Complexity of Designing Clinical Trials for Sarcoma: Shifting Focus to Constellation of Subtypes

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Sarcoma has bedeviled researchers for many years because of its heterogeneity. Sarcoma encompasses more than 100 different subtypes, which makes it difficult to design studies to identify effective therapies. As researchers dig deeper into the constellation of subtypes of sarcoma, some therapies have been found for specific subtypes, explained William D. Tap, MD, of Memorial Sloan Kettering Cancer Center, New York.

William D. Tap, MD

William D. Tap, MD

“The management of soft-tissue sarcoma involves a heterogeneous group of malignancies that can arise from bone and soft tissues—a gathering of more than 100 to 150 different subtypes, each with unique biology. In the not-so-distant past, we actually treated many of these subtypes in the same fashion. Now, with a greater understanding of their biology, we have unique treatment opportunities for many. Sarcoma is an open field for new technology and scientific advances. Most of the new treatments that have been identified are subtype-specific,” Dr. Tap told the audience during the virtual 2020 Chemotherapy Foundation Symposium.1

However, the field of opportunity does not always allow for clear vision. “As we see a swinging tide of research and drug development with lots of competing ideas, we may be overlooking important signals that can help us design personalized drugs for our patients,” he cautioned.

Signals From Studies

A preliminary study at Memorial Sloan Kettering Cancer Center suggested that doxorubicin plus the monoclonal antibody olaratumab, which targets the platelet-derived growth factor receptor–­alpha, may have significant promise in the treatment of sarcoma, and the combination received accelerated approval by the U.S. Food and Drug Administration based on a phase II study that included many different subtypes of sarcoma, Dr. Tap noted, which could confound a clinical trial.

Then, the phase III ANNOUNCE randomized trial showed no improvement in overall survival or progression-free survival with this combination in soft-tissue sarcoma and leiomyosarcoma.2 “The approval of olaratumab with doxorubicin was rescinded,” he commented. “This shows the complexity of designing trials for sarcoma. There can be tremendous inter- and intra-subtype variation. Perhaps that’s why we saw differential results from the phase II and phase III trials with olaratumab.”

In addition to the many subtypes, other variables can confound clinical trials of sarcoma. These factors include local vs metastatic disease, first-line vs subsequent line of treatment, differences in grade and clinical course, wide variation in clinical practice around the world, and the true numbers of comparable diseases that are being studied within and among trials.

“We have unique treatment opportunities for many sarcoma subtypes. This is an open field for new technology and scientific advances.”
— William D. Tap, MD

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Shift in Focus

“In the past few years, we have started to move away from thinking of sarcoma as a single disease entity and started looking at the nuances of each subtype. Now, we see many more subtype-specific trials. Some of these subtypes are newly described and not completely understood; still others have significant heterogeneity in their biology and clinical courses. Often, they don’t have validated approaches, which carries a tremendous amount of complexity, but also allows for opportunity and ingenuity. The international sarcoma community is working hard to build collaborative projects in rare and ultra-rare diseases to better serve our patients,” stated Dr. Tap.

Dr. Tap described a drug development strategy in tenosynovial giant cell tumor (TGCT), a rare neoplasm of joints and tendon sheaths. It has an incidence of about 600 cases per year in the United States, often occurring in young adults. Clinically, it usually presents in a single joint with swelling, pain, decreased range of motion, and stiffness, impairing function and often leading to the need for pain medications and narcotics and causing significant disability. A TGCT expansion cohort in phase I study of pexidartinib suggested significant activity in this disease.

“We learned a lot from that study,” commented Dr. Tap. “We didn’t have appropriate tools to measure this volume-centric tumor, and we needed to show that tumor shrinkage was important to the patient. This required time to develop novel strategies including TGCT-specific patient-reported outcomes.”

A randomized, placebo-controlled phase III trial designed with those lessons in mind led to approval of this first-in-class treatment of pexidartinib in patients with advanced and inoperable tenosynovial giant cell tumor.3 Pexidartinib significantly improved range of motion, stiffness, and physical function compared with placebo.

