Testing Trametinib as a Potential Targeted Treatment in Cancers With BRAF Genetic Changes (MATCH-Subprotocol R)

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT04439279
• Collaborator: (none)
• Enrollment: 35
• Location: 1
• Arm: 1

Study Details

Study Description

Brief Summary

This phase II MATCH treatment trial identifies the effects of trametinib in patients with cancer having genetic changes called BRAF mutations and fusions. Trametinib may block proteins called MEK1 and MEK2, which may be needed for growth of cancer cells that express BRAF mutations. Researchers hope to learn if giving trametinib will shrink this type of cancer or stop its growth.

Condition or Disease	Intervention/Treatment	Phase
Advanced Lymphoma; Advanced Malignant Solid Neoplasm; Hematopoietic and Lymphoid Cell Neoplasm; Refractory Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Plasma Cell Myeloma	Drug: Trametinib Dimethyl Sulfoxide	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.

SECONDARY OBJECTIVES:

1. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.

2. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.

3. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.

OUTLINE:

Patients receive trametinib dimethyl sulfoxide (trametinib) orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months if less than 2 years from study entry, and then every 6 months for year 3 from study entry.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: MATCH Treatment Subprotocol R: Phase II Study of Trametinib in Patients With BRAF Fusions, or With NonV600E, Non-V600K BRAF Mutations
• Actual Study Start Date: Aug 12, 2015
• Actual Primary Completion Date: Mar 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (trametinib) Patients receive trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Trametinib Dimethyl Sulfoxide; Given PO; Other Names: Mekinist

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [assessed at baseline, then every 2 cycles until disease progression, up to 3 years post registration]

   Overall response rate was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) among all eligible and treated patients. Best overall response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. The 90% two-sided binomial exact confidence interval was calculated for ORR.

Secondary Outcome Measures

1. 6-month Progression-free Survival (PFS) Rate [assessed at baseline, then every 2 cycles until disease progression, up to 3 years post registration]

   PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. The 6-month PFS rate was estimated using the Kaplan-Meier method which can provide a point estimate for any specific time point. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.

2. Progression-free Survival [assessed at baseline, then every 2 cycles until disease progression, up to 3 years post registration]

   PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol

• Patients must have a BRAF non-V600 mutation or BRAF fusion, or another aberration, as identified via the MATCH Master Protocol

• Patients must have an electrocardiogram (ECG) within 8 weeks prior to treatment assignment and must have NONE of the following cardiac criteria:

• Clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block)

• Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy

• Patients must have an echocardiogram (ECHO) or a nuclear study (multigated acquisition scan [MUGA] or First Pass) within 4 weeks prior to registration to treatment and must not have a left ventricular ejection fraction (LVEF) < the institutional lower limit of normal (LLN). If the LLN is not defined at a site, the LVEF must be > 50% for the patient to be eligible

• Patients who previously received monoclonal antibody therapy (e.g. ipilimumab, nivolumab, pembrolizumab and others) must have stopped the prior therapy for 8 or more weeks before starting on trametinib

Exclusion Criteria:

• Patients with a history of interstitial lung disease or pneumonitis are excluded

• Patients must not have known hypersensitivity to trametinib or compounds of similar chemical or biologic composition or to dimethyl sulfoxide (DMSO)

• Patients must not have a history or current evidence/risk of retinal vein occlusion (RVO). An eye exam is required at baseline

• Patients who previously received MEK inhibitors (including, but not limited to, trametinib, binimetinib, cobimetinib, selumetinib, RO4987655 (CH4987655), GDC-0623 and pimasertib) will be excluded

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ECOG-ACRIN Cancer Research Group	Philadelphia	Pennsylvania	United States	19103

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Douglas B Johnson, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

• Study Protocol - Mar 11, 2019

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04439279
• Other Study ID Numbers: NCI-2020-03272; NCI-2020-03272; EAY131-R; EAY131-R; U10CA180820; U24CA196172
• First Posted: Jun 19, 2020
• Last Update Posted: Jul 19, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Lymphoma; Neoplasms; Multiple Myeloma; Neoplasms, Plasma Cell; Trametinib; Dimethyl Sulfoxide

Study Results

Participant Flow

Recruitment Details	Subprotocol R was activated on August 12, 2015. A total of 50 patients were assigned to this arm after screening, 48 from screening cohort and 2 from outside assay. Of the 50 patients, 35 patients were enrolled to arm R between December 4, 2015 and August 17, 2017.
Pre-assignment Detail	To be assigned to a specific MATCH subprotocol, patients needed to submit a tumor biopsy for molecular characterization and those with molecular variants addressed by treatments included in the trial entered corresponding MATCH subprotocol. For the subprotocol R, patients had to have BRAF fusion or Non-V600E, Non-V600K mutations.

