non-Japanese Pts Research Articles

Safety, PK and preliminary efficacy of talazoparib in Japanese patients with advanced solid tumors; Phase 1 Study

Abstract Background Talazoparib is a potent, orally bioavailable, small molecule poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. The recommended dose (RD) of single-agent talazoparib in non-Japanese patients (pts) was determined as 1 mg/day [QD]. This ongoing Phase 1 study evaluated the safety, preliminary efficacy, and PK profile of single-agent talazoparib in Japanese pts with advanced solid tumors. Methods Primary endpoint was first-cycle dose limiting toxicity (DLT). The single dose and multiple-dose PK and anti-tumor activity were evaluated as secondary endpoints. Two dose levels (0.75 mg and 1 mg QD) of talazoparib were studied using modified 3 + 3 dose escalation scheme. Talazoparib was administered continuously with the cycle length of 28 days. Results A total of 9 pts (3 pts in 0.75 mg and 6 pts in 1 mg QD) with a variety of tumor types were enrolled. No DLT was reported in either dose levels. The most common treatment-related (TR) adverse events (AEs) were neutrophil count decreased, platelet count decreased and stomatitis (22.2%, 2 pts each). No grade 3 or more TRAEs were reported. Based on the preliminary PK analysis, the median time to reach maximum plasma concentration (Tmax) was ranging from 1.0 to 2.0 hours. Talazoparib was eliminated with terminal phase half-life ranging from 49 to 133 hours after single dose. The distributions of maximum plasma concentration (Cmax) and area under concentration-time curve (AUC) after single and multiple dose were within the range of those in non-Japanese pts. RD in Japanese pts was determined to be 1 mg QD. Conclusions No DLT was reported in Japanese pts who received up to 1 mg QD. Hematological toxicity was common AEs in Japanese pts as well as non-Japanese pts. RD in Japanese pts was determined as 1 mg QD. The PK profile in Japanese pts was comparable with that in non-Japanese pts. Now the study is expanding to evaluate the efficacy in Japanese pts with germline BRCA mutated advanced breast cancer.

Population PK/PD Analysis of Necitumumab: Dose justification for Squamous Cell Lung Cancer (SqCLC) Patients in Japan

Abstract Background Necitumumab (NEC) in combination with gemcitabine+cisplatin (GC) demonstrated significant improvement in overall survival (OS) compared to GC in advanced SqCLC patients (pts) in Global Ph3 study JFCC. In Study JFCM Ph2 part, NEC in combination with GC improved OS compared to GC in SqCLC pts in Japan. Population PK/PD analysis including Study JFCM was conducted to determine the adequacy of the dose in pts in Japan based on NEC PK, and relationship between exposure and efficacy and safety. Methods Two studies, one of which Study JFCM, were added into the analysis previously performed with five Ph 1, 2, and 3 studies. The effect of Japan/non-Japan origin on NEC PK was assessed. Simulations were performed to compare predicted NEC serum concentrations after flat 800 mg and body weight based dosing. The relationship between exposure and OS in Studies JFCC and JFCM Ph2 part was explored. The relationship between exposure and safety measurements (hypomagnesemia, rash and thromboembolic events) in Studies JFCC and JFCM Ph2 part was explored. Results Population PK analysis included blood samples collected from 967 pts (including 114 pts in Japan) treated with NEC. PK parameters were similar between Japanese and non-Japanese pts. NEC PK is dependent on body weight; however, simulations indicated weight-based dosing would not significantly decrease PK variability. Exposure-response analysis included 1195 pts, including 181 pts in Japan. Exposure-efficacy analysis suggested that pts with higher NEC concentration had longer OS, however, majority of pts in both studies had steady state exposure greater than EC80. No correlation was observed between NEC serum exposure and severity of hypomagnesemia or rash. No correlation was observed between NEC serum exposure and risk of treatment emergent thromboembolic events. Conclusion Population PK/PD analysis supports the administration of 800 mg NEC on Day 1 and 8 of a 21-day cycle as an appropriate dose in SqCLC pts in Japan.

