ATTRACT, PD-1 Blockade, and more

LEUKEMIA
Selected by David Steensma, MD

Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis With Thrombocytopenia (NCT02055781)

  • Study Design: Randomized, open-label, parallel assignment safety/efficacy study
  • Study Start Date: December 2013
  • Estimated Study Completion Date: April 2018
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 300
  • Sponsor: CTI BioPharma

Currently, ruxolitinib is the only JAK2 inhibitor approved for myelofibrosis. While this agent is effective at reducing splenomegaly and improving constitutional symptoms in many patients, treatment-emergent thrombocytopenia can be problematic, especially for patients with pre-treatment thrombocytopenia from the underlying disease. Pacritinib (formerly known as SB1518) appeared to cause less thrombocytopenia than ruxolitinib in earlier phase trials. The drug is now being compared in a randomized fashion with “best available therapy” in patients with myelofibrosis and splenomegaly. Best available therapy includes any available myelofibrosis therapy, including ruxolitinib or hydroxyurea, glucocorticoids, erythropoietic agents, immunomodulatory agents, mercaptopurine, danazol, interferons, cytarabine, melphalan, or other agents, and may also include no treatment and symptom-directed treatment without myelofibrosis-specific treatment.

A Study of Inotuzumab Ozogamicin Versus Investigator’s Choice of Chemotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia (NCT 01564784)

  • Study Design: Randomized, open-label, parallel assignment safety/efficacy study
  • Study Start Date: August 2012
  • Estimated Study Completion Date: March 2017
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 325
  • Sponsor: Pfizer

The FDA recently granted accelerated approval for relapsed/refractory B-cell acute lymphocytic leukemia (ALL) blinotumumab, a bispecific CD19-CD3 antibody – the first new class of drug for B-cell ALL to achieve regulatory approval in many years. Inotuzumab, a CD22 antibody conjugated to the same toxin used in the formerly approved AML drug gemtuzumab ozogamicin, showed dramatic activity in early-phase trials of relapsed/refractory B-ALL expressing CD22. Currently, inotuzumab is being compared in a randomized fashion to three commonly used regimens (FLAG, HAM, and high-dose cytarabine). While the incidence of hepatic sinusoidal syndrome needs to be watched closely given the history of gemtuzumab, if the efficacy of this new agent outweighs its toxicity and, if inotuzumab is approved, this agent will provide additional options for patients with relapsed/refractory ALL. These new agents are likely to be tried soon in the upfront setting – adding to the current combination chemotherapy regimens.


BLEEDING DISORDERS
Selected by Alice Ma, MD

A Study in Older Subjects to Evaluate the Safety and Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Apixaban (NCT02207725)

  • Study Design: Randomized, double-blind, parallel assignment safety/efficacy study
  • Study Start Date: March 2014
  • Estimated Study Completion Date: November 2014
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 64
  • Sponsor: Portola Pharmaceuticals

A Study in Older Subject to Evaluate the Safety and Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Rivaroxaban (NCT02220725)

  • Study Design: Randomized, double-blind, parallel assignment safety/efficacy study
  • Study Start Date: May 2014
  • Estimated Study Completion Date: December 2014
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 79
  • Sponsor: Portola Pharmaceuticals

The use of the new oral anticoagulant agents has been hampered by lack of safe, effective specific reversal agents. Andexanet alpha, a novel, first-in-class molecule, is being tested for its ability to reverse the anticoagulant effects of both rivaroxaban and apixaban, two direct factor Xa inhibitors. Andexanet is a modified factor Xa molecule that lacks a GLA-domain – making it unable to bind to membranes – and is also catalytically inactive. Andexanet competes with native factor Xa for binding to rivaroxaban and apixaban (and presumably other factor Xa inhibitors), serving as a decoy and limiting drug availability. Andexanet alfa has been designated as a “breakthrough therapy” by the FDA, and these phase 3 studies are continuing to recruit patients.

Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT) (NCT00790335)

  • Study Design: Randomized, open-label, parallel assignment safety/efficacy study
  • Study Start Date: November 2009
  • Estimated Study Completion Date: May 2016
  • Study Status: Ongoing, but not recruiting participants
  • Estimated Enrollment: 692
  • Sponsor: Washington University School of Medicine

The optimal treatment for patients with iliofemoral deep-vein thrombosis (DVT) has been controversial. Smaller, non-randomized studies have suggested that lytic therapy might reduce the risk of development of post-phlebitic syndrome in patients with proximal clots, but this has never been shown in a randomized, prospective trial. The ATTRACT trial enrolled 692 patients with iliofemoral DVTs not associated with malignancy and randomized them to best standard care or to catheter-directed lysis with r-tPA (alteplase). It enrolled its last patient in December 2014, just after the ASH annual meeting, and we are eagerly awaiting final results, expected in 2016.


LYMPHOMA & MYELOMA
Selected by Keith Stewart, MBChB, MBA

Safety Study in Nivolumab Alone and in Combination With Ipilimumab or Lirilumab in Lymphoma and Multiple Myeloma (NCT01592370)

  • Study Design: Non-randomized, open-label, single-group assignment safety study
  • Study Start Date: June 2012
  • Estimated Study Completion Date: March 2018
  • Study Status: Currently recruiting participants
  • Estimated Enrollment: 315
  • Sponsor: Bristol-Myers Squibb

This is an ongoing study designed to determine the side effects of the PD-1 inhibitor nivolumab alone, and in combination with ipilimumab or lirilumab. In a recent report by Ansell et al. published in The New England Journal of Medicine, nivolumab demonstrated strong response rates and acceptable safety in a cohort of 23 patients with relapsed or refractory Hodgkin lymphoma. Results were also presented at the 2014 ASH Annual Meeting. These heavily treated patients had few other therapeutic options available – 78 percent had relapsed after autologous stem cell transplantation, and 78 percent had relapsed after treatment with brentuximab vedotin. Response rates were high: 20 patients (87%) experienced an objective response, including 17 percent with a complete response and 70 percent with a partial response. Adverse events were mainly low grade, with no life-threatening adverse events. Based on these findings – which support nivolumab-mediated PD-1 blockade as a promising targeted treatment for these patients – the FDA has granted nivolumab breakthrough status and a multinational phase 2 trial is underway.

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