A Phase I Study of An Oral Hedgehog Pathway Antagonist, BMS-833923, in Patients with Relapsed or Refractory Multiple Myeloma,

Aberrant hedgehog (HH) pathway signaling has been suggested to play a role in the development and progression of multiple myeloma (MM). BMS-833923 is a oral, small molecule antagonist of the HH signaling component Smoothened (SMO).

The trial is designed to identify a maximum tolerated dose (MTD) and evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-833923 administered in escalating dose cohorts as monotherapy or in combination with lenalidomide plus dexamethasone or with bortezomib in subjects with relapsed or refractory MM. The study consists of three treatment arms: i) BMS-833923 alone; ii) BMS-833923 in combination with lenalidomide (25 mg daily [QD] for 21 days of a 28 day cycle) plus dexamethasone (40 mg once weekly); and iii) BMS-833923 in combination with bortezomib (1.3 mg/m²on Days 1, 4, 8, and 11 for a 21 day cycle). A 3-plus-3 design was followed using drug related CTCAEs (v3.0) to inform dose escalation increments. In the first two dose cohorts of the single agent arm, a loading dose was employed during the first week of dosing, followed by a continuation dose. The starting dose was 60 mg QD for 7 days followed by a 30 mg QD continuation dose. Patients who developed progressive disease after 2 cycles or had stable disease after 3 cycles could add on either lenalidomide plus dexamethasone or bortezomib, which allowed for the exploration of the effect of the standard of care agents on BMS-833923 exposures, safety in combination, and clinical activity. The PK parameters of BMS-883923 co-administered with lenalidomide/dexamethasone or bortezomib was evaluated using noncompartmental PK analysis.

As of June 20, 2011, 19 patients have been treated at six dose levels in the single agent arm: 60/30 mg (n=3), 120/60 mg (n=3), 90 mg (n=5), 135 mg (n=3), 270 mg (n=3), and 500 mg (n=2); 6 of these patients added lenalidomide plus dexamethasone and 4 patients added bortezomib; and 1 patient has been treated in the combination arm with 90 mg QD of BMS-833923 plus lenalidomide and dexamethasone. This dose range includes dose levels of BMS-833923 with demonstrated anti-tumor activity in patients with advanced or metastatic basal cell carcinoma. In the current study, treated patients had a median age of 62 (range 41–71) and ECOG performance status of 0–2. No DLTs have been observed. The most common drug related AEs (>10%) include muscle spasms, dysgeusia, ageusia, lipase increased, alopecia, decreased appetite, nausea, and fatigue. All the common AEs (> 10%) were Grade 1 or 2 with the exception of a Grade 3 muscle spasms and Grade 3 elevated lipase. Other drug related Grade 3 AEs included thrombocytopenia, sinusitis, streptococal bacteraemia, and otitis media. In the single agent treatment arm, for patients that did not add on standard of care therapies, the median duration of treatment with BMS-833923 was 31 days (range 10–49 days). Median duration of BMS-833923 single agent treatment for patients that added on standard therapy was 90 days (42–175 days). Preliminary analysis of BMS-833923 exposures determined that the geometric mean Cmax ratio of BMS-833923 (dose range of 30 mg/day to 135 mg/day) with or without lenalidomide and dexamethasone was 0.99 (n=4). Similarly, the geometric mean Cmax ratio of 135 mg/day BMS-833923 with or without bortezomib was 0.92 (n=2). Clinical response data is being collected and will be presented.

BMS-833923 is generally tolerated at the dose levels tested.

Huff:Bristol-Myers Squibb: Honoraria, Research Funding. Padmanabhan:Bristol-Myers Squibb: Research Funding. Somlo:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zonder:Bristol-Myers Squibb: Research Funding. Fischer:Bristol-Myers Squibb: Employment. Lang:Bristol-Myers Squibb: Employment. Zhang:Bristol-Myers Squibb: Employment. Gestone:Bristol-Myers Squibb: Employment. Bennett:Bristol-Myers Squibb: Employment.