Abstract CT143: Baseline circulating tumor DNA (ctDNA) analysis in Asian women with HR+/HER2- advanced breast cancer (ABC) receiving ribociclib + endocrine therapy in the Phase Ib MONALEESASIA trial

Abstract Background: MONALEESASIA (NCT02333370) is an ongoing Phase Ib study in which Asian patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC are treated with ribociclib (a cyclin-dependent kinase 4/6 inhibitor) and either letrozole (all pts), fulvestrant, or tamoxifen (Japanese pts). Tumor biomarker analysis in MONALEESASIA using NanoString technology for gene expression was presented previously (Yap YS, et al. ESMO Asia 2018 [Abstract 400]). Here we report additional biomarker analysis of baseline ctDNA. Methods: Plasma samples were collected at baseline and end of treatment; ctDNA was extracted and used to generate next-generation sequencing libraries. The DNA libraries were then enriched for a specific 2.9 Mb of the human genome containing ≈550 oncogenes and tumor suppressor genes. Captured libraries were then combined in equimolar pools and sequenced, targeting ≥70 million sequencing reads per sample to ensure that unique coverage of the genes was >1000× or approached the maximal complexity of the library. Results: ctDNA was analyzed in baseline plasma samples collected from 77 pts (49 Japanese and 28 non-Japanese). Similar gene alteration frequencies were observed in Japanese and non-Japanese pts except for ESR1 alterations, which were more common in Japanese pts (Table). TP53 alterations were more common in pts with progressive disease, and the frequencies of TP53, ESR1, and FAT1 were slightly lower in pre- vs postmenopausal pts; however, these differences were not statistically significant. Response rates by genetic alteration are shown in the table. Conclusion: There appeared to be a trend toward a higher likelihood of alterations in TP53 and PIK3CA in pts with poorer responses, although the sample size was small. These data are hypothesis generating, and additional analysis is ongoing. Gene AlterationsPIK3CATP53CCND1FAT1ESR1FGFR1CDH1Frequency, n (%)Japanesen=4917 (35)11 (22)5 (10)3 (6)7 (14)5 (10)4 (8)Non-Japanesen=288 (29)7 (25)3 (11)5 (18)02 (7)0Best Overall Response, n of Patients with Alteration (% Response Type)PRn=359 (26)6 (17)5 (14)3 (9)2 (6)4 (11)0SDn=299 (31)7 (24)1 (3)3 (10)3 (10)03 (10)NCRNPDn=63 (50)1 (17)002 (33)1 (17)1 (17)PDn=74 (57)4 (57)2 (29)2 (29)02 (29)0CCND1, cyclin D1; CDH1, cadherin 1; ESR1, estrogen receptor 1; FAT1, FAT atypical cadherin 1; FGFR1, fibroblast growth factor receptor 1; NCRNPD, not complete response nor progressive disease; PD, progressive disease; PIK3CA, phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit α; PR, partial response; SD, stable disease; TP53, tumor protein p53. Citation Format: Yoon-Sim Yap, Faye Su, Nadia Solovieff, Yoshinori Ito, Norikaza Masuda, Takashi Ishikawa, Tomoyuki Aruga, Seung Jin Kim, Wei He, Mihaela Gazdoiu, Joanne Chiu. Baseline circulating tumor DNA (ctDNA) analysis in Asian women with HR+/HER2- advanced breast cancer (ABC) receiving ribociclib + endocrine therapy in the Phase Ib MONALEESASIA trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT143.

Phase I study on preliminary safety and efficacy of rovalpituzumab tesirine in Japanese patients (pts) with advanced, recurrent small cell lung cancer (SCLC).

8557 Background: SCLC rapidly recurs after first-line platinum therapy, and while several agents are approved in the relapsed/refractory setting, there is no approved agent or existing standard of care for third-line in Japan. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting Delta-like 3 protein (DLL3), an atypical Notch ligand that is highly expressed in SCLC but not in normal tissue. This was the first study evaluating safety, PK, and preliminary anti-tumor activity of Rova-T in Japanese pts. Methods: This was an open label Phase 1, 3+3 dose-escalation study of Rova-T in Japanese pts with advanced recurrent SCLC (NCT03086239). Eligibility: progressive disease after ≥2 prior systemic regimens incl. ≥1 platinum-based regimen; ECOG 0-1. Pts received 0.2 or 0.3 mg/kg Rova-T IV on Day 1 of a 6-week cycle for 2 cycles. Objective was to evaluate safety, tolerability, PK, and preliminary efficacy and expression of DLL3. Antitumor activity was measured by RECISTv1.1, and DOR, PFS, OS were evaluated. Results: 29 pts were treated with Rova-T (6 at 0.2mg/kg, 23 at 0.3 mg/kg). Median age 68 yrs; 76% male; 64% DLL3 high (≥75% expression); 86% DLL3 positive (≥25%). 20 pts (69%) had received ≥3 prior lines of therapy. Similar PK and AEs were seen compared to previous studies in non-Japanese pts. The most frequently reported study drug-related AEs were platelet count decreased, pleural effusion, oedema peripheral, and aspartate aminotransferase increased, the majority Grade 1/2. No DLTs occurred, and both dose levels were tolerated. Three pts previously treated with ≥3 prior lines of therapy had confirmed partial response by investigator (10% of all pts; 17% of DLL3 high pts). For DLL3 high pts, mDOR was 3.0 mos (95% CI: 2.9, 4.1), mPFS was 2.9 mos (1.2-3.6), and mOS was 7.4 mos (4.1-11.9). Individual responses were analyzed in detail and radiographic data with tumor shrinkage will be shown. Conclusions: Rova-T demonstrated a manageable safety profile with promising preliminary efficacy in Japanese SCLC pts, in particular pts with DLL3 high expression. These data support further exploration of Rova-T treatment in Japanese pts with SCLC in global Phase 3 studies. Clinical trial information: NCT03086239.

