What side effects are associated with this type of intervention?

Common treatments for colorectal cancer that target the MAPK pathway include inhibitors of the RAS/RAF/MEK/ERK pathway. Known side effects of these inhibitors can include skin rash, diarrhea, fatigue, and liver enzyme abnormalities. Additionally, other common treatments for colorectal cancer, such as chemotherapy with oxaliplatin and fluorouracil, can cause neuropathy, myelosuppression, and gastrointestinal symptoms like nausea and vomiting. Targeted therapies like cetuximab may lead to acneiform rash and infusion reactions.

What prior FDA approvals exist?

The FDA has approved several treatments for colorectal cancer that target the MAPK pathway. Notably, cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR), which is upstream of the RAS/RAF/MEK/ERK pathway. Additionally, the combination of encorafenib (a BRAF inhibitor) with cetuximab has been approved for patients with BRAF V600E-mutant metastatic colorectal cancer. These treatments highlight the focus on targeting specific components of the MAPK pathway in colorectal cancer therapy.

What other types of research exist?

For colorectal cancer patients considering treatment in 2024, promising novel alternatives to MAPK pathway inhibitors include targeting the PI3K/PTEN/AKT/mTOR pathway with agents like temsirolimus and everolimus. Additionally, immune checkpoint inhibitors such as anti-PD-1 or anti-PD-L1 therapies are emerging as potential options. These therapies are being evaluated in clinical trials and have shown promise in other cancer types, suggesting potential applicability to colorectal cancer.

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MAPK Pathway Inhibitor

Tovorafenib + Pimasertib for Cancer

Phase 1 & 2

Waitlist Available

Research Sponsored by Day One Biopharmaceuticals, Inc.

Eligibility Criteria Checklist

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

Must have

Substudy A-specific inclusion criterion: Patients must have a report of histologically confirmed diagnosis of melanoma or other solid tumor and a concurrent BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 amplification through a tumor or liquid biopsy as assessed by genomic sequencing, PCR, FISH, or another clinically accepted molecular diagnostic method recognized by local laboratory or agency.

If brain metastases are present, they must have been previously treated and be stable as assessed by radiographic imaging

Must not have

Patients with current evidence or a history of central serous retinopathy (CSR), retinal vein occlusion (RVO)

Substudy A-specific exclusion criterion: Prior therapy of any RAS- RAF-, MEK-, or ERK-directed inhibitor therapy

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 48 months

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing Tovorafenib, a drug that blocks proteins needed for cancer cell growth, in patients aged 12+ with hard-to-treat melanoma or other solid tumors.

Who is the study for?

This trial is for people aged 12 and older with certain types of cancer, like melanoma or colorectal cancer, that have specific genetic changes in the MAPK pathway. They must have measurable disease progression and provide a tissue sample. It's not for those who've had prior treatment targeting the RAS-RAF-MEK-ERK pathway or have certain eye conditions.

What is being tested?

The study tests Tovorafenib alone or combined with Pimasertib on patients with solid tumors having alterations in the MAPK pathway. This includes different substudies focusing on various genetic mutations related to this pathway.

What are the potential side effects?

Potential side effects may include typical reactions to targeted cancer therapies such as skin rash, fatigue, gastrointestinal issues (like diarrhea), liver enzyme elevation, vision problems, and possibly high blood pressure.

Eligibility Criteria

Inclusion Criteria

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

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My cancer diagnosis is confirmed and has a BRAF or CRAF/RAF1 change.

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My brain metastases have been treated and are stable.

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My cancer diagnosis is confirmed and it has a MAPK pathway alteration.

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My cancer has grown or returned and can be measured by scans.

Exclusion Criteria

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

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I have or had eye conditions like CSR or RVO.

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I have never been treated with RAS, RAF, MEK, or ERK inhibitors.

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My cancer has a known activating mutation.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 48 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 48 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 48 months for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Phase 1b: Determine the MTD and RP2D of tovorafenib in combination with other therapies

Phase 1b: Determine the safety of tovorafenib in combination with other therapies

Phase 2: Evaluate the efficacy of tovorafenib monotherapy or in combination with other therapies

Secondary study objectives

Phase 1b & 2: Assess additional efficacy parameters of tovorafenib alone and in combination with other therapies

Phase 1b & 2: Characterize the pharmacodynamic (PD) profile of tovorafenib alone and in combination with other therapies

Phase 1b & 2: Characterize the pharmacokinetic (PK) profile of tovorafenib alone and in combination with other therapies

+3 more

Awards & Highlights

No Placebo-Only Group

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

Trial Design

2Treatment groups

Experimental Treatment

Group I: Arm #2Experimental Treatment2 Interventions

Tovorafenib plus pimasertib

Group II: Arm #1 (Closed to Enrollment)Experimental Treatment1 Intervention

Tovorafenib monotherapy

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Pimasertib

2021

Completed Phase 2

~380

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

The MAPK pathway, involving RAS, RAF, MEK, and ERK proteins, is essential for cell division and survival. Mutations in this pathway, particularly in KRAS, are common in colorectal cancer and lead to uncontrolled cell growth. Inhibitors targeting this pathway, such as MEK inhibitors, block these signals, reducing tumor growth and proliferation. This is crucial for colorectal cancer patients as it offers a targeted approach to control tumor progression, especially when traditional chemotherapy is less effective.