E-Newsletter - July 2019
Spotlight on Alliance Trials



Alliance Trial to Explore New Treatment Option for Older Adults with Acute Myeloid Leukemia

Alliance A041701 - A randomized phase II/III study of conventional chemotherapy +/- uproleselan (GMI-1271) in older adults with acute myeloid leukemia receiving intensive induction chemotherapy

This Alliance phase II/III trial will test a novel agent, uproleselan, in combination with daunorubicin and cytarabine in treating older adult patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy. The combination of daunorubicin and cytarabine has been a standard of care in treating older adults with AML for more than 40 years.  The researchers will test whether the addition of uproleselan may work better in treating patients with AML compared to daunorubicin and cytarabine alone.

Note: Alliance, National Cancer Institute (NCI), and GlycoMimetics are collaborating on A041701. Results from this trial may be submitted to the Food and Drug Administration (FDA) to seek approval to market uproleselan as part of first-line therapy for patients with previously untreated acute myeloid leukemia. For this reason, the Alliance has developed this trial as an FDA registration protocol

Study Rationale
For more than 40 years, 7+3 regimens (i.e., cytarabine infused for seven days with three days of an anthracycline) have been a standard for AML induction therapy [1]. Despite widespread use in older adults, 7+3 induction in these patients is associated with lower complete remission rates (50-60 percent), increased early mortality (up to 20 percent), and higher relapse rates compared with younger adults[2, 3]. Attempts at improving 7+3 through the addition of novel agents or intensification of post-remission therapy have largely failed to improve outcomes [4-6].

In Alliance A041701, investigators will test the addition of uproleselan to a standard daunorubicin/cytarabine regimen in older adults with previously untreated AML. Uproleselan blocks E-selectin, an adhesion molecule, which allows cells in the bone marrow to bind to and interact with leukemia cells and is importing in protecting leukemia cells from the effects of chemotherapy.  Blocking E-selectin with uproleselan is hypothesized to sensitize leukemia cells to the effect of chemotherapy.  Furthermore, uproleselan may reduce the damage to the mucosal lining of the gastrointestinal tract caused by chemotherapy by interfering with the binding of inflammatory cells to the gut. In a Phase 1/2 clinical trial, uproleselan was evaluated in both newly diagnosed elderly and relapsed/refractory patients with AML. In both populations, patients treated with uproleselan together with standard chemotherapy achieved better than expected remission rates and overall survival, as well as lower than expected induction-related mortality rates, as compared to historical controls.

The primary endpoint in the phase II portion of the study will be event-free survival (EFS) and in the phase III portion, overall survival. 

Study Outcomes
The primary and secondary objectives are described below.

Primary objectives:
Phase II
Compare the event-free survival (EFS) of daunorubicin, cytarabine plus uproleselan versus daunorubicin and cytarabine in subjects ≥age 60 with previously untreated acute myeloid leukemia.

Phase III
Compare the overall survival (OS) of the daunorubicin, cytarabine plus uproleselanto daunorubicin and cytarabine in this patient population.

Secondary objectives:
1. Determine the rates of complete remission (CR), complete remission with incomplete count recovery (CRi), complete remission with incomplete hematopoietic recovery (CRh) and cytogenetic complete remission (CCyR) for each chemotherapy regimen.
2. Determine the overall survival (OS), and remission duration of patients for each chemotherapy regimen.
3. Describe the frequency and severity of adverse events for patients for each chemotherapy regimen.
4. Describe the interaction of pretreatment disease and patient characteristics including morphology, cytogenetics, molecular genetic features, WBC count and hemogram, and performance status on clinical outcomes.

Key Eligibility Criteria
Some of the eligibility criteria include:

-- Diagnosis of acute myeloid leukemia (AML) based on 2017 WHO criteria excluding acute promyelocytic leukemia with PML-RARA
-- No activating mutation in Fms-like tyrosine kinase-3 (FLT3)
-- No evidence of CNS involvement of AML
-- No prior chemotherapy for myelodysplastic syndrome (MDS) or AML including hypomethylating agents or lenalidomide with the following exceptions:
   -- Emergency leukapheresis
   -- Hydroxyurea
   -- Growth factor/cytokine support
   -- All-trans retinoic acid (ATRA)
   -- Single-dose of intrathecal cytarabine and/or methotrexate for patients undergoing a lumbar puncture to evaluate for CNS involvement
-- Age ≥ 60 years

Description of Treatment
Patients will be randomized into one of two groups. Those in Group 1 will receive the 7+3 regimen of cytarabine infused for seven days with three days of daunorubicin as part of remission induction. Patients with residual disease indicated by bone marrow examination receive a second induction. For consolidation, patients who achieve complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) will receive cytarabine intravenously for five days. Treatment will repeat every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Those in Group 2 will receive the 7+3 regimen of cytarabine infused for seven days with three days of daunorubicin plus 10 days of uproleselan as part of remission induction. Patients with residual disease indicated by bone marrow examination receive a second induction. For consolidation, patients who achieve complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) will receive uproleselan for eight days. Treatment will repeat every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

There will be three sub-studies within the A041701 trial. Cytogenetics and Molecular Genetic Analysis are required for all patients. A041701-LC1 is an integrated substudy and patients are encouraged to participate.

Refer to the study protocol, which can be found on the Alliance website at www.AllianceNCTN.org, for complete information on the trial design, treatment plan, and patient eligibility.

Study Chair: Geoffrey L. Uy, MD - Washington University - Siteman Cancer Center
E-mail: guy@wustl.edu
Activated: 1/16/2019
Status: Now Accepting New Patients
ClinicalTrials.gov Identifier: NCT03701308

References
1. Rai, K.R., et al., Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood, 1981. 58(6): p. 1203-12.
2. Kayser, S., et al., The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood, 2011. 117(7): p. 2137-45.
3. Schoch, C., et al., Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia, 2003. 18(1): p. 120-125.
4. Dombret, H. and C. Gardin, An update of current treatments for adult acute myeloid leukemia. Blood, 2016. 127(1): p. 53-61.
5. Mayer, R.J., et al., Intensive post remission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B.N Engl J Med, 1994. 331(14): p. 896-903.
6. Burnett, A.K., et al., The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol, 2009. 145(3): p. 318-32.

 

 

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