Clinical Trial Spotlight: Trial 17-049

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Jacqueline Garcia, MD


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The median age of patients with myelodysplastic syndrome (MDS) is more than 70 years. About one-half of MDS patients present with higher-risk (HR)-MDS (by the International Prognostic Scoring System, IPSS) and have a median survival < 1 year with best supportive care. DNA hypomethylating agents (HMAs) such as azacitidine (Vidaza) and decitabine (Dacogen) are standard therapies for treatment-naïve HR-MDS. Azacitidine treatment offers a ~9.5-month survival advantage compared to conventional care regimens, but most patients relapse or experience disease progression within two years.

Over-expression of BCL-2 (an anti-apoptotic [cell death] protein) is associated with drug resistance to HMA therapy. In preclinical studies, higher BCL-2 expression was seen in bone marrow progenitor cells from patients that had HR-MDS compared to those with lower-risk MDS. Venetoclax (ABT199; an oral, selective BCL-2 inhibitor) was specifically toxic to cells derived from patients with HR-MDS. Combining venetoclax with azacitidine appears to be more active than azacitidine alone in preclinical MDS studies.

In an ongoing clinical trial with HMA plus venetoclax for the treatment of patients with treatment-naive acute myeloid leukemia (AML), interim results showed a striking overall response rate (>70%). Venetoclax, which is FDA-approved for chronic lymphocytic leukemia, now has Breakthrough Therapy Designation from the FDA for the treatment of AML. The most frequent grade 3 or higher adverse events (AE) observed with venetoclax include febrile neutropenia (less than one-third of patients) and other common but tolerable AEs, including nausea and cytopenias.

We thus hypothesize that venetoclax may similarly augment the clinical activity of azacitidine compared to azacitidine alone in MDS. We are therefore participating in two trials incorporating venetoclax into MDS therapy: one for treatment-naïve subjects and the other for subjects who have failed prior HMA.

A phase 2, open-label, 3-arm randomized multicenter clinical trial will compare the safety, pharmacokinetics and efficacy of venetoclax when given with azacitidine compared to azacitidine alone in patients with treatment-naïve HR-MDS (NCT02942290). Eligible subjects have treatment-naïve HR-MDS (IPSS Int-2 or High), are 18 years and older with excess blasts (5 to 30%) by marrow evaluation at time of screening, and are not candidates for intensive chemotherapy or transplantation.

We are also participating in a phase 1b clinical trial of venetoclax as a single agent or in combination with azacitidine in subjects with HR-MDS after HMA failure (NCT02966782). Eligible subjects must have disease that has failed prior therapy with HMA (defined as relapse or failure to achieve complete or partial response or hematological improvement after at least 6 cycles of azacitidine or 4 cycles of decitabine within last 2 years).

For more information about this study or to discuss a patient who may be eligible, please contact Jacqueline S. Garcia, MD at, phone 617-632-6349. Note: From April through June 2017, Dr. Garcia will be away and Dr. David Steensma will be acting PI until her return (

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Trial schema for azacitidine +/- venetoclax in treatment naïve MDS