Arm/Group Title	Subprotocol R
Arm/Group Description	Patients receive trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	35
Started Protocol Therapy	35
Eligible	33
Reported Adverse Events Data	34
COMPLETED	0
NOT COMPLETED	35

Baseline Characteristics

Arm/Group Title	Subprotocol R
Arm/Group Description	Patients receive trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	33
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	19 57.6%
Male	14 42.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.1%
Not Hispanic or Latino	29 87.9%
Unknown or Not Reported	2 6.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	31 93.9%
More than one race	0 0%
Unknown or Not Reported	2 6.1%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) among all eligible and treated patients. Best overall response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. The 90% two-sided binomial exact confidence interval was calculated for ORR.
Time Frame	assessed at baseline, then every 2 cycles until disease progression, up to 3 years post registration

Outcome Measure Data

Analysis Population Description

eligible and treated patients

Arm/Group Title	Subprotocol R
Arm/Group Description	Patients receive trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	33
Number (90% Confidence Interval) [percentage of participants]	3 9.1%

2. Secondary Outcome

Title	6-month Progression-free Survival (PFS) Rate
Description	PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. The 6-month PFS rate was estimated using the Kaplan-Meier method which can provide a point estimate for any specific time point. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.
Time Frame	assessed at baseline, then every 2 cycles until disease progression, up to 3 years post registration

Outcome Measure Data

Analysis Population Description

eligible and treated patients

Arm/Group Title	Subprotocol R
Arm/Group Description	Patients receive trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	33
Number (90% Confidence Interval) [percentage of participants]	20 60.6%

3. Secondary Outcome

Title	Progression-free Survival
Description	PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.
Time Frame	assessed at baseline, then every 2 cycles until disease progression, up to 3 years post registration

Outcome Measure Data

Analysis Population Description

eligible and treated patients

Arm/Group Title	Subprotocol R
Arm/Group Description	Patients receive trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	33
Median (90% Confidence Interval) [months]	1.8

Adverse Events

Time Frame	Assessed every 28 days while on treatment and for 30 days after the end of treatment, up to 3 years
Adverse Event Reporting Description	All 35 patients enrolled to the trial were monitored for mortality, 34 patients were monitored for adverse events as one patient refused to submit adverse event data right after starting the protocol therapy.
Arm/Group Title	Subprotocol R
Arm/Group Description	Patients receive trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Subprotocol R
	Affected / at Risk (%)	# Events
Total	9/35 (25.7%)
Serious Adverse Events
	Subprotocol R
	Affected / at Risk (%)	# Events
Total	14/34 (41.2%)
Blood and lymphatic system disorders
Anemia	5/34 (14.7%)
Gastrointestinal disorders
Nausea	1/34 (2.9%)
Vomiting	1/34 (2.9%)
General disorders
Sudden death NOS	1/34 (2.9%)
Investigations
Ejection fraction decreased	1/34 (2.9%)
Lymphocyte count decreased	1/34 (2.9%)
Metabolism and nutrition disorders
Anorexia	1/34 (2.9%)
Dehydration	1/34 (2.9%)
Hypoalbuminemia	1/34 (2.9%)
Hyponatremia	1/34 (2.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/34 (2.9%)
Skin and subcutaneous tissue disorders
Pruritus	1/34 (2.9%)
Rash acneiform	1/34 (2.9%)
Rash maculo-papular	1/34 (2.9%)
Skin and subcutaneous tissue disorders - Other, specify	1/34 (2.9%)
Vascular disorders
Hypotension	1/34 (2.9%)
Thromboembolic event	1/34 (2.9%)
Other (Not Including Serious) Adverse Events
	Subprotocol R
	Affected / at Risk (%)	# Events
Total	29/34 (85.3%)
Blood and lymphatic system disorders
Anemia	10/34 (29.4%)
Blood and lymphatic system disorders - Other, specify	2/34 (5.9%)
Gastrointestinal disorders
Abdominal pain	2/34 (5.9%)
Constipation	4/34 (11.8%)
Diarrhea	9/34 (26.5%)
Dry mouth	5/34 (14.7%)
Mucositis oral	5/34 (14.7%)
Nausea	13/34 (38.2%)
Vomiting	7/34 (20.6%)
General disorders
Chills	2/34 (5.9%)
Edema limbs	12/34 (35.3%)
Fatigue	6/34 (17.6%)
Infections and infestations
Paronychia	2/34 (5.9%)
Investigations
Alanine aminotransferase increased	4/34 (11.8%)
Alkaline phosphatase increased	5/34 (14.7%)
Aspartate aminotransferase increased	10/34 (29.4%)
Ejection fraction decreased	2/34 (5.9%)
Lymphocyte count decreased	2/34 (5.9%)
Platelet count decreased	4/34 (11.8%)
White blood cell decreased	3/34 (8.8%)
Metabolism and nutrition disorders
Anorexia	4/34 (11.8%)
Hyperglycemia	2/34 (5.9%)
Hypoalbuminemia	6/34 (17.6%)
Hypocalcemia	2/34 (5.9%)
Hypomagnesemia	3/34 (8.8%)
Nervous system disorders
Dizziness	2/34 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	3/34 (8.8%)
Dyspnea	2/34 (5.9%)
Skin and subcutaneous tissue disorders
Alopecia	3/34 (8.8%)
Dry skin	3/34 (8.8%)
Pruritus	5/34 (14.7%)
Rash acneiform	11/34 (32.4%)
Rash maculo-papular	8/34 (23.5%)
Skin and subcutaneous tissue disorders - Other, specify	7/34 (20.6%)
Vascular disorders
Hypertension	3/34 (8.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.