E-Newsletter - February 2018

SPOTLIGHT - Alliance Experimental Therapeutics and Rare Tumor Committee

Nearly 20 percent of all cancers diagnosed in adults ages 20 and older are rare. That equates to approximately 208,000 new cases last year. Although there is no set definition, the U.S. Food and Drug Administration defines a “rare disease” as “a disease or condition that affects less than 200,000 people in the United States.” The National Cancer Institute defines “rare cancers” as fewer than 15 cases per 100,000 people per year. According to RARECARENet, the European Union defines rare cancers as those with fewer than six cases per 100,000 people per year.

The problems with rare cancers are vast. Rare cancers tend to affect small populations, and children and adolescents. There is usually heterogeneity between and within diseases. Their complex biology makes them poorly understood, and there is often a delay in diagnosis. Many are life-threatening illnesses that have unmet medical need due to lack of effective treatments and treatment guidelines. The five-year survival rate for patients with rare cancers is inferior compared to those with common cancers.

The Alliance Experimental Therapeutics and Rare Tumor Committee has six specific aims:

  • to develop therapeutic trials using novel agents focused on pathways important in cancer cell survival, DNA damage, angiogenesis, metabolism, and immunotherapy

  • to advise and collaborate with disease committees where the pathways targeted are relevant

  • to incorporate biomarkers (genomic, proteomic, and imaging) that demonstrate biologic effect and to develop markers predicting response and toxicity

  • to develop trials for tumors where there are no existing Alliance disease committees, e.g., rare cancers, sarcoma, melanoma, head and neck, and gynecologic cancers

  • to facilitate education of members concerning novel therapeutics through research symposia at annual meetings

  • to promote career development of young investigators interested in rare cancers and experimental therapeutics.

The Alliance ETRTC has a substantial portfolio of rare tumor trials with numerous such studies underway. The phase I dose escalation protocol of A091304 with MLN-0128, the Tor1/Torc2 inhibit has been completed and the dose of 30 mg po weekly was established as the phase II dose. With completion of the phase I, the randomized phase II trial of MLN-0128 versus pazopanib, the multi-receptor tyrosine kinase inhibitor, has opened and this has become an active sarcoma study. This study is based on preclinical data generated by the committee. In head and neck cancer, the committee opened the phase II study of enzalutamide in patients with androgen receptor positive salivary cancers (A091404). The primary end-point is response in an Optimal Simon 2 stage design (five responses required in 41 patients to be deemed a positive trial). Another study is a randomized phase II study of pembrolizumab versus pembrolizumab with stereotactic body radiation in Merkel cell carcinoma (A091605).

Other studies in rare forms of thyroid cancer include a phase II trial of sorafenib with the mTor inhibitor everolimus in patients with iodine refractor Hurthle cell thyroid cancer (A091302) and phase II trial of efatutazone, an oral PPARγ agonist in combination with paclitaxel in patients with advanced anaplastic thyroid cancer (A091305). This study has completed the first stage of its Simon-2 stage design (seven patients) and the committee is awaiting the results to see if it can expand to the second stage of the trial. Efatutazone is also being tested in a phase II study of this agent in patients with unresectable and chemotherapy refractory myxoid liposarcoma (A091202). 

Heres a quick list of active trials.  

Alliance A091302
Randomized phase II study of sorafenib with or without everolimus in patients with radioactive iodine refractory hürthle cell thyroid cancer
Study Chair: Eric Sherman, MD

Alliance A091304
A phase I/randomized phase II study of MLN-0128 vs. pazopanib in patients with advanced/unresectable and/or metastatic sarcoma
Study Chair: William Tap, MD

Alliance A091401
Randomized phase II study of nivolumab with or without ipilimumab in patients with metastatic or unresectable sarcoma|
Study Chair: Sandra DAngelo

Alliance A091404
A phase II study of enzalutamide for patients with androgen receptor positive salivary cancers
Study Chair: Alan Ho, MD

Alliance A091605
Randomized phase II study of stereotactic body radiotherapy + anti-PD1 antibody (pembrolizumab) in advanced Merkel cell carcinoma
Study Co-Chairs: Jason Luke, MD and Steven Chmura, MD, PhD

