MONALEESASIA is an ongoing Phase Ib dose-escalation/-expansion study evaluating RIB + LET in a subset of Asian pts from Hong Kong and Singapore with HR+, HER2–ABC.
Postmenopausal pts from Hong Kong and Singapore with HR+, HER2– ABC and no prior systemic therapy for ABC received RIB (400 or 600 mg/day; 3-weeks-on/1-week-off) + LET (2.5 mg/day; continuous). Dose escalation used a Bayesian Logistic Regression Model with overdose control. The primary endpoint was to determine the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D); secondary endpoints included safety and pharmacokinetic (PK) profile. Blood samples for PK non-compartmental analysis were collected on Days 1 and 21 of Cycle 1 from pre-dose to 24 h post-dose.
At data cut-off (Jan 16, 2017), 26 pts were enrolled (RIB 400 mg: n = 6; 600 mg: n = 20). One dose-limiting toxicity was observed at 600 mg (Grade 3 increased alanine transaminase [ALT]); the MTD/RP2D was RIB 600 mg/day (3-weeks-on/1-week-off) + LET 2.5 mg/day (continuous). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 4/6 pts at 400 mg and 17/20 pts at 600 mg during the dose-escalation and -expansion parts. The most common Grade 3/4 TRAEs (≥20% in either cohort; 400 mg vs 600 mg) were decreased neutrophil count (n = 3 vs n = 7), neutropenia (n = 1 vs n = 6), increased ALT (n = 1 vs n = 4), and increased aspartate transaminase (n = 0 vs n = 4). After a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 21), absorption of both RIB and LET was rapid (Table); increases in RIB exposure were dose dependent.
The MTD/RP2D was declared as RIB 600 mg/day (3-weeks-on/1-week-off) + LET 2.5 mg/day (continuous) in Asian pts from Hong Kong and Singapore with HR+, HER2– ABC. Preliminary safety and PK data are consistent with prior observations in non-Asian pts.
CLEE011A2115C/NCT02333370.
Novartis Pharmaceuticals Corporation
Novartis Pharmaceuticals Corporation
Y-S. Yap: Received honoraria and provided consultancy for Novartis. Y. Ito: Yoshinori Ito reports grants from MSD, AstraZeneca, Novartis, Parexel, Chugai, and Lilly. O. Bornstein: Orna Bornstein is an employee of Novartis Pharmaceuticals Corporation. Y. Han: Yu Han is an employee at Novartis Pharmaceuticals Corporation. T. Samant: Tanay Samant is an employee of Novartis Pharmaceuticals Corporation and owns stocks/shares in Novartis Pharmaceuticals Corporation. X. Liu: Xiaochun Liu is an employee of Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharmaceuticals Corporation. J. Chiu: Dr. Chiu served on advisory boards for Novartis and Pfizer. Summary of RIB and LET PK profiles AUC, area under the plasma concentration-time curve; Cmax, maximum concentration; CV % geo-mean = sqrt (exp [variance for log transformed data] – 1)*100; CV, coefficient of variation; exp, experiment; geo-mean, geometric mean; sqrt, square root; T1/2, acc, effective accumulation half-life; T1/2, elimination half-life; Tmax, time to reach CmaxRIB LET Day Dose level (mg) Geo-mean Cmax (CV % geo-mean), ng/ml[n] Median Tmax (range), h[n] Geo-mean AUC0–24h (CV % geo-mean), h*ng/ml[n] Geo-mean T1/2, acc(CV % geo-mean), h[n] Geo-mean Cmax(CV % geo-mean), ng/ml[n] Median Tmax (range), h[n] Geo-mean AUC0–24hCV % geo-mean), h*ng/ml[n] Geo-mean T1/2, acc(CV % geo-mean), h[n] RIB LET Cycle 1 Day 1 400 (n = 6) 2.5 802.0 (27.7) [6] 1.02 (0.50–4.00) [6] 7540.0 (25.2) [6] Not reported 30.0 (30.4) [6] 2.02 (0.50–4.03) [6] 479.0 (13.0) [6] Not reported 600 (n = 20) 2.5 1120.0 (45.5) [20] 2.15 (1.00–6.08) [20] 12,100.0 (39.5) [20] Not reported 38.5 (82.8) [20] 2.00 (0.50–8.05) [20] 629.0 (96.7) [20] Not reported Cycle 1 Day 21 400 (n = 6) 2.5 1390.0 (0.5) [2] 1.50 (1.00–2.00) [2] 15,400.0 (31.1) [2] 25.1 (10.6) [2] 170.0 (21.4) [2] 1.00 (1.00–1.00) [2] 3320.0 (28.0) [2] 97.9 (25.2) [2] 600 (n = 20) 2.5 1620.0 (15.0) [6] 2.26 (2.00–4.00) [6] 21,500.0 (21.0) [6] 22.9 (34.8) [6] 117.0 (31.0) [11] 1.00 (0.50–7.88) [11] 2330.0 (33.0) [11] 50.6 (105.4) [11]