Dapagliflozin Exposure Response in Japanese vs. Non-Japanese Patients with Type 1 Diabetes

Dapagliflozin (DAPA), an SGLT2 inhibitor, reduces blood glucose by increasing urinary glucose excretion (UGE). The pharmacokinetics and pharmacodynamics of DAPA in Japanese and non-Japanese patients (pts) with type 1 diabetes (T1D) have been evaluated in 2 studies (Japanese: NCT01498185, n=42, DAPA 5, 10 mg or placebo [PBO] for 14 days; Non-Japanese: NCT02582814, n=70, DAPA, 1, 2.5, 5, 10 mg or PBO for 7 days). A clear dose-response for 24-hour UGE was seen in the non-Japanese study but not in the Japanese study. An exposure-response model was used to characterize the relationship between DAPA exposure and 24-hour UGE using a nonlinear mixed-effect modeling approach, and the effect of patient-level characteristics (baseline and Day 7) on this was investigated. Covariates were identified using a stepwise procedure. Average self-monitored blood glucose (SMBG) at Day 7, Day 7 change from baseline in total insulin dose, and baseline eGFR all had a significant effect on UGE; SMBG was the most influential. When these covariates are included, the model fits the data well for both populations (Figure; for the Japanese study, 1 and 2.5 mg data were simulated using median AUC from non-Japanese pts, for 5 and 10 mg median covariate values were from the Japanese study). The lack of clear dose-response in UGE in Japanese pts may primarily be caused by high SMBG, which is likely a result of greater insulin dose reductions in the Japanese study. Disclosure V. Sokolov: None. T. Yakovleva: None. S. Ueda: Employee; Self; AstraZeneca. J.R. Parkinson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Novartis Pharmaceuticals Corporation. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. W. Tang: Employee; Self; AstraZeneca.

Abstract P5-21-28: Phase Ib study of ribociclib + letrozole in Asian non-Japanese patients with hormone receptor-positive, HER2-negative advanced breast cancer: MONALEESASIA

