Evaluation of a spray-dried dispersion (SDD) formulation of MGCD265, a receptor tyrosine kinase (RTK) inhibitor, in a phase 1 study of patients (pts) with advanced solid tumors

Background: MGCD265 is an ATP-competitive inhibitor of MET and Axl RTKs and has demonstrated anti-tumor activity in xenograft cancer models of MET or Axl dysregulation and in Phase 1 clinical trial pts selected for these alterations. Methods: Study objectives were to evaluate the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), safety, PK, PD, and clinical activity of MGCD265. Eligible pts received MGCD265 on Cycle 1 Day 1 and initiated continuous dosing on Cycle 1 Day 3 in 21-day cycles. PK/PD were evaluated after single and repeated dose administration. Results: 18 pts received MGCD265 - 12 in softgel capsules and 6 in SDD tablets. With softgel capsules the MTD was established at 1050 mg BID; treatmentrelated AEs ( > 20% all grades) included diarrhea, nausea, vomiting, fatigue, AST increase, ALT increase and lipase increase. With 500 mg SDD, exposures partially overlapped those observed with 1050 mg softgel capsules. 1 of 6 SDD pts experienced a doselimiting toxicity (DLT) of Gr 3 transaminase increase without clinical symptoms. Treatmentrelated AEs reported in > 20% of pts included Gr 12 diarrhea and Gr 2 fatigue, with fewer patients treated for diarrhea. Dose escalation of SDD is ongoing at 1000 mg BID. The rates of absorption and elimination of the two formulations were comparable with a median tmax of 8 hrs and an average t1/2 of 40 ± 17 hrs for SDD versus 35 ± 12 hrs for softgel capsules. The extent of absorption was 1.8 times greater with SDD tablets. The observed Cave,ss and AUC0-12,ss were 480 ng/mL and 5757 ng h/mL with 500 mg BID of SDD tablets and 561 ng/mL and 6731 ng h/mL with 1050 mg BID of softgel capsules, respectively. Conclusions: The SDD tablet formulation of MGCD265 shows similar PK characteristics as the softgel capsule formulation but with greater bioavailability, thus reducing the pill burden, and a more favorable safety profile to date. Expansion cohorts of softgel capsules demonstrating antitumor activity in pts with NSCLC with genetic alterations for MET and AXL are ongoing and may include evaluation of the SDD formulation as emerging data confirm similar or greater exposure and a better safety profile.