ function, no severe heart conditions). Participants need to consent, use contraception if needed, and have a life expectancy over 3 months.

What is being tested?

The trial tests selumetinib combined with cyclosporine to see the effects on tumor growth by blocking enzymes needed for cell growth and modifying immune responses. It aims to find the best dose with acceptable side effects in patients whose cancers haven't responded to standard therapies.

What are the potential side effects?

Possible side effects include allergic reactions similar to those from compounds like AZD6244 or cyclosporine A. There may also be risks of high blood pressure, heart issues like arrhythmias or low ejection fraction, eye problems such as increased pressure or retinopathy, liver function changes, and electrolyte imbalances.

Eligibility Criteria

Inclusion Criteria

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

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My advanced cancer does not respond to standard treatments or no standard treatment exists.

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I am fully active or can carry out light work.

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I am using birth control and had a negative pregnancy test recently.

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My kidney function, measured by eGFR, is normal or above 60.

Exclusion Criteria

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

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I do not have any severe illnesses or conditions that my doctor is still trying to get under control.

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I have eye conditions like high pressure, uncontrolled glaucoma, or past eye vein issues.

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I cannot swallow pills.

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I am not pregnant and will stop breastfeeding if treated with AZD6244.

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I am allergic to AZD6244, cyclosporine A, or similar drugs.

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I have moderate heart valve disease.

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I take medication other than beta blockers or digoxin for heart rhythm problems.

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I haven't had extensive radiotherapy in the last 4 weeks or targeted radiotherapy in the last 2 weeks.

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I have moderate to severe heart failure.

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I haven't had a recent heart attack or unstable heart disease in the last year.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ pre-dose, 0.5, 1, 2, 4, 8, and 24 hours on days -7, -3, and 1 of course 1

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~pre-dose, 0.5, 1, 2, 4, 8, and 24 hours on days -7, -3, and 1 of course 1

This trial's timeline: 3 weeks for screening, Varies for treatment, and pre-dose, 0.5, 1, 2, 4, 8, and 24 hours on days -7, -3, and 1 of course 1 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Incidence of DLT defined as any grade 3 non-hematological toxicity or grade 4 hematological toxicity attributed to selumetinib or cyclosporine graded per National Cancer Institute (NCI) CTCAE version 4.0

Secondary study objectives

Incidence of adverse events that occur after course 1, day 1 assessed using NCI CTCAE version 4.0

Objective tumor response based on computed tomography scans (or magnetic resonance imaging if patients are allergic to iodinated contrast) per RECIST 1.1 criteria

Pharmacokinetic (PK) parameters, including the distribution of area under the curve and maximum concentration

+1 more

Awards & Highlights

No Placebo-Only Group

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

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (selumetinib and cyclosporine)Experimental Treatment4 Interventions

Patients receive selumetinib PO BID on day -7 of course 1 and then on days 1-28 (one dose on day 1 only). Patients also receive cyclosporine PO BID on day -3 of course 1 and then on days 1-28 (one dose on day 1 only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Cyclosporine

1997

Completed Phase 3

~1820

Selumetinib

2010

Completed Phase 2

~2080

0 / 14Eligibility 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 often involve enzyme inhibition and immune modulation. Enzyme inhibitors, such as Selumetinib, target specific enzymes necessary for cancer cell growth and survival, thereby halting tumor progression. Immune modulators, like Cyclosporine, alter the immune system's response to help it recognize and attack cancer cells more effectively. These mechanisms are crucial for colorectal cancer patients as they offer targeted approaches to disrupt cancer cell proliferation and enhance the body's natural defenses against the tumor, potentially leading to better treatment outcomes and prolonged survival.