Results from the Phase I Portion of a Phase I/II Study of ATN-224 and Bortezomib for Patients with Multiple Myeloma Relapsed from or Refractory to Bortezomib

ATN-224 (bis-choline tetrathiomolybdate) is an orally-available small molecule that is currently being studied in several phase II oncology clinical trials. ATN-224 inhibits copper-zinc superoxide dismutase (Cu/Zn-SOD; SOD1) in endothelial and tumor cells. SOD1 is an enzyme that mediates signaling by a number of mitogens including VEGF, FGF-2, EGF, IGF-1 and PDGF. The inhibition of SOD1 by ATN-224 leads to the inhibition of proliferation in endothelial cells and the induction of apoptosis in tumor cells. In a preclinical mouse model using multiple myeloma (MM) cells obtained from a patient that was refractory to bortezomib, the combination of ATN-224 and bortezomib was more effective than either agent alone and led to tumor regression. Based on this data, a phase I/II clinical study evaluating the combination of ATN-224 and bortezomib for MM patients that had previously failed bortezomib was initiated. The phase I portion of this study evaluated the safety of several doses of both ATN-224 and bortezomib and established a recommended dose and schedule of this combination for the phase II portion of the study. The phase I study has completed enrollment and results are presented here. Patients with recurrent or refractory MM that had previously failed bortezomib and currently showing evidence of disease progression were enrolled. Patients had adequate ECOG performance status (PS 0–2) and hematologic and organ function. Patients were monitored for safety and preliminary evidence of efficacy. Blood samples were collected at specific intervals for pharmacokinetic and pharmacodynamic analyses. Twenty-one patients (62% male), aged 46–80 (mean 66) with PS 0–1 were enrolled into 6 cohorts. Dose Limiting Toxicity (DLT) was defined as grade 3 or 4 neutropenia with neutropenic fever, grade 4 neutropenia, grade 3 or 4 thrombocytopenia, grade 2 peripheral neuropathy with pain, grade 3 or 4 neuropathic pain and/or peripheral sensory neuropathy, grade 4 anemia or a fall in hemoglobin by >3 g/dL when day 1 hemoglobin is ≥11 g/dL or >2 g/dL when day 1 hemoglobin is <11 g/dL over a 28-day interval, or any grade 3 or 4 non-hematologic treatment-related toxicity (excluding alopecia) that cannot be reduced to grade 2 or less with symptomatic therapy within 7 days. In the initial 3 cohorts of the trial (n=10), ATN-224 was administered at doses of either 240, 180, or 210 mg daily in combination with bortezomib at a dose of 0.7 mg/m²/dose on days 1, 4, 8 and 11 of a 21 day cycle. Several DLTs [hemoglobin decreased >2g/dL from baseline (n=3) and grade 3 fatigue (n=1)] were observed within the first three cohorts. After review of this data, it was determined that the more appropriate dosing schedule included a 7 day drug holiday. In cohorts 4 through 6 (n=11), ATN-224 was administered at doses of either 180 or 210 mg daily for 21 days in combination with bortezomib at a dose of either 1.0 or 1.3 mg/m²/dose on days 8,11, 15 and 18 of a 28 day cycle. One DLT (grade 4 thrombocytopenia) was observed and occurred in the 180 mg ATN-224 plus 1.3mg/m²/dose bortezomib cohort. By incrementally increasing each dose of ATN-224 and bortezomib individually and modifying the treatment schedule, treatment-related toxicities have been minimized while maximizing the treatment doses. One patient experienced a complete response that was durable for over 10 months. The other 20 patients experienced disease progression within 90 days. A daily dose of 210 mg of ATN-224 for 21 days and a dose of bortezomib at 1.0 mg/m² on days 8, 11, 15, and 18 of a 28 day cycle was well tolerated and recommended for the phase II portion of this trial, which is now enrolling patients. The phase I portion of the study demonstrates that the combination of ATN-224 and bortezomib can be safely administered and may be an effective treatment for MM patients that are relapsed from or refractory to bortezomib.