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NCI announces launch of genetic sequencing trial

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The NCI intends to launch a pilot trial to assess whether assigning treatment based on specific gene mutations can benefit patients with metastatic solid tumors.

The Molecular Profiling based Assignment of Cancer Therapeutics (M-PACT) trial is one of the first to use a randomized trial design to evaluate whether assigning treatment based on genetic screening can improve the rate and duration of response in patients with advanced solid tumors.

In addition to the knowledge gained about assigning therapy based on results of genetic sequencing of tumors, researchers hope the trial results will help identify patient subgroups most likely to benefit from certain treatments and result in the rapid development of novel treatments for some cancers.

“Patients will have their tumors genetically screened and, if a pre-defined mutation is found, they will receive treatment with targeted agents,” Shivaani Kummar, MD, head of NCI’s Developmental Therapeutics Clinic and the principal investigator of the trial, said in a press release. “What we don’t know, however, is whether using this approach to assign targeted treatments is really effective at providing clinical benefit to patients, as most tumors have multiple mutations and it’s not always clear which mutation to target and which agent is most likely to provide maximal benefit. This study hopes to address some of these questions in the context of a prospective, randomized trial.”

Few tumor types have only one mutated gene that triggers cancer progression; once a gene is mutated, it can lead to the activation of multiple pathways, resulting in disease progression and potentially requiring multiple interventions. The M-PACT trial is designed to determine whether people with specific mutations found to affect drug effectiveness will benefit from a specifically chosen targeted intervention and if these interventions lead to better outcomes.

For NCI’s M-PACT study, after screening hundreds of people, 180 patients with advanced refractory solid tumors will be enrolled based on their genetic profile. During the screening process, samples of the tumors will be genetically sequenced to look for 391 different mutations in 20 genes known to affect the utility of targeted therapies.

If mutations of interest are detected, using a molecular sequencing protocol for tumor biopsy samples evaluated by the FDA, those patients will be enrolled in the trial and randomly assigned to one of two treatment arms to receive one of the four treatment regimens that are part of this study.

To ensure that patients receive the best treatment, patients with specific tumor types should have received certain therapies prior to being enrolled in M-PACT. For instance:

• Patients with melanoma whose tumors have mutations in the V600E region of the BRAF gene should have received and progressed on a specific BRAF inhibitor therapy to be eligible for the M-PACT trial.
• Patients with lung cancer should have had their tumors tested for the presence of EGFR and ALK gene mutations, and, if mutations were detected, they should have received and progressed on therapies targeting EGFR or ALK.

Patients with all types of solid tumors will be considered for trial eligibility. For the randomization, patients will be assigned to either a group that will receive treatment targeted to their specific mutation/pathway, or a secondary treatment group with a treatment not targeted to their specific mutation/pathway. Patients in the second treatment group will have the option to cross over to the first treatment group to receive mutation/pathway-targeted therapy if their disease progresses on their initial study treatment.

The study is open for patient accrual. Clinicians hope that they can report results by 2017.

“We believe that this study will aid patients in the trial that will be conducted initially at the NCI, and subsequently expanded to clinical trials sites participating in the NCI-supported Early Therapeutics Clinical Trials Network,” James Doroshow, MD, NCI deputy director for clinical and translational research said. “We also believe that M-PACT can be a model for trials nationwide, particularly those that employ genetically-driven treatment selection approaches in their design.”