ACE-536 for MDS, Vorinostat in SCD, and more

LEUKEMIA

Selected by David Steensma, MD

A Phase 2, Open-Label, Ascending Dose Study of ACE-536 for the Treatment of Anemia in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (NCT01749514)

  • Study Design: Open-label, single-group assignment safety/efficacy study
  • Study Start Date: January 2013
  • Estimated Study Completion Date: April 2015
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 60
  • Sponsor: Acceleron Pharma, Inc.

Patients with myelodysplastic syndromes (MDS)–associated anemia who have not responded to erythropoiesis-stimulating agents (ESAs), such as darbepoetin and epoetin, have limited treatment options. Luspatercept, or ACE-536, is an activin receptor IIB ligand trap, which decreases levels of ligands in the transforming growth factor-β superfamily, including GDF11. GDF11 inhibits erythropoiesis at a later stage of red cell development than that altered by ESAs. Early data presented at the 2014 ASH Annual Meeting in December suggest that ACE-536 improves anemia in some patients with MDS who have not responded to or are unlikely to respond to ESAs.

APG101 in Transfusion-Dependent Patients With Low or Intermediate Risk Myelodysplastic Syndrome (NCT01736436)

  • Study Design: Open-label, single-group assignment, safety study
  • Study Start Date: January 2013
  • Estimated Study Completion Date: November 2015
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 18
  • Sponsor: Apogenix GmbH

AGP101 is a soluble CD95-Fc fusion protein that blocks the CD95–ligand (CD95L, Fas ligand) from binding to the CD95-receptor (CD95, Fas), thereby inhibiting apoptosis. Because Fas ligand (death receptor)–mediated apoptosis contributes to anemia in MDS, this agent may result in improved erythropoiesis and improve anemia in MDS.


BLEEDING DISORDERS

Selected by Alice Ma, MD

Pharmacologic prevention and treatment of sickle cell crises has relied on a single agent – hydroxyurea – for many years. However, a recent spate of promising new agents are now in clinical trials. These new therapies have a variety of targets: blocking adhesion receptors, increasing fetal hemoglobin, altering the oxygen affinity of sickle cell hemoglobin, blocking ischemia/reperfusion injury, and altering the arginine metabolome. Last month, I focused on trials targeting selectins in sickle cell disease (SCD). This month’s roundup focuses on histone deacetylase (HDAC) inhibitors. HDAC inhibitors were first tried in treatment of malignancies but were also noted to increase levels of fetal hemoglobin (HbF). Additionally, HDAC inhibitors have been shown to potently inhibit cell-specific inflammation, which is a primary contributor to the debilitating effects of SCD.

Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease (NCT01000155)

  • Study Design: Open-label, single-group assignment, safety/efficacy study
  • Study Start Date: October 2009
  • Estimated Study Completion Date: October 2014
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 15
  • Sponsor: Dana-Farber Cancer Institute

This phase 2 trial is investigating the safety and efficacy of once-daily, three-times-weekly vorinostat for the treatment of patients with SCD resistant to hydroxyurea. All babies are born with HbF; soon after birth, HbF production slows down and adult hemoglobin (HbA) is made. Clinical studies have shown that increasing the amount of HbF in the blood may prevent “sickling” of the red blood cells associated with SCD. Vorinostat has been used in the treatment of cancers and in other research studies, and information from those suggests that it may help treat SCD by increasing the amount of HbF in the blood.

Phase I Study to Determine the Safety and Tolerability of Escalating Doses of Panobinostat (LBH589) in Patients With Sickle Cell Disease (NCT01245179)

  • Study Design: Open-label, single-group assignment, safety/efficacy study
  • Study Start Date: November 2010
  • Estimated Study Completion Date: December 2016
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 27
  • Sponsor: Novartis Pharmaceuticals

This is a phase 1 trial testing the safety and tolerability of escalating doses of the HDAC inhibitor panobinostat in SCD patients. Panobinostat may prove to contribute significantly to the management of SCD patients – a population in critical need of further effective treatment options.

Evaluation of Different Dose Regimens of Aes-103 Given for 28 Days to Subjects with Stable Sickle Cell Disease (NCT01987908)

  • Study Design: Randomized, parallel assignment, safety study
  • Study Start Date: October 2013
  • Estimated Study Completion Date: June 2015
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 50
  • Sponsor: AesRx, LLC

Aes-103 is being evaluated as a novel agent for the long-term management of SCD. This agent has a different mechanism of action than hydroxyurea: the active ingredient in Aes-103 is 5-hydroxymethyl furfural, a naturally occurring small molecule that is chemically related to glucose. It binds to the amino terminal of the alpha chain of hemoglobin and stabilizes the hemoglobin in the high oxygen affinity state or R-state, thus preventing sickling. This phase 2, placebo-controlled study will evaluate the safety and pharmacokinetic profile of two dosing regimens of Aes-103.


LYMPHOMA & MYELOMA

Selected by Keith Stewart, MBChB, MBA

There are currently two pivotal phase 3 trials of ibrutinib-based therapies in chronic lymphocytic leukemia (CLL) underway – their results will be important to patients with CLL, as the hope is that they will confirm the activity of this drug seen in earlier phase studies. The first (NCT03048813) seeks to determine whether ibrutinib plus rituximab can replace bendamustine-rituximab as the standard of care for first-line treatment for older patients with previously untreated CLL. The second (NCT01886872) examines whether ibrutinib plus rituximab or ibrutinib alone can replace FCR as the standard of care for first-line treatment of CLL patients aged 65 years or older.

Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Patients With Untreated CLL or Small Lymphocytic Lymphoma (NCT02048813)

  • Study Design: Open-label, parallel assignment, efficacy study
  • Study Start Date: February 2014
  • Estimated Study Completion Date: April 2017
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 519
  • Sponsor: National Cancer Institute

Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated CLL (NCT01886872)

  • Study Design: Randomized, open-label, crossover assignment, efficacy study
  • Study Start Date: December 2013
  • Estimated Study Completion Date: March 2018
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 523
  • Sponsor: National Cancer Institute

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