Oral ABL001 in CML, poloxamer 188 in vaso-occlusive crisis of SCD, and more


David Steensma, MD

Dana-Farber Cancer Institute

A Phase I, Multicenter, Open-label Study of Oral ABL001 in Patients With Chronic Myelogenous Leukemia (CML) or Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) (NCT02081378)

  • Study Design: Non-randomized, open-label, single-group assignment safety study
  • Study Start Date: April 2014
  • Estimated Study Completion Date: February 2017
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 60
  • Sponsor: Novartis Pharmaceuticals

Patients with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) often develop resistance to tyrosine kinase inhibitor therapy (TKI) via ABL kinase point mutations, and even patients who achieve deep molecular remissions frequently relapse after TKI discontinuation. All currently available TKIs for CML and Ph+ ALL bind to the ATP binding pocket of the ABL1 kinase, and mutations that alter the conformation of this pocket induce remission. The small molecule ABL001, in contrast, was developed to target the myristoyl pocket of the ABL1 kinase and inhibits proliferation of BCR-ABL positive cells with clinically observed TKI resistance mutations. This study is designed to assess the safety, tolerability, and clinical activity of ABL001 in patients with CML or Ph+ ALL who have either developed resistance to at least TKIs or have the T315I ABL mutation and are resistant to at least one TKI.

A Dose Escalation and Cohort Expansion Study of TEN-010 in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndromes (NCT02308761)

  • Study Design: Open-label, single-group assignment, safety study
  • Study Start Date: October 2014
  • Estimated Study Completion Date: April 2017
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 68
  • Sponsor: Tensha Therapeutics

Bromodomains are protein domains that bind acetylated histones and are important for chromatin remodeling and neoplasia-associated protein-histone interactions. TEN-010 is a small molecule bromodomain and extra-terminal domain (BET) bromodomain inhibitor that has anti-leukemic effects in vitro. This study is designed to characterize the safety, tolerability, and pharmacokinetics of TEN-010 in patients with relapsed/refractory acute myeloid leukemia and hypomethylating agent-refractory myelodysplastic syndromes.


Alice Ma, MD

University of North Carolina School of Medicine

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 being evaluated 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. In the February issue, we discussed trials targeting selectins in sickle cell disease (SCD), and in the March issue we focused on HDAC inhibitors in SCD. I’ll close the sickle cell roundup with drugs that target integrins and other adhesive molecules in SCD.

Evaluation of Purified Poloxamer 188 in Vaso-Occlusive Crisis of Sickle Cell Disease (EPIC) (NCT01737814)

  • Study Design: Randomized, double-blind, parallel-assignment efficacy study
  • Study Start Date: May 2013
  • Estimated Study Completion Date: December 2015
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 388
  • Sponsor: Mast Therapeutics, Inc.

MST-188, purified polaxamer 188, is a synthetic polymer of polyoxyethylene (POE) and polyoxypropylene (POP) thought to have beneficial effects on blood flow, as well as having anti-inflammatory and antithrombotic effects. An initial trial of 50 patients with SCD in crisis showed significant reductions in crisis duration, length of hospital stay, and a reduction in analgesia use. Though no side effects were reported in this trial, sudden worsening of renal function was seen in patients treated with polaxamer 188 after a myocardial infarction. Elimination of the low-molecular-weight components of the polymeric mix lowered the risk of renal dysfunction, leading to the current trial. This phase III study evaluates whether MST-188 can reduce the duration of vaso-occlusive crisis (VOC) in subjects with SCD, as well as its effect on reducing the frequency of rehospitalization of SCD patients due to VOC recurrence. Additionally, this study will compare the development of acute chest syndrome during VOC in subjects who receive MST-188 with those who do not.

A Pharmacokinetic (PK) and Pharmacodynamic (PD) Dose-ranging Phase II Study of Ticagrelor Followed by a 4 Weeks Extension Phase in Paediatric Patients With Sickle Cell Disease (HESTIA 1)  (NCT02214121)

  • Study Design: Randomized, double-blind, parallel-assignment pharmacokinetics/dynamics study
  • Study Start Date: September 2014
  • Estimated Study Completion Date: September 2015
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 39
  • Sponsor: AstraZeneca

This is a phase II dose-ranging study to investigate pharmacokinetic and pharmacodynamic properties of various doses of ticagrelor followed by four weeks of twice-daily treatment in pediatric patients with SCD. Ticagrelor is an inhibitor of the integrin IIb-IIIa, which may be involved in abnormal adhesion of sickled red cells to endothelium.


Keith Stewart, MBChB, MBA

Mayo Clinic, Arizona

Studies of monoclonal antibodies promise to add new therapies to the multiple myeloma treatment landscape. In particular, there is great excitement about the potential of anti-CD38 antibodies in this disease.

A Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma (NCT02076009)

  • Study Design: Randomized, open-label, parallel assignment, efficacy study
  • Study Start Date: May 2014
  • Estimated Study Completion Date: September 2020
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 560
  • Sponsor: Janssen Research & Development, LLC

This phase III trial examines the efficacy of a novel anti-CD38 monoclonal antibody (daratumumab) added to standard-of-care drugs in relapsed myeloma. If positive, the results from this trial might result in the introduction of a novel class of agents for myeloma therapy at the time of early relapse.

SAR650984, Pomalidomide and Dexamethasone in Combination in RRMM Patients (PomdeSAR) (NCT02283775)

  • Study Design: Open-label, single-group assignment, safety study
  • Study Start Date: March 2015
  • Estimated Study Completion Date: January 2017
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 24
  • Sponsor: Sanofi

SAR650984 is another monoclonal antibody targeting CD38 that is now being studied in phase II combination studies, such as this recently opened phase II trial combining SAR650984 with pomalidomide and dexamethasone.