Aug 21, 2015
ASCO is preparing to expand the boundaries of precision medicine with the launch of its first clinical trial. At a press briefing during the 2015 ASCO Annual Meeting, the Society formally announced its plans for the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
At a time when physicians are frequently confounded by how to act on the results of genomic testing to benefit their patients, TAPUR and similar investigations are critical. “We have a big knowledge gap and an unbelievable opportunity,” said ASCO Past President Clifford A. Hudis, MD, FACP, of Memorial Sloan Kettering Cancer Center, who moderated the press conference.
Rationale and design
ASCO recognized two significant challenges slowing the pace of discovery in precision medicine: a lack of access to drugs prescribed off label and a lack of data collection on the safety and efficacy of such treatments. TAPUR has the potential to address both issues, by making targeted drugs available to participants at no cost and by creating a registry to record and share key clinical outcomes.
“Clinical reports, to date, suggest that 30% to 80% of advanced solid tumors harbor potentially actionable genomic variants, but the outcomes of patients treated based on such tests remain largely anecdotal or unknown,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO, who is leading the study.
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 its outset, TAPUR will evaluate 10 to 15 drugs contributed by five pharmaceutical companies, with cohorts of up to 35 patients defined by tumor type, genomic abnormality, and drug. Patient enrollment is expected to open in early 2016.
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 TAPUR 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 or stable disease for at least 16 weeks; other endpoints include progression-free survival (PFS), overall survival, duration of treatment, and treatment-related serious adverse events.
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:
- A Steering Committee will oversee study operations, establish datasharing 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.
Practical applications of TAPUR
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, Dr. Schilsky said.
Edward S. Kim, MD, confirmed that in his practice, patients and their family members frequently ask about the effectiveness of targeted therapies and request commercially available marker panels to assess their tumors.
“The truth is that scientists and clinicians don’t know what to do with many of these markers. We have no idea how impactful they are when applying a therapy. Sometimes, physicians have to make independent decisions based on their own knowledge. Sometimes, there are opportunities to use a molecular tumor board to have a forum discussion about markers and treatments. But we’re all still learning. There is no instruction booklet that tells us, ‘If A, use B.’ The levels of evidence vary, and there can be a lot of bias in the decision-making. Capturing this information prospectively and being able to analyze outcomes based on drug selection is the best way to start making better informed decisions moving forward,” he said.
Dr. Kim is Chair of Solid Tumor Oncology and Investigational Therapeutics at Levine Cancer Institute, Carolinas HealthCare System, one of the three clinical sites at which TAPUR will launch. He is a veteran of personalized medicine studies, having served as lead investigator for the BATTLE (Biomarker- Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial while at The University of Texas MD Anderson Cancer Center.
Care providers across the regional network of the Levine Cancer Institute are excited to be among the first to enroll patients in TAPUR, he said, and are hopeful that the trial will lead to clinically meaningful outcomes to guide future decisions about targeted therapies.
“Can we create better outcomes for patients by applying the selected drug to tumors with the identified markers?
People are spending a lot of time and resources on this question, and we still have mostly anecdotal evidence. With TAPUR, we will have real evidence to evaluate whether there’s a benefit,” Dr. Kim said.
From a clinical perspective, he believes, the most exciting aspect of TAPUR is access. Too often, a panel will yield an interesting marker in a patient’s tumor for which there is a drug that may be effective, but the drug is not approved or indicated for that particular setting.
“The patient is put in an impossible position. Should they divest their life savings, get a third mortgage, and spend tens of thousands of dollars to try a drug for a few months? Should they appeal to the drug company and spend months trying to get access to the drug?” Dr. Kim explained. Because selected targeted therapies will be made available to TAPUR participants at no cost, “we don’t have to ask our patients to make that choice. That access is incredible. I love being able to give my patients options. For patients who have already completed standard therapy, a new option is a new hope.”
A collaborative effort
Numerous partners have contributed knowledge, expertise, and resources to make TAPUR possible.
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.
Cancer researchers and patient advocates are important partners in the study and will contribute to the planning and conduct of TAPUR, as well as assist in increasing public and patient awareness. Jane Perlmutter, PhD, a cancer survivor and nationally recognized patient advocate, is lending her expertise in trial development and will help coordinate patient advocate recruitment and training for the study.
“TAPUR has enormous potential to improve our understanding of the effectiveness of currently available therapies in treating cancers with genomic variations and to learn from patients who are treated with off-label drugs,” said Dr. Perlmutter. “I applaud ASCO for undertaking this important study and believe its findings will improve cancer care, especially for those with advanced cancer for whom traditional therapies are no longer working.”
TAPUR will launch at clinical sites within the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, and the Levine Cancer Institute, Carolinas HealthCare System, with the goal of expanding nationally.
ASCO has invited a number of pharmaceutical companies to provide marketed, targeted drugs and additional resources to support TAPUR. Five companies have signed memoranda of understanding agreeing to participate in the study as of July 2015: AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Genentech, and Pfizer.
“At least 13 drugs that target more than 20 unique genomic variants will be provided by these companies. We are extremely grateful for the generosity of these companies without whose support TAPUR would not be possible,” said ASCO Immediate Past President Peter Paul Yu, MD, FACP, FASCO. “We anticipate additional companies will sign on and are extremely encouraged by the level of interest we have received so far.”
Two technology companies will provide key support to the study’s data collection: Syapse and Illumina. Syapse will provide its Syapse Precision Medicine Data Platform to automate the study workflow (including the Molecular Tumor Board and the Data and Safety Monitoring Board) and capture structured data from participating practices. Illumina will provide its NextBio knowledge base platform to support and inform the case review by the Molecular Tumor Board, as well as to support analysis of TAPUR data by the study team.
ASCO will collaborate and share data from TAPUR with the Netherlands Center for Personalized Cancer Treatment, which is conducting a clinical trial using a very similar study protocol.
“We are very fortunate that this leading cancer center has the same focus as TAPUR,” Dr. Schilsky said. “Technological advancements will allow us to pool our information in a seamless fashion and give us the ability to learn from the experience of a larger group of patients.”
NCI-MATCH: A complementary study
At the same Annual Meeting press conference, the National Cancer Institute (NCI) announced the launch of its own precision medicine study, NCI-MATCH: Molecular Analysis for Therapy Choice (EAY131; cancer.gov/nci-match).
TAPUR and NCI-MATCH were developed and will be conducted independently, but they will complement each other in the quest to define the optimal use of targeted therapies.
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, increasing to 20 or more within months. Patient enrollment opened in July 2015.
NCI-MATCH “is the largest, most rigorous precision oncology trial in history,” said James H. Doroshow, MD, NCI Deputy Director for Clinical and Translational Research, at the press conference.
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.
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 (up to 35 patients in each arm). 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 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 six-month PFS (secondary endpoint). Within molecularly targeted subpopulations, an ORR of 16% to 25% or higher and a six-month PFS of 35% or higher will be considered promising results.
NCI-MATCH is a “highly coordinated effort,” said study co-chair Barbara A. Conley, MD, of NCI. The study was codeveloped 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: ECOGACRIN, 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.