A Phase 1 Trial of the Combination of Ibrutinib and Azacitidine for the Treatment of Higher Risk Myelodysplastic Syndromes: University of California Hematologic Malignancies Consortium (UCHMC) Study 1503

Introduction: Higher risk myelodysplastic syndromes (HR-MDS) have poor outcomes, particularly after hypomethylating agent (HMA) failure. The HMA azacitidine (AZA) is a standard of care for HR-MDS and works through several mechanisms, including inhibition of NF-kB signaling. Ibrutinib (IBR) inhibits Bruton's Tyrosine Kinase (BTK) and has an antiproliferative effect on myeloblasts in preclinical models through BTK binding and inhibition of NF-kB signaling. IBR also has immunomodulatory activity mediated through binding interleukin-2-inducible kinase (ITK) and promoting Th1-polarized immunity, which is decreased in HR-MDS. These features suggest that the combination of IBR and AZA may improve outcomes in HR-MDS.

Methods: This is an ongoing multicenter prospective Phase 1 dose-escalation trial of IBR in combination with AZA in patients with HR-MDS (NCT02553941). Results of the dose escalation phase are reported. Eligibility included World Health Organization or French-American-British classification-defined MDS and Revised International Prognostic Scoring System (IPPS-R) intermediate or higher risk. Any prior therapy was allowed or patients could be untreated if unfit for, or had refused, high intensity chemotherapy. Transfusion-dependent patients were eligible. Patients received AZA 75 mg/m2 IV/SC daily for 7 days and IBR orally daily for 28 days. Cycles repeated every 28 days. Dose-escalation used a 3+3 design with IBR dose levels of 420 mg (Cohort 1) and 560 mg (Cohort 2). The primary objective was to determine the safety and tolerability of IBR in combination with AZA. Adverse events (AEs) were monitored throughout treatment, and dose-limiting toxicities (DLT) were assessed during cycle 1. The secondary objective was to assess preliminary efficacy using modified International Working Group Response Criteria. Exploratory objectives evaluated pharmacodynamic and biological effects of the combination, including BTK occupancy in CD34+ bone marrow mononuclear cells (BMMC).

Results: As of June 1, 2017, 9 patients [89% male, median age 80 years (range 64-81)] were enrolled into Cohort 1 (n=3) and Cohort 2 (n=6). MDS subtypes included single lineage dysplasia (n=1), multilineage dysplasia (n=1), excess blasts (EB)-1 (n=2), EB-2 (n=3), refractory anemia with EB in transformation (n=1) and unclassifiable (n=1). IPSS-R scores were intermediate (n=2), high (n=2) and very high (n=5). Three patients were HMA-naïve and six had prior HMA therapy [AZA (n=3), decitabine (n=2), both (n=1)]. All patients completed cycle 1. No DLTs were observed. All patients experienced at least one treatment-emergent adverse event (TEAE). Seven patients experienced a grade 3-4 TEAE with neutropenia (n=6), thrombocytopenia (n=3) and febrile neutropenia (n=3) most common. Four patients (three in Cohort 1 and one in Cohort 2) experienced a serious adverse event including febrile neutropenia (n=3) and gastric hemorrhage (n=1). No patients experienced atrial fibrillation. Median time on study was 160 days (range 42-283) with a median of five cycles (range 1-10) received. Six patients remain on IBR plus AZA, and three patients have discontinued study therapy (two disease progression and one withdrawal of consent and subsequent death on hospice). Four patients have reduced AZA to 5 days per cycle per investigator discretion, and four patients have had interruptions of IBR dosing due to febrile neutropenia (n=3) and concurrent azole use (n=1). Three patients (33%) achieved complete remission (CR), one (11%) had a partial remission (PR), and five (55%) had stable disease (SD). All three CRs occurred in patients without prior HMA exposure and included one complete and two partial cytogenetic responses. CR was achieved after 1, 4 and 6 cycles in these patients. One patient (11%) with SD had a hematologic improvement-erythroid response (HI-E). The overall hematologic normalization rate (CR+PR+HI) was 55%. BTK occupancy in CD34+ BMMC after cycle 1 was 42.0% and 51.7% in two patients at IBR 420 mg and 41.5% in one patient at IBR 560 mg.

Conclusions: The combination of IBR and AZA demonstrates a tolerable safety profile in patients with HR-MDS. No DLTs were observed at either IBR dose level. The combination shows promising preliminary efficacy, including responses in patients with prior HMA exposure. CD34+ BMMC BTK occupancy was seen. An expansion cohort at the IBR 560 mg dose level in AZA-naïve patients is ongoing.