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Protein Kinase Inhibitor

Tazemetostat + Dabrafenib + Trametinib for Melanoma

Phase 1 & 2

Recruiting

Led By Tanner M Johanns

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

Patient must have a diagnosis of BRAF^V600E/K-mutated metastatic melanoma

Creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min

Must not have

History of interstitial lung disease or pneumonitis

History or evidence of cardiovascular risks including any of the following: QT interval corrected for heart rate using Fridericia's formula (QT corrected by Fridericia [QTcF]) >= 450 msec, History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization, History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system, Intra-cardiac defibrillators, Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (ECHO); (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study, History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: Subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible, Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy, Left ventricular ejection fraction (LVEF) < institutional lower limit of normal (LLN) by ECHO or multigated acquisition scan (MUGA), Known cardiac metastases

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 3 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is investigating whether a combination of tazemetostat, dabrafenib, and trametinib can effectively treat melanoma that has spread to other parts of the body and has a specific BRAF gene mutation.

Who is the study for?

Adults with BRAFV600 mutated metastatic melanoma that has worsened despite treatment can join this trial. They must have had prior anti-PD-1 therapy, be able to perform daily activities (ECOG <=2), and have organs functioning well. Pregnant women, those with certain psychiatric or medical conditions, or a history of specific cancers are excluded.

What is being tested?

The trial is testing Tazemetostat combined with Dabrafenib and Trametinib to see if it's safe and effective for advanced melanoma after the usual treatments fail. It includes finding the right dose and understanding how these drugs might control tumor growth by blocking enzymes.

What are the potential side effects?

Possible side effects include reactions related to immune system changes, liver issues, blood clots, heart problems like irregular heartbeat or heart failure, high blood pressure, eye problems such as retinal vein occlusion or detachment, skin reactions from drug sensitivity, gastrointestinal disturbances affecting absorption.

Eligibility Criteria

Inclusion Criteria

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

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My melanoma is BRAF V600E/K mutation positive.

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My kidney function is normal or near normal.

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I can take care of myself but might not be able to do heavy physical work.

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

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I am 18 years old or older.

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I am an adult.

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I can take pills and don't have major gut issues affecting drug absorption.

Exclusion Criteria

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

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I have had interstitial lung disease or pneumonitis.

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You have a history of certain heart problems like prolonged QT interval, recent heart attacks or procedures, severe heart failure, abnormal heart valves, uncontrolled arrhythmias, or certain high blood pressure that can't be controlled with medication.

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I do not have any unmanaged ongoing illnesses.

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I have a history of T-cell leukemia or lymphoma.

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My cancer does not have a RAS mutation.

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I am not pregnant or breastfeeding.

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I have been treated with drugs that affect cell DNA or EZH2 before.

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I am not taking any medication that could interfere with the study.

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I have had eye conditions like RVO or RPED.

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I've had severe allergic reactions to specific cancer treatments or their ingredients.

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I am not HIV-positive or not on combination antiretroviral therapy.

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I am currently receiving IV treatment for an infection.

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I have had another cancer that was not treated to cure it.

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My tests show genetic changes linked to MDS and MPN.

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I don't have ongoing major side effects from cancer treatment, except for hair loss.

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I have a history of blood cell cancer or related conditions.

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My diabetes is not under control.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 3 years

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

Treatment Details

Study Objectives

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

Primary study objectives

Median progression-free survival (PFS) (Phase II)

Recommended phase 2 dose (R2PD) (Phase I)

Secondary study objectives

Incidence of adverse events

Overall response rates (complete response [CR], partial response [PR])

Overall survival

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

Active Control

Group I: Arm II (tazemetostat, dabrafenib, trametinib) phase I/phase IIExperimental Treatment8 Interventions

Patients receive tazemetostat orally PO BID, dabrafenib PO BID, and trametinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI, MUGA or ECHO throughout the study.

Group II: Arm I (tazemetostat) phase IIActive Control4 Interventions

Patients receive tazemetostat PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan and MRI throughout the study. At the time of progression, patients may crossover to Arm II after completion of radiation therapy.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Multigated Acquisition Scan

2015

Completed Phase 3

~270

Biopsy

2014

Completed Phase 4

~1090