Summary of recent accomplishments

In the area of sarcoma, the committee has completed two sarcoma trials. The first (A091105) was a randomized phase III study of sorafenib versus placebo in desmoid tumors or aggressive fibromatosis.  This was based on compelling phase II data indicating a high response rate and improved quality of life (decrease in pain and improved ambulation) with sorafenib in this disease. For this study, patients were randomized 2:1 to either sorafenib or placebo. At time of progression patients on placebo could be unblinded and transitioned to drug. The primary objective was to increase mPFS from 6 months with placebo to 15 months with placebo (HR: 0.4). There were also exploratory pre- and post-tumor biopsies built into the study funded through external resources. More than 144 Alliance sites participated in the U.S. and Canada, and 88 patients were enrolled in 17 months for an average of five patients per month.  This is an extraordinary achievement for a rare cancer. This study has now completed accrual and the data are being analyzed with the plan to have these data ready for presentation at this year’s ASCO meeting.

A second completed sarcoma trial is A091401, a randomized phase II study of nivolumab (the PD-1 inhibitor) with or without ipilimumab (the CTLA-4 inhibitor) in patients with metastatic or unresectable sarcoma. There were no specific sarcoma sub-types for this trial. The primary endpoint of this study was to achieve a confirmed response rate of 20 percent in either arm of the study. Similar to the desmoid trial, this study accrued rapidly. This study was targeted at 84 patients. In fact within the first three weeks of the study opening, 67 patients were registered to the trial. After a brief hold to allow the study to “catch up”, the study was reopened in March 2016 and has now completed accrual. The results from the study were presented by Sandra D’Angelo at ASCO 2017 (https://meetinglibrary.asco.org/record/145287/abstract) at the oral sarcoma session, and also published January 2018 in The Lancet Oncology (Lancet Oncol 2018; 19: 416–26; http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30006-8/abstract). The results indicated that the response rate to nivolumab and ipilimumab was superior to nivolumab alone. Also there appeared to be clinical benefit in patients with either undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLS), which was also seen in the SARC single agent pembrolizumab (PD-1 inhibitor) trial. Therefore the study was amended to add expansion cohorts for these two sarcoma sub-types as well as a randomized study for patients with GIST, who were excluded from the original study design. Correlative studies were also built into this study including assessment of PD-L1 and neo-antigen expression, as well as mutational burden in baseline tissue as well as markers of inflammation in the tumor (CD3, CD4, CD8, PD-1, FOXP3, LAG-3 and TIM-3) as well as the peripheral blood (ki67+CD8+ T cells, ki67+CD4+ T effector cells and ki67+CD4+ T regulatory (FoxP3+)). The results from these studies are now being prepared for publication.

In non-sarcomas, the committee completed study A091104, the randomized phase II study comparing the MET inhibitor XL184 to DTIC in uveal melanoma. For this study, patients were randomized to XL184 (cabozantinib) or Temozolomide (TMZ). The primary endpoint was improvement in PFS. There was a 2:1 randomization favoring XL184. After the study accrued 39 patients, there was a pre-planned futility analysis. Unfortunately, the data reviewed no improvement in mPFS (57 days with XL184 vs. 59 days with TMZ/DTIC) and the study was closed for futility. 

Trials in development

The committee has several trials under development, including a randomized phase II study of CDX-1401, a fully human DEC205 antibody fused to the full-length NY-ESO antigen, in combination with atezolizumab (anti-PD-1 antibody), CDX-301 (the flt-3 ligand) and poly-ICLC in NY-ESO + synovial cell sarcoma (A091607). Patients will be randomized to this drug combination with or without atezolizumab.

Gary K. Schwartz, MD
Dr. Schwartz is Division Chief of Hematology and Oncology and Deputy Director of the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Columbia University Medical Center. Actively involved in translational and clinical research, he focuses on the identification of new targeted agents for cancer therapy, especially in the treatment of sarcoma and melanoma. While those agents are not disease specific, they hold promise in the treatment of all solid-tumor malignancies. Dr. Schwatz’s laboratory studies allow for a bridge between the laboratory and the clinic, and many of these drugs that originated in the lab are now being evaluated in clinical trials.
E-mail: gks2123@cumc.columbia.edu

Pamela Munster, MD
Dr. Munster is a Professor in the Department of Medicine (Hematology/Oncology) at the University of California San Francisco; Director of the Early Phase Clinical Trials Unit and Leader of the Developmental Therapeutics Program at the UCSF Helen Diller Family Comprehensive Cancer Center. Her clinical research interests are first-in-human early phase clinical trials of novel compounds and alternative strategies for the treatment and prevention of cancer.
E-mail: Pamela.Munster@ucsf.edu



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