What side effects are associated with this type of intervention?

The combination of Onalespib (HSP90 inhibitor), Dabrafenib (BRAF inhibitor), and Trametinib (MEK inhibitor) for treating melanoma can lead to several side effects. Common side effects of Dabrafenib and Trametinib include fever, fatigue, nausea, diarrhea, and skin rash. More serious but less common side effects can include heart problems, eye issues, and liver toxicity. HSP90 inhibitors like Onalespib may cause gastrointestinal disturbances, fatigue, and hematologic abnormalities. Patients undergoing these treatments should be closely monitored for these adverse effects.

What prior FDA approvals exist?

The FDA has approved several treatments for melanoma, particularly targeting the BRAF V600E mutation. Dabrafenib, a BRAF inhibitor, and Trametinib, a MEK inhibitor, have been approved both as monotherapies and in combination for the treatment of BRAF V600E-mutant melanoma. This combination has shown efficacy in inhibiting tumor growth by targeting different points in the MAPK/ERK pathway. Other related drugs include Vemurafenib, another BRAF inhibitor, and Cobimetinib, another MEK inhibitor, which have also been approved for similar indications. These treatments represent a significant advancement in targeted therapy for melanoma.

What other types of research exist?

Promising novel alternatives for melanoma treatment in 2024 include: 1) Combination immunotherapy with agents such as nivolumab and ipilimumab, which have shown significant efficacy in metastatic melanoma. 2) Talimogene laherparepvec (T-VEC) combined with pembrolizumab, which has demonstrated promising results in advanced melanoma. 3) Targeted therapies like encorafenib (BRAF inhibitor) combined with binimetinib (MEK inhibitor), which offer an alternative to dabrafenib and trametinib. These options provide new mechanisms of action and have shown potential in recent clinical trials.

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Protein Kinase Inhibitor

Onalespib + Dabrafenib + Trametinib for Skin Cancer

Phase 1

Waitlist Available

Led By Ryan J Sullivan

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

Able to swallow and retain oral medication, and must not have any clinically significant gastrointestinal abnormalities

All prior anti-cancer treatment-related toxicities must be less than or equal to grade 1

Must not have

History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED)

History or evidence of cardiovascular risk

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 1 year

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of three drugs to treat patients with specific types of advanced cancer. The drugs aim to stop cancer cells from growing by interfering with the chemicals they need to multiply.

Who is the study for?

This trial is for adults with BRAF-mutant melanoma or solid tumors that have spread (metastatic) or can't be surgically removed. They should have manageable side effects from previous cancer treatments, good physical health, and a life expectancy over 3 months. Women must test negative for pregnancy and use birth control. Participants must not have had HSP90 inhibitors before, no uncontrolled illnesses, no recent anti-cancer therapies within 3 weeks, and no history of certain severe reactions or diseases.

What is being tested?

The trial tests the combination of Onalespib with Dabrafenib and Trametinib to find the safest dose and see how it affects tumor growth in patients with advanced melanoma or solid tumors carrying a specific mutation (BRAF V600E/K). It's an early-phase study focusing on dosage safety rather than effectiveness.

What are the potential side effects?

Potential side effects include issues related to blocking enzymes needed by tumor cells which may affect normal cell functions too. This could lead to problems like fatigue, digestive disturbances, skin reactions, liver enzyme changes, heart complications among others depending on individual patient responses.

Eligibility Criteria

Inclusion Criteria

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

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I can take pills and don't have major stomach or intestine problems.

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My side effects from previous cancer treatments are mild.

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I am fully active and can carry on all pre-disease activities without restriction.

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My cancer is BRAF V600E/K mutant, cannot be surgically removed, and has spread.

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I have previously been treated with full-dose BRAF or BRAF and MEK inhibitors, or I have never received BRAF-targeted therapy.

Exclusion Criteria

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

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I have or am at risk for eye blood vessel blockage or retinal detachment.

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I have a history of heart problems or am at risk for them.

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I have not had any other cancer besides the one being studied in the last 5 years.

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I am not taking any medications that are not allowed in the study.

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I have never been treated with HSP90 inhibitors.

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I do not have any unmanaged ongoing illnesses.

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I don't have cancer spread to the brain or spinal cord causing pressure.

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I do not have an active hepatitis B or C infection.

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I haven't had cancer treatment in the last 3 weeks.

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My cancer has a positive RAS mutation.

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I have had interstitial lung disease or pneumonitis.

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I am HIV-positive and not on antiretroviral therapy.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 1 year

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~1 year

This trial's timeline: 3 weeks for screening, Varies for treatment, and 1 year for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Maximum Tolerated Dose of Dabrafenib

Maximum Tolerated Dose of Onalespib

Maximum Tolerated Dose of Trametinib

+1 more

Secondary study objectives

Objective Response Rate

Overall Survival at 1 Year

Progression-free Survival

+1 more

Other study objectives

Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination

Awards & Highlights

No Placebo-Only Group

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

Trial Design

5Treatment groups

Experimental Treatment

Group I: Dose level 4 (dabrafenib, trametinib, onalespib)Experimental Treatment5 Interventions

Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m\^2

Group II: Dose level 3 (dabrafenib, trametinib, onalespib)Experimental Treatment5 Interventions

Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m\^2

Group III: Dose level 2 (dabrafenib, trametinib, onalespib)Experimental Treatment5 Interventions

Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m\^2

Group IV: Dose level 1 (dabrafenib, trametinib, onalespib)Experimental Treatment5 Interventions

Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m\^2

Group V: Dose level -1 (dabrafenib, trametinib, onalespib)Experimental Treatment5 Interventions

Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). Fallback dose level -1 is initiated if more than 1 of 6 subjects in dose level 1 (starting dose) develop DLTs. Dose Level -1 (fallback dose): * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m\^2

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Dabrafenib

2011

Completed Phase 3

~4120

Onalespib

2017

Completed Phase 1

~30

Trametinib

2014

Completed Phase 2

~1630

0 / 17Eligibility 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

Melanoma treatments often target specific molecular pathways critical for tumor growth and survival. Dabrafenib is a BRAF inhibitor that targets the BRAF V600 mutation, which is present in about half of melanomas, thereby blocking the abnormal signaling that promotes cancer cell proliferation. Trametinib is a MEK inhibitor that works downstream of BRAF, further inhibiting the MAPK/ERK pathway, which is essential for cell division and survival. Onalespib, an HSP90 inhibitor, disrupts the function of multiple proteins required for tumor growth by inhibiting the HSP90 chaperone protein. This combination therapy is significant for melanoma patients as it targets multiple points in the cancer growth pathway, potentially reducing the likelihood of resistance and improving treatment efficacy.