Clinical trial NCT04439318: Testing Trametinib as a Potential Targeted Treatment in Cancers With NF1 Genetic Changes (MATCH-Subprotocol S1)
Official title: MATCH Treatment Subprotocol S1: Phase II Study of Trametinib in Patients With Tumors With NF1 Mutations
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Advanced Lymphoma
Advanced Malignant Solid Neoplasm
Hematopoietic and Lymphoid Cell Neoplasm
Refractory Lymphoma
Refractory Malignant Solid Neoplasm
Refractory Multiple Myeloma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2020-06-19
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II MATCH treatment trial identifies the effects of trametinib in patients whose cancer has a has a genetic change called NF1 mutation. Trametinib blocks proteins called MEK1 and MEK2, which may be needed for cancer cell growth when an NF1 mutation is present. Researchers hope to learn if trametinib will shrink this type of cancer or stop its growth.

Detailed description: PRIMARY OBJECTIVE:

I. 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:

I. 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.

II. 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.

IV. 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 orally (PO) once daily (QD) on days 1-28. 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.

Eligibility criteria: Inclusion Criteria:

* Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol
* Patients must have deleterious inactivating mutations of NF-1, or another aberration, as determined 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 (eg. ipilimumab, nivolumab, pembrolizumab and others) must have stopped the prior therapy for 8 or more weeks before starting on trametinib
* Patients with glioblastoma must have histologically or radiographically confirmed recurrent or progressive World Health Organization (WHO) grade 4 glioma (glioblastoma)

  * NOTE: All baseline and post-baseline disease assessments must be performed using contrast-enhanced cranial magnetic resonance spectroscopy (MRI) or contrast-enhanced computed tomography (CT) for subjects who cannot have MRI performed

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

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Tumor assessments occurred at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter until disease progression, up to 3 years post registration
Secondary outcomes:
measure: 6-month Progression-free Survival (PFS) Rate
timeFrame: Assessed at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration, from which 6-month PFS rate is determined
measure: Progression Free Survival (PFS)
timeFrame: Assessed at baseline, then every 2 cycles for the first 26 cycles and every 3 cycles thereafter until disease progression, up to 3 years post registration
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: ECOG-ACRIN Cancer Research Group
state: Pennsylvania
Study officials:
affiliation: ECOG-ACRIN Cancer Research Group
name: Jason J Luke
role: PRINCIPAL_INVESTIGATOR
References: