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The AG-221 Study, ASPIRE, and More

December 30, 2021


Phase I Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation (NCT01915498) 

  • Study design: Open-label, single-group assignment safety study
  • Study start date: August 2013
  • Estimated study completion date: January 2016
  • Study status: Currently recruiting participants
  • Estimated enrollment: 136
  • Sponsor: Agios Pharmaceuticals, Inc.

David Steensma, MD: The AG-221 study is an exciting early-phase trial using a narrowly targeted oral agent that inhibits the mutant isocitrate dehydrogenase (IDH) 2 enzyme – a member of the citric acid cycle – in patients with advanced hematologic malignancies. Up to 15 percent of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), as well as more than half of patients with malignant gliomas and a smaller proportion of those with other solid tumors, have oncogenic mutations in IDH2 or the closely related enzyme, IDH1. Early response data with AG-221 presented at the American Association for Cancer Research Annual Meeting earlier in 2014 are highly encouraging, and those results will be updated at this year's ASH Annual Meeting. A similar trial of AG-120 (NCT02074839), an oral agent targeted against IDH1 mutations, is also accruing. The clinical activity of this class of drugs validates the importance of altered cell metabolism in leukemia and other malignancies, and IDH inhibitors seem likely to offer a subset of patients with AML a new treatment option.

An Open-Label Study of Quizartinib Monotherapy Versus Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects (NCT02039726) 

  • Study design: Randomized, open-label, parallel assignment safety/efficacy study
  • Study start date: April 2014
  • Estimated study completion date: February 2016
  • Study status: Currently recruiting participants
  • Estimated enrollment: 326
  • Sponsor: Ambit Biosciences Corporation

David Steensma, MD: One of the most potent and narrowly targeted FLT3 inhibitors, quizartinib (formerly AC220), is now being tested in a randomized fashion against three commonly used "salvage" chemotherapy regimens (low-dose cytarabine, MEC, and FLAG-Ida combination chemotherapy) in patients with relapsed/ refractory AML. FLT3 internal tandem duplications and mutations in the FLT3 tyrosine kinase domain are common in AML (25-30% of patients) and are independently associated with poorer outcomes. Sorafenib, a multi-kinase inhibitor with anti-FLT3 activity, is FDA-approved for renal carcinoma and is currently commonly used off-label for patients with relapsed AML associated with FLT3 mutations. Several other FLT3- targeting tyrosine kinase inhibitors are currently in clinical development, including midostaurin (formerly PKC412), which was added to 7+3 induction chemotherapy in FLT3+ mutation patients in the randomized RATIFY (CALGB 10603) trial. The results of RATIFY are eagerly awaited.


Open-Label Single Ascending Dose of Adeno- Associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (NCT01687608) 

  • Study design: Open-label, single-group assignment safety study
  • Study start date: September 2012
  • Estimated study completion date: November 2019
  • Study status: Currently recruiting participants
  • Estimated enrollment: 16
  • Sponsor: Baxter Healthcare Corporation

Alice Ma, MD: Until recently, gene therapy for hemophilia has long been considered an unattainable dream. A study published in the New England Journal of Medicine found that patients treated with higher doses of an AAV8 vector experienced episodes of hepatitis associated with a decrease in FIX levels. After a course of corticosteroids, the hepatitis resolved, and the patients eventually achieved FIX levels of 2 to 11 percent of normal. With the current clinical trial, Paul Monahan, MD, and colleagues at the Gene Therapy Center at the University of North Carolina have made two important modifications to the gene therapy product used in the NEJM study. First, the packaging process is more efficient, with fewer empty viruses – decreasing the dose of viral particles needed for a therapeutic effect and the chance of provoking an immune response. Additionally, the Factor IX gene has been engineered to express the FIX Padua mutation (R338L), a gain-of-function mutation that has eight times the activity of wild-type FIX.

Phase I Study of ACE910 in Healthy Volunteers and Hemophilia A Patients (JapicCTI-121934) 

  • Study design: Randomized, placebo-controlled, double-blind, parallel assignment safety study
  • Study start date: August 2012
  • Estimated study completion date: June 2015
  • Study status: Recruiting closed (ongoing study)
  • Estimated enrollment: 82
  • Sponsor: Chugai Pharmaceutical Co., Ltd.

Alice Ma, MD: Treating hemophilic patients with inhibitors is cumbersome, costly, and less effective than in patients without inhibitors. For decades, treatment has relied on two bypassing agents: prothrombin complex concentrates and recombinant FVIIa. A novel agent developed by Chugai Pharmaceutical Co., ACE910, is now on the horizon. ACE910 is a recombinant humanized monoclonal antibody with specificity against factor IXa (FIXa) and factor X (FX). ACE910 places these two factors into spatially appropriate positions in order to mimic the cofactor function of factor VIIIa (FVIIIa) and reconstitute the tenase complex. The safety and efficacy of ACE910 has been tested in primate models of acquired hemophilia and in human volunteers and persons with hemophilia. ACE910 can be given subcutaneously and has a prolonged half-life – two novel properties for patients who have been looking for novel therapeutic agents.


Phase III Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs. Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma (NCT01080391) 

  • Study design: Randomized, open-label, parallel assignment safety/efficacy study
  • Study start date: June 2010
  • Estimated study completion date: June 2016
  • Study status: Recruiting closed (ongoing study)
  • Estimated enrollment: 780
  • Sponsor: Onyx Therapeutics, Inc.

Keith Stewart, MBChB, MBA: The ASPIRE study is a large, randomized, international Phase III trial asking whether the addition of carfilzomib to lenalidomide and dexamethasone will improve outcomes in multiple myeloma patients in relapse. The primary endpoint (improvement in progression-free survival) was met, with an impressive 26.3 months of progressionfree survival in the three-drug regimen. Full results of an interim analysis are expected at the 2014 ASH Annual Meeting, which should shine a light on depth of response, outcomes in high-risk patients, and the toxicity and quality-of-life profile of the triplet combination, compared to lenalidomide and dexamethasone regimen. ASPIRE will join two other recent trials comparing three-drug and two-drug combinations: one examining panobinostat, bortezomib, and dexamethasone; and another incorporating elotuzumab (a monoclonal antibody targeting SLAMF7) or ixazomib (an oral protease inhibitor).

Rituximab and Combination Chemotherapy With or Without Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Diffuse Large B-Cell Lymphoma (NCT01856192)

  •  Study design: Randomized, open-label, parallel assignment efficacy study
  • Study start date: August 2013
  • Estimated study completion date: May 2015
  • Study status: Currently recruiting participants
  • Estimated enrollment: 300
  • Sponsor: National Cancer Institute

Keith Stewart, MBChB, MBA: This Eastern Cooperative Oncology Group–supported Phase III clinical trial will determine whether the addition of lenalidomide to RCHOP improves survival outcomes in diffuse large B-cell lymphoma (DLBCL). Phase II testing results reported earlier this year demonstrated good tolerance and an impressive response rate: 98 percent achieved overall response and 80 percent achieved complete response. At 24 months, event-free and overall survival rates were 59 percent and 78 percent, respectively. Should these Phase III trial results show more frequent response, improved survival outcomes, and tolerability, the results could prove practice-changing in a disease which has seen few advancements over RCHOP in the last decade.


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