Combination of the KSP Inhibitor ARRY-520 with Bortezomib or Revlimid Causes Sustained Tumor Regressions and Significantly Increased Time to Regrowth in Models of Multiple Myeloma.

The allosteric kinesin spindle protein (KSP) inhibitor ARRY-520 has potent antitumor activity as a single agent in xenograft models of multiple myeloma, with complete response rates as high as 100% in some models (Eur J Cancer Supp 6(12): 447, 2008). These observations led to a phase 1 clinical trial (currently in progress) in patients with advanced / refractory multiple myeloma who have failed treatment with both bortezomib and an imid. In further preclinical work, we report the activity of ARRY-520 in combination with standard agents used for the treatment of multiple myeloma, bortezomib and revlimid.

RPMI8226, JJN3 and H929 multiple myeloma tumor xenografts were grown in female SCID-beige mice by implanting 0.5 –2 × 10⁷ cells subcutaneously in the right flank. When tumors reached a volume of ∼ 150 – 250 mm³, mice were randomized into treatment groups based on tumor volume. Compounds were administered on schedules similar to those used in the clinic: bortezomib twice a week for two weeks, revlimid QD, and a single course of ARRY-520 on d1,2. ARRY-520 was formulated in normal saline and administered IP. Bortezomib was formulated following the supplier's instructions and also administered IP. Revlimid was formulated in 1% CMC / 0.5% Tween-80 and administered PO. Animal weights and tumor volumes were measured two or three times a week during the course of the experiments.

In mice bearing JJN3 or RPMI8226 xenografts, ARRY-520 administered alone was highly efficacious, with a 100% response rate (CR + PR) at doses of 12.5 to 20 mg/kg. Bortezomib administered alone at the maximum tolerated dose (MTD) of 1 mg/kg was only marginally efficacious (short term stable disease in JJN3 and H929), as was revlimid administered at 50 mg/kg (short term stable disease in RPMI8226). Because of the high initial response rate to ARRY-520 in these models, the best way to quantify the additional activity of combinations was to compare time to regrowth (time for tumor volume to return to the volume at initiation of treatment). As shown in the table, the combination of ARRY-520 with bortezomib or revlimid produced a significant increase in time to regrowth in several cases, compared to ARRY-520 alone. The additivity was schedule dependent, with greater efficacy observed when ARRY-520 was administered simulataneously with bortezomib, compared to ARRY-520 treatment before bortezomib. The activity of the ARRY-520 + bortezomib combination was specific for multiple myeloma models, as no additivity was observed in xenograft models of solid tumors (BxPC-3, LoVo, N87 and Hs294T).

Combination of ARRY-520 with either bortezomib or revlimid has significantly greater activity than the single agents in xenograft models of multiple myeloma, suggesting these as rational combinations for evaluation in clinical trials.

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