Clinical Trial Updates

A look at ongoing clinical trials in myeloid malignancies

PHASE III

Controlled Study of Rigosertib Versus Physician’s Choice of Treatment in MDS Patients After Failure of an HMA (NCT02562443)

  • Estimated Study Completion Date: September 2018
  • Estimated Enrollment:  225
  • Sponsor: Onconova Therapeutics, Inc.

In a previous study, ONTIME, the multikinase inhibitor rigosertib did not improve survival, compared with conventional care, for patients with myelodysplastic syndromes (MDS) for whom hypomethylating agents (HMAs) failed (median survival = 8.2 months for rigosertib vs. 5.9 months for supportive care with or without low-dose cytarabine; p=0.33). However, patients who were primary-refractory to HMAs seemed to fare better with rigosertib in a subset analysis. The INSPIRE study has a similar design to the ONTIME trial, but enriches for higher-risk patients with no or transient responses to HMAs.

 

A Phase III, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) Versus Treatment Choice in Adults With Previously Treated Acute Myeloid Leukemia (NCT02920008)

  • Estimated study Completion Date: June 2019
  • Estimated enrollment: 404
  • Sponsor:  Astex Pharmaceuticals

This multicenter study will compare the next-generation HMA guadecitabine with physician’s choice (including a variety of high- or low-intensity chemotherapeutic regiments), or best supportive care alone in adults with previously treated acute myeloid leukemia (AML). Guadecitabine was granted orphan drug status by the U.S. Food and Drug Administration (FDA) in 2015.

Azacitidine With or Without Nivolumab or Midostaurin, or Decitabine and Cytarabine Alone in Treating Older Patients With Previously Untreated AML or High-Risk MDS (NCT03092674)

  • Estimated Primary Completion Date: June 2022
  • Estimated Enrollment:  1,670
  • Sponsor: National Cancer Institute

This randomized phase II/III trial will evaluate azacitidine-based regimens for the treatment of older patients with previously untreated AML or high-risk MDS: azacitidine with or without nivolumab or midostaurin, and azacitidine with or without decitabine plus cytarabine. These combinations are intended to stop the growth of cancer cells by interfering with the ability of cells to grow and spread by blocking some of the enzymes needed for cell growth.

A Study of ASP2215 (Gilteritinib), Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects With FMS-like Tyrosine Kinase 3 (FLT3/ITD) AML in First Complete Remission (NCT02927262)

  • Estimated Study Completion Date: March 2024
  • Estimated Enrollment: 354
  • Sponsor: Astellas Pharma, Inc.

This randomized, parallel-assignment, double-blind study will compare relapse-free survival  (RFS) in patients with AML and FLT3/ITD mutations in first complete remission treated with either gilteritinib (a novel oral FLT3/AXL inhibitor) or placebo. Earlier trials demonstrated that FLT3 inhibition with gilteritinib improved survival in patients with FLT3-mutated relapsed/refractory AML.

Study of Iomab-B Prior to HCT Versus Conventional Care in Older Subjects With Active, Relapsed, or Refractory AML (NCT02665065)

  • Estimated Primary Completion Date: April 2018
  • Estimated Enrollment:  150
  • Sponsor: Actinium Pharmaceuticals

In this randomized, open-label study, iomab-B, an anti-CD45 antibody conjugated to the radioisotope iodine 131, in combination with a reduced-intensity conditioning regimen, is being compared with conventional care as a preparatory regimen for patients with AML undergoing alloHCT. Iomab-B may facilitate alloHCT by selectively ablating bone marrow and destroying CD45-expressing leukemia cells and host immune system cells.

PHASE II

A Two-Arm Phase II Clinical Study of the Clinical Efficacy and Safety of Tosedostat in Patients With MDS After Failure of HMA-Based Therapy (NCT02452346)

  • Estimated Study Completion Date: March 2021
  • Estimated Enrollment:  80
  • Sponsor: Weill Medical College of Cornell University

Tosedostat, an oral inhibitor of aminopeptidase that influences cellular protein clearance, has demonstrated activity in relapsed/refractory AML. This investigator-sponsored study will examine its efficacy in patients with MDS who have relapsed or are refractory to HMAs. Patients will be enrolled in two arms: patients with low- and intermediate-risk disease and patients with very high-risk disease.

A Study Evaluating Venetoclax in Combination With Azacitidine Compared With Azacitidine Alone in Participants With Previously Untreated Higher-Risk MDS (NCT02942290)

  • Estimated Study Completion Date:  May 2022
  • Estimated Enrollment:  90
  • Sponsor: AbbVie, Inc.

The BCL2 inhibitor venetoclax has demonstrated single-agent activity in relapsed/refractory AML and synergistic activity with HMAs in preclinical studies, and is FDA-approved for chronic lymphocytic leukemia. This randomized, phase II, dose-ranging study will compare the safety, pharmacokinetic profile, and efficacy of azacitidine with or without venetoclax in patients with treatment-naïve, higher-risk MDS.

A Biomarker-Directed Phase II Trial of SY-1425 in Patients With AML or MDS (NCT02807558)

  • Estimated Study Completion Date: August 2019
  • Estimated Enrollment:100
  • Sponsor: Syros Pharmaceuticals

While retinoids such as tretinoin are the backbone of treatment of patients with acute promyelocytic leukemia (APL), a subset of patients with non-APL, AML, or MDS will respond to treatment with retinoic acid derivatives. Tamibarotene is a retinoid analogue licensed for treatment of APL in Japan. In this open-label, single-group assignment study, patients who have a gene expression signature (RARA or IRF8 genes) that preclinical testing has suggested indicates a higher likelihood of response to tamibarotene will be eligible for treatment with this drug.

