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Good news for patients with rare cancers: Arrival of dual immunotherapy basket trial designed for rare tumors

Rare cancers when combined are not a rare entity any more; rather, they are ‘common cancers’ as an aggregate. They comprise approximately a quarter of all cancers diagnosed each year worldwide [1].

Common cancers have more standard-of-care treatment options than rare cancers and some rare cancers do not even have any established effective treatment options. Yet, most oncology trials are performed in common cancers, such as breast or colorectal cancers. By contrast, patients with rare tumors remain under-represented and often neglected. They mostly do not have any clinical trials they are eligible for.

Recently, cancer immunotherapy has undoubtedly been named the major breakthrough in science and medicine. Immunotherapy aims to boost our immune cells, mostly T cells designed to kill cancer cells. Unlike chemotherapy or targeted therapy, it often works across different tumor types regardless of driver oncogenes. T-cell mediated immunotherapy drugs are currently US FDA approved in a variety of cancers types such as lung and bladder cancers. Immunotherapy has also been shown to be effective in rare tumors such as Merkel cell carcinoma or Hodgkin’s lymphoma.

Bridging the gap between the two, there is finally good news for patients with rare cancers; they now have a way to access immunotherapy in the clinic. Individuals with rare cancers may join a national immunotherapy clinical trial designed for a wide variety of rare tumors. It is the first federally funded immunotherapy trial devoted to rare cancers. This trial is termed DART, which stands for Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (ClinicalTrials.gov Identifier: NCT02834013).

DART has been activated since 18 January 2017 [2]. It is designed and managed by SWOG, the cancer clinical trials group, which is part of the National Cancer Institute’s (NCI) National Clinical Trials Network (NCTN). In DART, rare cancers are defined as diseases with the incidence of less than six in 100,000 per year.

DART is the first histology-agnostic basket trial effort in rare tumors. It has been a challenge to engineer such a trial for rare tumors given its unprecedented approach. It is broken up into 33 cohorts (baskets), where there are no existing NCI NCTN trials evaluating CTLA-4 and PD-1/PD-L1 blockade for those histologies. Of note, DART cohorts include the cancer of unknown primary cohort and the ‘not otherwise specified’ cohort that is reserved for ultra-rare tumors.

This unique design suggests that DART is truly dedicated to exploring new response signals in all rare tumors. This signal-finding navigation trial will likely lead to new discoveries and many subsequent clinical trials in a variety of rare tumor types. This is very different from many pivotal trials that enroll common cancers to demonstrate statistically significant superiority of novel treatments in efficacy over existing standard-of-care treatments. For rare tumors, due to high unmet need and practical limitation in patient accrual, Phase III randomized trials are often not required for drug approval. For example, a historical signal-finding imatinib Phase II basket trial led to FDA approval of the drug in four different rare diseases including dermatofibrosarcoma protuberance [3].

DART patients will be treated with two immunotherapy agents – nivolumab and ipilimumab. The FDA approved the combination to treat melanoma [4], and it is currently being tested on a variety of cancers including lung cancer. The DART regimen is different from the melanoma regimen, which is considered to be relatively toxic. It utilizes a lower dose of ipilimumab with a wider interval, 1 mg / kg every 6 weeks, in addition to a fixed dose of nivolumab, 240 mg, both delivered intravenously. In melanoma trials, dual immunotherapy worked irrespective of a well-known immune biomarker, PD-L1 immunohistochemistry status. Therefore, in DART, no biomarker is utilized to select patients.

DART tries to answer the question of whether this combination can generate response in various rare tumors. Response is measured by CT scans taken upon enrollment, then every 12 weeks over the course of treatment. It will be very important to learn as much as possible from this basket trial. Not to learn anything from this pivotal trial, from a translational medicine aspect, would be almost a sin. Tumor tissue samples and blood samples will be used to explore how immune cells and tumor cells respond to the drug combination, and see if there are any biomarkers that can predict treatment response among patients. Since not much is known about the genomic or immune traits of rare tumors, DART could have very strong scientific benefits by exploring the genomic and immune landscape of rare tumors and its association with response to combination immunotherapy. Currently, DART plans to enroll 300 patients within 2 years.

Currently, the DART trial is provided in conjunction with another landmark trial, NCI Molecular Analysis for Therapy Choice (MATCH) ClinicalTrials.gov Identifier: NCT02465060 [5]. DART fully takes advantage of the scale of MATCH offered through the NCTN. Patients with rare cancers become eligible for DART when they screen fail from NCI MATCH trial.

MATCH is a precision medicine basket trial currently open at more than 1000 clinical sites led by ECOG-ACRIN and NCI. MATCH uses comprehensive genomic profiling of tumors to match cancer patients to multiple targeted treatments. Currently, there are 24 treatment arms offered, with plans to add approximately ten more. For patients with rare tumors that do not have any molecular alterations with available targeted therapy within MATCH, arrival of the DART trial surely provides more option for them. Of note, approximately one fifth of MATCH patients are deemed to have rare tumors eligible for the DART trial. Once the MATCH trial closes to accrual, DART will become a stand-alone trial for rare tumors.

DART is a true team effort within SWOG. Study chairs and principal investigators of DART include Drs. Young Kwang Chae, translational medicine chair for DART, Francis Giles (both from Northwestern University, IL, USA), Sandip Patel, and Razelle Kurzrock (both from UC San Diego, CA, USA). DART team also includes Dr. Donna Hansel (pathologist, UC San Diego); SWOG biostatisticians Megan Othus, Ph.D., and Melissa Plets, M.S. (both from Fred Hutchinson Cancer Research Center, WA, USA); Dr. Christopher Ryan, SWOG executive officer for early therapeutics and rare cancers (Knight Cancer Institute at Oregon Health & Science University, OR, USA); SWOG protocol coordinator, Cara Laubach; and Drs. Jeffrey Chuang, and Karolina Palucka (The Jackson Laboratory, ME, USA – a SWOG basic science partner).

DART partners also include ECOG-ACRIN and the NCI’s Cancer Therapy Evaluation Program. DART is funded by the NCI, with support from Bristol-Myers Squibb (NY, USA), which is providing the study drugs.


  1. Rare Care Net: Information Network on Rare Cancers
  2. Nivolumab and Ipilimumab in treating patients with rare tumors, Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DUAL) www.clinicaltrials.gov/ct2/show/NCT02834013
  3. Heinrich MC, Joensuu H, Demetri GD, et al.; Imatinib Target Exploration Consortium Study B2225. Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin. Cancer Res. 14(9):2717-25. doi: 10.1158/1078-0432.CCR-07-4575 (2008).
  4. Postow MA, Chesney J, Pavlick AC, et al. . Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372(21):2006-17. doi: 10.1056/NEJMoa1414428 (2015).
  5. NCI-MATCH: Targeted therapy directed by genetic testing in treating patients with advanced refractory solid tumors, lymphomas, or multiple myeloma https://clinicaltrials.gov/show/NCT02465060

Author biography

Dr. Francis Giles is chief of the Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine, deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, and SWOG principal investigator at Northwestern. Dr. Young Kwang Chae (photo below) is assistant professor of medicine and co-director of the Developmental Therapeutics Program of the Division of Hematology/Oncology at Northwestern University, SWOG principal investigator for the translational medicine component of DART.

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