A similarly designed trial showed that sorafenib was effective in the treatment of desmoid tumors (neoplasms that arise in connective tissue anywhere in the body). There is no standard of care for these tumors. The randomized, double-blind, ­placebo-controlled trial showed that sorafenib significantly prolonged progression-free survival (2-year progression-free survival was 86% with sorafenib vs 36% with placebo, P < .001) and induced durable responses.4 In that study, about 20% of patients had disease regression on placebo.4

“Ultimately, trials like this serve as examples of how to approach and study rare diseases. This trial showed the importance of having a placebo arm and novel outcomes measures that are specific to the disease being treated. Many of the sarcoma subtypes are very complex and require clinical trial designs that can account for their unique behaviors and biology. In some patients, desmoids can spontaneously regress without antitumor treatment. In addition, these tumors can scar down inside, forming collagenous masses that can remain inactive and inert for some time. This can happen with or without treatment. We could never develop and apply drugs correctly for this and many other sarcomas without truly understanding and defining the natural history of these diseases and how each one affects our patients. This study is a beautiful example of the comprehensive approach that is needed in many sarcomas, inclusive of incorporating novel imaging techniques, patient-reported outcomes, study objectives, and correlative studies,” noted Dr. Tap.

Other Subtype-Specific Trials

Dr. Tap provided examples of other subtype-specific trials with early encouraging results. A phase I trial of the IDH1 inhibitor ivosidenib showed promising activity in patients with advanced chondrosarcoma.5 This study was made possible by improved understanding of the molecular and clinical variations in chondrosarcoma.

“In the past few years, we have started to move away from thinking of sarcoma as a disease entity and started looking at subtypes.”
— William D. Tap, MD

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“There are many things to understand about chondrosarcoma,” he added. They include conventional vs dedifferentiated tumors; variable natural history in conventional chondrosarcoma; large, difficult-to-image bony components; lack of utility with Response Evaluation Criteria in Solid Tumors criteria; variable locations of this disease; and the biology and clinical impact of IDH mutations.

A phase II study of tazemetostat, a first-in-class EZH2 inhibitor, led to accelerated approval of tazemetostat in epithelial sarcoma.6 “The question now is whether we can design the right confirmatory pivotal study [of tazemetostat] to validate the results we saw in phase II,” he said.

AMPECT, an open-label phase II trial, was a registration trial for ABI-009 (nab-sirolimus) in advanced malignant perivascular epithelioid cell tumors.7 The overall response rate with nab-sirolimus was 42%; 35% had stable disease, and the disease control rate was 77%.

“These studies show the complexity of the disease we are treating. When we think of pillars of cancer care, we have to consider that sarcoma is not just one disease. We need large collaborative efforts to decide how to choose the right drug and developmental strategies for each disease subtype. We in the field are all cognizant that we need to think about the disease and the technologies we are working with,” Dr. Tap concluded.

DISCLOSURE: Dr. Tap has served in a leadership role for Atropos Pharmaceuticals and Certis Oncology Solutions; holds stock or other ownership interests in ­Atropos and Certis Oncology Solutions; has served as a consultant or advisor to Agios, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, EMD Serono, GlaxoSmithKline, Lilly, and NanoCarrier; has received research funding from ­BioAtla, Blueprint Medicines, Daiichi Sankyo, Deciphera, Immune Design, Lilly, Novartis, Plexxikon, and Tracon Pharma; and holds patents or other intellectual property in a companion diagnostic for CDK4 inhibitors.


1. Tap W: Recent advancements in personalized management of soft-tissue sarcomas. 2020 Chemotherapy Foundation Symposium. Presented November 6, 2020.

2. Tap WD, Wagner AJ, Schöffski P, et al: Effect of doxorubicin plus olaratumab vs doxorubicin plus placebo on survival in patients with advanced soft tissue sarcomas: The ANNOUNCE randomized clinical trial. JAMA 323:1266-1276, 2020.

3. Tap WD, Wainberg ZA, Anthony SP, et al: Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med 373:428-437, 2015.

4. Gounder MM, Mahoney MR, Van Tine BA, et al: Sorafenib for advanced and refractory desmoid tumors. N Engl J Med 379:2417-2428, 2018.

5. Tap WD, Villalobos VM, Cote GM, et al: Phase I study of the mutant IDH1 inhibitor ivosidenib: Safety and clinical activity in patients with advanced chondrosarcoma. J Clin Oncol 38:1693-1701, 2020.

6. Stacchiotti S, Schoffski P, Jones R, et al: Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients with epithelioid sarcoma (NCT02601950). 2019 ASCO Annual Meeting. Abstract 11003. Presented June 3, 2019.

7. Wagner AJ, Ravi V, Ganjoo KN, et al: ABI-009 (nab-sirolimus) in advanced malignant perivascular epithelioid cell tumors. 2019 ASCO Annual Meeting. Abstract 11005. Presented June 3, 2019.