A Safety and Tolerability Study of Crenolanib in Combination With Chemotherapy in Newly Diagnosed AML Patients With FLT3 Mutations (NCT02283177)

  • Estimated Study Completion Date: January 2019
  • Estimated Enrollment: 48
  • Sponsor:  Arog Pharmaceuticals, Inc.

In the Alliance Cooperative Group-led RATIFY trial, the combination of conventional anthracycline/cytarabine induction and cytarabine consolidation with the multi-kinase inhibitor midostaurin improved survival in patients with FLT3-mutated AML, compared with chemotherapy without midostaurin. This non-randomized, parallel-assignment, open-label study tests a novel FLT3/PDGFR inhibitor, crenolanib, given sequentially during standard induction and consolidation in patients with newly diagnosed AML with FLT3-activating mutations. Crenolanib inhibits both wild-type FLT3 and type 1 mutations.

PHASE I

Dose Escalation of OXi4503 as Single Agent and Combination With Cytarabine w/ Subsequent Phase II Cohorts for AML and MDS (NCT02576301)

  • Estimated Study Completion Date: October 2020
  • Estimated Enrollment:105
  • Sponsor: Mateon Therapeutics

The first phase of this randomized, open-label, single-group assignment study will investigate the maximum tolerated dose of OXi4503 (combretastatin A1 di-phosphate), a vascular disrupting agent, as a single agent and in combination with intermediate-dose cytarabine in subjects with relapsed/refractory AML or MDS. The second phase will investigate the overall response rate of OXi4503 in combination with intermediate-dose cytarabine in two groups: Patients with MDS after failure of one prior HMA and patients with relapsed and refractory AML after treatment failure of up to one prior chemotherapy regimen.

Study to Determine Safety, Pharmacokinetics and Efficacy of GMI-1271 in Combination With Chemotherapy in AML (NCT02306291)

  • Estimated Study Completion Date:  December 2018
  • Estimated Enrollment:102
  • Sponsor:  GlycoMimetics, Inc.

This non-randomized, single-group assignment, open-label study will evaluate the safety and efficacy of GMI-1271, in combination with a standard 7+3 regimen, for the treatment of patients with AML. GMI-1271 blocks the adhesion molecule E-selectin from binding with AML cells to disrupt mechanisms of leukemic cell resistance within the bone marrow microenvironment. In June 2016, the FDA granted fast-track designation to GMI-1271.

SPOTLIGHT: The Beat AML Master Trial

A Master Protocol for Biomarker-Based Treatment of AML (NCT03013998)

  • Estimated Study Completion Date: December 2021
  • Estimated Enrollment:500
  • Sponsor: The Leukemia & Lymphoma Society

In October 2016, The Leukemia & Lymphoma Society (LLS) announced the Beat AML Master Trial – the latest effort in the society’s Beat AML initiative, which launched in 2013 to unite researchers, patients, pharmaceutical companies, and physicians to analyze the genomic causes of AML and identify new treatment options.

This trial will enroll older patients (≥60 years of age) with newly diagnosed, untreated AML who will undergo genomic testing to assign them to a treatment strategy. The primary endpoint is clinical response to each novel therapy, and the trial will also include patient-reported outcomes.

Enrollment comprises three phases:

  • Patients will undergo a bone marrow biopsy, followed by genomic screening within a 7-day period.
  • Based on their genetic profile, patients will be assigned to receive personalized investigational therapy. Unlike other clinical trials where one drug or drug combination is studied, this trial will begin with four different treatments. Combination regimens may also be studied during the trial. If a patient does not have a genetic marker that would place him or her in a specific treatment cohort, then he or she will be offered a different investigational broad-acting AML agent.
  • There will be a follow-up period of ≥28 days after treatment is complete. The total duration may be 1 to 3 years.

Enrollment has already begun at the five participating centers: Memorial Sloan Kettering Cancer Center in New York, New York; The Ohio State University Comprehensive Cancer Center in Columbus, Ohio; Oregon Health & Science University’s Knight Cancer Institute in Portland, Oregon; and Dana-Farber Cancer Institute and Massachusetts General Hospital Cancer Center in Boston, Massachusetts.

Six additional clinical sites are set to begin enrollment this year, and the trial will eventually expand to between 15 and 20 sites with up to 10 different treatment arms. Trial participants will be treated with one of four investigational drugs (samalizumab, BI 836858, enasidenib, or entospletinib) provided by participating pharmaceutical companies.

The American Society of Hematology (ASH) and LLS have teamed up to educate and raise awareness about the need for new treatments for AML. At the 2016 ASH Annual Meeting, the trial’s three lead investigators, Brian Druker, MD, John Byrd, MD, and Ross Levine, MD, discussed the rationale of the Beat AML Master Trial. “This trial is about matching the right patients with the right drug,” Dr. Druker said. ”It’s time to stop treating AML like one disease; it is multiple blood cancers, each driven by different genetic mutations.”

“We have seen too few drugs achieve approval for AML, and, even when drugs are approved, getting them into the clinic takes too long and these agents generally are not tailored to a patient’s genotype,” Dr. Levine said. “We hope this trial increases the speed in which we can bring new drugs to patients and provides a template for new master trials and drug development in a wider spectrum of human cancers.”

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