CLINICAL NEWS
Trial Roundup
ASH Clinical News’ Associate Editors select
clinical trials to keep an eye on.
LEUKEMIA
BLEEDING DISORDERS
LYMPHOMA & MYELOMA
David Steensma, MD
Dana-Farber Cancer Institute
Alice Ma, MD
University of North Carolina School of Medicine
Keith Stewart, MBChB, MBA
Mayo Clinic, Arizona
Phase I Study of AG-221 in Subjects With
Advanced Hematologic Malignancies With
an IDH2 Mutation (NCT01915498)
Open-Label Single Ascending Dose of AdenoAssociated Virus Serotype 8 Factor IX Gene
Therapy in Adults With Hemophilia B
(NCT01687608)
Phase III Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs.
Lenalidomide and Dexamethasone (Rd) in
Subjects With Relapsed Multiple Myeloma
study design: Open-label, single-group assignment safety study
(NCT01080391)
estimated study completion date:
study start date:
study design:
study status:
estimated study completion date:
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.
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.
study design: Open-label, single-group assignment safety study
study start date:
August 2013
January 2016
Currently recruiting participants
estimated enrollment: 136
sponsor: Agios Pharmaceuticals, Inc.
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 e nrollment: 326
sponsor: Ambit Biosciences Corporation
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 FLT3targeting 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.
54
ASH Clinical News
September 2012
November 2019
study status: Currently recruiting participants
estimated enrollment: 16
sponsor: Baxter Healthcare Corporation
Phase I Study of ACE910 in Healthy
Volunteers and Hemophilia A Patients
(JapicCTI-121934)
study design:
Randomized, placebo-controlled, doubleblind, 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.
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.
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.
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
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.
December 2014