A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by 24 Hour Infusion Every 2 Weeks to Patients with Myeloid Malignancies and Chronic Lymphocytic Leukemia (CLL).
Authors: Borthakur Gautam , O’Brien Susan , Ravandi-Kashani Farhad , Giles Francis , Schimmer Aaron D. , Viallet Jean , Kantarjian Hagop 
Published: October 2019

Obatoclax is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It activates apoptosis and has clinical activity in CLL (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. This Phase I trial was designed to evaluate the potential of prolonged infusions to minimize these toxicities while maintaining biological and clinical activity. We enrolled 14 patients at doses ranging from 7–40 mg/m2 over 24 hours every 2 weeks utilizing a modified accelerated titration design with 3–6 patients per cohort and doubling of the dose until 28 mg/m2. Cycle 1 was administered in a clinical research unit to accommodate PK sampling but subsequent cycles were administered in the ambulatory setting using portable infusion pumps. Median age was 62 (range 56–82) and 10 patients were male. The following diagnoses were included: myelodysplatic syndromes (MDS; 8, 4 secondary), refractory acute myelogenous leukemia (AML; 5) and CLL (1). A total of 51 infusions were administered. At doses ≤28 mg/m2, adverse events (AE) of Grade 1 dizziness (2/9), headache (2/9), euphoric mood (2/9) and Grade 2 somnolence (2/9) were of lesser frequency and intensity then at equivalent dose levels previously administered with a 3 hour infusion. At the 40 mg/m2 dose level, dose-limiting toxicities of Grade 3 QTc prolongation with no accompanying arrythmias were reported in 2/5 patients who both had QTc prolongation at baseline. Other toxicities included Grade 2 somnolence (4/5), Grade 1 euphoric mood (3/5), Grade 1 anxiety (2/5) and single reports of Grade 1 dizziness, dysarthria, dysphasia, confusion, hallucination and disorientation. The pharmacokinetics (PK) of obatoclax following a 24-hr IV infusion is dose proportional for both Cmax and AUC24h. Induction of apoptosis was monitored quantitatively with serial determinations of plasma concentration of histone-oligonucleosomal DNA (ODNA) complexes. An early release of ODNA greater than 4-fold occurred in 10/14 patients by the midpoint of the infusion and was sustained to the end of the infusion. The rapid elimination of the plasma obatoclax concentration immediately following the end of infusion was associated with a decline of the plasma oligonucleosomal DNA level; however multiple additional peaks of oligonucleosomal DNA concentrations occurring over days following the infusion were still detected in 9 of 14 patients. 3/8 patients with MDS showed hematological improvement with red blood cell or platelet transfusion independence. Bone marrow blasts were reduced from 14% to 4% in another patient with secondary MDS.

Conclusions: Single agent obatoclax is well tolerated when administered as a 24 hour continuous infusion, with abrogation of previously noted infusional CNS toxicities. Biological and clinical activity are retained. Further prolongation of the infusion may lead to more robust activity and will be explored. Phase II single agent trials using 28 mg/m2 over 24 hours every 2 weeks have been initiated in patients with myelofibrosis and previously untreated MDS with anemia and/or thrombocytopenia to further evaluate the potential for hematological improvement in response to obatoclax.