MONALEESASIA (NCT02333370) is an ongoing Phase Ib dose-escalation (RIB + letrozole [LET]) and dose-expansion (RIB + LET, fulvestrant [FUL], or tamoxifen [TAM]) study in Asian patients (pts) with HR+, HER2– ABC; here we present results from Japanese pts.
In the dose escalation, postmenopausal pts (no prior therapy for ABC) received RIB (starting dose 400 mg/day [d]; 3 weeks on/1 week off) + LET (2.5 mg/d). In the dose expansion, pre- and postmenopausal pts (≤1 line of any prior therapy for ABC) received RIB (at the recommended Phase II dose [RP2D]) + LET (2.5 mg/d), FUL (500 mg, d1 and 15 of Cycle 1, then every 28 d), or TAM (20 mg/d) + goserelin (3.6 mg every 28 d; premenopausal pts only). Primary objectives: dose escalation = maximum tolerated dose (MTD) and/or RP2D of RIB + LET; dose expansion = safety of RIB (at the RP2D) + ET. Secondary objectives: antitumor activity, pharmacokinetics.
As of Mar 2, 2018, 59 Japanese pts out of 88 Asian pts were enrolled into 4 cohorts (Table). Two dose-limiting toxicities occurred (RIB 400 mg; increased aspartate aminotransferase [n = 1]; increased blood creatinine [n = 1]); MTD = RIB 400 mg + LET; RP2D = RIB 300 mg + LET. Median duration of RIB exposure was higher in the LET vs TAM/FUL cohorts (Table). See table for all-causality Grade 3/4 adverse events ≥10% (in any cohort). New Fridericia’s corrected QT interval (QTcF) >480 ms occurred in 0/5, 2/22, 2/15, and 0/16 pts in the RIB 400 mg + LET, RIB 300 mg + LET, RIB 300 mg + TAM, and RIB 300 mg + FUL cohorts; no QTcF >500 ms occurred. Preliminary efficacy was observed in all cohorts (Table). At steady state, RIB was rapidly absorbed in all cohorts; RIB 300 mg exposure was comparable between the LET and FUL cohorts and lower in the TAM cohort (Table).Table: 42P
|RIB 400 mg + LET 2.5 mg (escalation)||RIB 300 mg + LET 2.5 mg (escalation/expansion)||RIB 300 mg + TAM 20 mg (expansion)||RIB 300 mg + FUL 500 mg (expansion)|
|Median duration offollow-up, months||21.6||13.8||12.9||10.1|
|Treatment ongoing, n (%)||1 (16.7)||14 (63.6)||8 (53.3)||7 (43.8)|
|Primary reason for discontinuation, n (%)|
|Disease progression||5 (83.3)||6 (27.3)||4 (26.7)||9 (56.3)|
|Median duration of exposure to RIB, months (range)||19.1 (0–34)||14.2 (0–27)||12.5 (0–17)||10.2 (1–16)|
|Most common (≥10% in any cohort) all-causality Grade 3/4 adverse events, n (%)|
|Neutropenia||5 (83.3)||13 (59.1)||6 (40.0)||9 (56.3)|
|Leukopenia||2 (33.3)||3 (13.6)||2 (13.3)||3 (18.8)|
|Increased ALT||2 (33.3)||2 (9.1)||4 (26.7)||3 (18.8)|
|Increased AST||1 (16.7)||0||1 (6.7)||0|
|Increased lipase||1 (16.7)||2 (9.1)||1 (6.7)||1 (6.3)|
|Abnormal hepatic function||1 (16.7)||1 (4.5)||0||0|
|Preliminary efficacy data,* %|
|RIB pharmacokinetic parameters at Cycle 1 Day 21|
|Geo-mean Cmax (CV% geo-mean§), ng/ml [n]||1150.0 (6.7) ||804.0 (42.0) ||428.0 (48.2) ||708.0 (67.7) |
|Median Tmax (range), h [n]||2.03 (2.02–6.00) ||3.92 (1.97–5.92) ||3.98 (1.88–4.10) ||2.99 (0.98–4.13) |
|Geo-mean AUC0–24h (CV% geo-mean§), hr•ng/ml [n]||14600 (25.3) ||10600 (37.8) ||5450 (42.9) ||9060 (58.9) |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC0–24h, area under the plasma concentration-time curve from 0 to 24 hours; CBR, clinical benefit rate; Cmax, maximum concentration; CV, coefficient of variation; geo-mean, geometric mean;
ORR, overall response rate; Tmax, time to reach Cmax.*
Pts with measurable disease (n = 54).†
ORR = complete response + partial response.‡
CBR = complete response + partial response + (stable disease + non-complete response/non-progressive disease ≥24 weeks).§
CV% geo-mean = sqrt (exp [variance for log transformed data] – 1)*100.
In Japanese pts with HR+, HER2– ABC, the MTD of RIB was 400 mg and the RP2D was 300 mg. Preliminary safety and efficacy data are consistent with observations in non-Japanese pts.
Editorial assistance was provided by Claire Wilson PhD of ArticulateScience Ltd.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharmaceutical Corporation.
Novartis Pharmaceutical Corporation.
N. Masuda: Personal fees: Chugai, AstraZeneca, Pfizer, Kyowa-Kirin, Eisai, Takeda and Eli-Lilly, outside the submitted work. S. Noguchi: Grants: Novartis, AstraZeneca, Chugai; Other: Eisai, Takeda, Daiichi-Sankyo; Grants: Sysmex; Other: Kyowa Kirin, Fuji Film; Grants: Pfizer, outside the submitted work. S.J. Kim: Personal fees: Novartis, outside the submitted work. T. Toyama: Grants: Novartis Pharma, Eisai Co, Ltd, Chugai Pharmaceutical Co, Ltd, Nippon Kayaku Co, Ltd, Pfizer Japan Inc, Kyowa Hakko Kirin Co, Ltd, Taiho Pharma, Daiichi Sankyo Co, Ltd, Takeda Pharmaceutical Co, Ltd. T. Saeki: AstraZeneca, Eisai, Ono, Kyowa Hakko Kirin Taiho, Chugai, Nippon Kayaku, Hamamatsu photonics, Novartis, Global Software. T. Yamanaka: Personal fees: Novartis, Chugai, Pfizer, Taiho, outside the submitted work. J. Watanabe: Personal fees: Novartis Pharma, outside the submitted work. S. Nakamura: Research Funding AstraZeneca, Chugai Pharmaceutical Co., Daiichi Sankyo Co., Eisai Co., Ltd., Kyowa Hakko Kirin, Novartis Pharma KK, Pfizer Japan Inc., Taiho Pharmaceutical, Takeda Pharmaceutical Co; Personal fee (honoraria): AstraZeneca, Chugai Pharmaceutical Co., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Novartis Pharma KK, Pfizer Japan Inc., Taiho Pharmaceutical, Takeda Pharmaceutical Co. K. Inoue: Novartis, Pfizer, Chugai, DaiichiSankyo, Parexel / Puma Biotechnology, MSD, Bayer, Lilly, Esai. I. Gounaris: Employment: Novartis. Y. Han: Employee, stockholder: Novartis. T.S. Samant, M. Gazdoiu: Employee: Novartis. Y. Ito: Grants: Daiichi Sankyo, Chugai, Novartis, Parexel, EPS, MSD, AstraZeneca, Lilly, Kyowa Hakko Kirin, Covance, Taiho, A2 Healthcare. All other authors have declared no conflicts of interest.