ASCO, NCI Announce Plans for Precision Medicine Trials

ASCO, NCI Announce Plans for Precision Medicine Trials

Dr. Clifford A. Hudis

Two upcoming clinical studies will endeavor to expand the boundaries of precision medicine. At a press briefing during the 2015 ASCO Annual Meeting on Monday, June 1, plans were announced for ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) study and the National Cancer Institute (NCI)-MATCH: Molecular Analysis for Therapy Choice trial (EAY131).

At a time when physicians are frequently confounded by how to act on the results of genetic testing to benefit their patients, these investigations are critical. “We have a big knowledge gap, and an unbelievable opportunity,” moderator Clifford A. Hudis, MD, FACP, of Memorial Sloan Kettering Cancer Center, said.

Dr. Richard L. Schilsky

TAPUR

The prospective, nonrandomized TAPUR clinical trial will collect information on the antitumor activity and toxicity of commercially available targeted cancer drugs in a range of cancer types (including advanced solid tumors, multiple myeloma, and B-cell non-Hodgkin lymphoma) with a genomic variation known to be a drug target. At launch, TAPUR will evaluate 10-15 drugs contributed by 5 pharmaceutical companies, with cohorts of up to 24 patients defined by tumor type, genomic abnormality, and drug. Patient enrollment is expected to open before the end of the year.
 
Patients will be screened to determine if they are healthy enough to participate based on broad inclusion/exclusion criteria. If and when a patient meets the defined trial criteria, the treating physician will select a drug from among those available in the TAPUR study protocol that targets the identified genomic variation in the patient’s tumor. If a relevant drug–target match is not described in the protocol, the physician may consult the Molecular Tumor Board, which will review the clinical and genomic features of the case and suggest potential therapies on or off the study. 
 
The primary endpoint of TAPUR is objective tumor response defined by RECIST; other endpoints include progression-free survival (PFS), overall survival, duration of treatment, and treatment-related serious adverse events. 
 
According to ASCO Chief Medical Officer Richard L. Schilsky, MD, FASCO, TAPUR will harness information from discussions about molecular targets and potential treatments that are already happening in oncology practices every day—a source of knowledge that is currently lost because there is no mechanism to learn from the experience of patients who use targeted drugs in off-label settings. 
 
In the coming months, an Institutional Review Board will review the study protocol and consent form. ASCO has established three oversight committees that will include patient representatives, clinical oncologists, statisticians, and genomics specialists:
  • The Steering Committee will oversee study operations, establish data-sharing and publication policies, review plans to add or remove drugs from the study, and approve participation of clinical study sites.
  • A Molecular Tumor Board will review the proposed drug–target matches and suggest therapies on or off the study. 
  • A Data and Safety Monitoring Board will regularly review study results to ensure that severe or unexpected adverse events are carefully monitored, determine when enrollment of study cohorts should expand or cease, and decide when to release data and to which parties.
ASCO will sponsor and organize the operational aspects of the study, including the participation of multiple collaborators, such as patients, physicians, ASCO oversight committees, pharmaceutical companies, technology firms, and community-based study sites. TAPUR will launch at clinical sites within the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, and the Carolinas Healthcare System, with the goal of expanding nationally. ASCO will collaborate and share data with the Netherlands Center for Personalized Cancer Treatment, which is conducting a clinical trial using a very similar study protocol.
 
For more information visit TAPUR.org.
Table 1. Initial Substudies Planned in NCI-MATCH

Agent(s)

Molecular Target(s)

Estimated Prevalence

Afatinib*

EGFR activating mutations

1%-4%

Afatinib*

HER2 activating mutations

2%-5%

Crizotinib

ALK rearrangement

4%

AZD9291*

EGFR T790M mutations and rare EGFR activating mutations

1%-2%

Crizotinib

ROS1 translocations

5%

Dabrafenib and trametinib

BRAF V600E and V600K mutations

7%

Trametinib

BRAF fusions or non-V600E, non-V600K BRAF mutations

2.8%

TDM1*

HER2 amplification

5%

VS-6063*

NF2 loss

2%

Sunitinib*

cKIT mutations

4%

*Agents and associated targets are pending final regulatory review.

NCI-MATCH

The phase II NCI-MATCH trial will incorporate more than 20 different study drugs or drug combinations, each targeting a specific gene mutation, in order to match each patient in the trial with a therapy that targets a molecular abnormality in their tumor. Ten initial substudies are planned for the trial’s launch (Table 1), increasing to 20 or more within months. Patient enrollment will open in July 2015. 
 
NCI-MATCH “is the largest, most rigorous precision oncology trial in history,” NCI Deputy Director James H. Doroshow, MD, said. 
 
Each patient will initially enroll for screening, during which samples of their tumor will be biopsied and sequenced to detect genetic abnormalities that may be driving tumor growth and might be targeted by one of a wide range of drugs being studied. If a molecular abnormality is detected for which there is a substudy available, patients will be further evaluated to determine if they meet the specific eligibility requirements within that arm. Once enrolled, patients will be treated with the targeted drug regimen for as long as their tumor shrinks or remains stable. Trial investigators plan to screen at least 3,000 patients during the full course of the trial with the goal of enrolling approximately 1,000 patients in the various treatment arms (with up to 35 patients each). The trial’s design calls for at least one-quarter of the enrolled patients to have rare cancers (defined as cancers other than non–small cell lung, prostate, breast, or colon cancers).
 
Participants must be age 18 or older, with solid tumors or lymphomas that have advanced following at least one line of standard systemic therapy, or with tumors for which there is no standard treatment. 
 
Two endpoints will be evaluated: overall response rate (ORR; primary endpoint) and 6-month PFS (secondary endpoint). Within molecularly targeted subpopulations, an ORR of 16%-25% or higher and a 6-month PFS of 35% or higher will be considered promising results.
 
NCI-MATCH is a “highly coordinated effort,” study co-chair Barbara A. Conley, MD, of NCI, said. The study was co-developed by NCI and the ECOG-ACRIN Cancer Research Group, is part of the NCI-sponsored National Clinical Trials Network (NCTN), and is being led by ECOG-ACRIN. The principal investigators who will lead the substudies are situated throughout the NCTN and its participating network groups: ECOG-ACRIN, the Alliance for Clinical Trials in Oncology, NRG Oncology, and SWOG. Patient advocates were engaged in the development of the trial and will help oversee the protocol and other aspects of the study.
 
For more information, visit the National Cancer Institute.