Abstract Background: First-line ribociclib (RIB; a selective cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) significantly prolonged progression-free survival vs placebo + LET in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). The Phase Ib MONALEESASIA dose-escalation/-expansion study (NCT02333370) is investigating RIB + LET in Asian pts with HR+, HER2– ABC; here we report results in Asian non-Japanese pts. Methods: Asian, non-Japanese postmenopausal women with HR+, HER2– ABC, with no prior systemic treatment for ABC, received RIB (starting dose 400 mg/day; 3-weeks-on/1-week-off; option to escalate or de-escalate) + LET (2.5 mg/day; continuous) until disease progression or discontinuation for other reasons. Dose escalation was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control. The primary objective of the dose-escalation part was to estimate the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D), based on the BLRM, safety data, and pharmacokinetic analyses; secondary/exploratory objectives included safety and tolerability, and antitumor activity. Results: At data cut-off (January 16, 2017), 26 pts were enrolled; 13 in the dose escalation (RIB 400 mg: n=6; RIB 600 mg: n=7) and 13 in the 600 mg dose expansion. Treatment was ongoing in 18 pts (69%; 400 mg: n=3; 600 mg: n=15); the most common reason for discontinuation was disease progression (400 mg: n=3; 600 mg: n=4). One dose-limiting toxicity occurred at 600 mg (Grade 3 increased alanine transaminase [ALT]). The MTD/RP2D was declared as 600 mg/day RIB (3-weeks-on/1-week-off) + 2.5 mg/day LET (continuous). The most common all-grade, all-cause adverse events (AEs; ≥35% in either cohort; 400 mg vs 600 mg) were neutropenia (n=1 [17%] vs n=8 [40%]), increased ALT (n=1 [17%] vs n=7 [35%]), decreased neutrophil count (n=3 [50%] vs n=7 [35%]), and alopecia (n=3 [50%] vs n=2 [10%]). All-cause Grade 3/4 AEs occurred in 4 pts (67%) at 400 mg and 18 pts (90%) at 600 mg; the most common (≥25% in either cohort; 400 mg vs 600 mg) were decreased neutrophil count (n=3 [50%] vs n=7 [35%]) and neutropenia (n=1 [17%] vs n=6 [30%]). At least one RIB dose reduction due to AEs occurred in 2 pts at 400 mg and 10 pts at 600 mg. At least one RIB dose interruption due to AEs occurred in 4 pts at 400 mg and 13 pts at 600 mg. Post-baseline QTcF >480 ms occurred in 0 pts at 400 mg and 4 pts (20%) at 600 mg. No pt had a post-baseline QTcF >500 ms. The overall response rate was 50% (n=3) at 400 mg and 35% (n=7) at 600 mg (all partial responses). Stable disease was reported in 1 pt (17%) at 400 mg and 8 pts (40%) at 600 mg. Conclusions: RIB + LET demonstrated a manageable safety profile with preliminary signs of antitumor activity in Asian non-Japanese pts with HR+, HER2– ABC; the safety profile was broadly consistent with that seen in non-Asian pts. The MTD/RP2D was declared as 600 mg/day RIB (3-weeks-on/1-week-off) + 2.5 mg/day LET (continuous). Further safety and efficacy data for RIB + LET will be reported in this pt population after the dose expansion is completed. Citation Format: Yap YS, Ito Y, Suarez-Vizcarra J, Liu X, Han Y, Germa C, Chiu J. Phase Ib study of ribociclib + letrozole in Asian non-Japanese patients with hormone receptor-positive, HER2-negative advanced breast cancer: MONALEESASIA [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-28.

O3-5-1 - Phase I trial of pimasertib monotherapy in Japanese patients with solid tumors or hepatocellular carcinoma

Background: MAPK signalling is dysregulated in many human cancers. Pimasertib (Pim) is a selective MEK 1/2 inhibitor that has shown antitumor activity in preclinical studies. In non-Japanese patients (pts) with solid tumors (ST) the recommended phase II dose (RP2D) of Pim is 60 mg BID. Methods: Two-part, phase I dose-escalation and expansion study conducted in Japanese pts (≥18 years old) with advanced ST or hepatocellular carcinoma (HCC). Part 1: pts with ST (arm A) or HCC (arm B) received escalating doses (3 + 3 design) of oral Pim 45–60 mg BID in 21-day cycles, until disease progression or unacceptable toxicity (if 45 mg not tolerated, a 30 mg dose level was applied) to obtain the maximum tolerated dose (MTD) and confirm the global R2PD for Pim in Japanese pts. Part 2: expansion of both arms to investigate safety and preliminary efficacy in pts with ST and HCC. Results: In total, 26 pts (ST, 19; HCC, 7) were treated with Pim at doses of 30 mg (ST, 4; HCC, 5), 45 mg (ST, 9; HCC, 2), and 60 mg (ST, 6). Three dose-limiting toxicities (DLTs; stomatitis, hypokalemia and muscle weakness) occurred at Pim 60 mg in two pts with ST (2/3 pts). One DLT was reported at 45 mg (1/1 pt; diarrhea) and then at 30 mg (1/3 pts; retinal detachment) in pts with HCC. The MTD of Pim was 45 mg for ST, but was not established for HCC. All 26 pts had at least one treatment-related adverse event (AE); the most common were retinal detachment (ST, 74%; HCC, 57%), blood creatinine phosphokinase increase (ST, 79%; HCC, 29%) and diarrhea (ST, 42%; HCC, 57%). Partial response and stable disease were seen only in pts with ST (Pim 45 mg: n = 3 and 1, respectively). Conclusion: In Japanese pts with advanced ST, DLTs and the MTD observed occurred at lower doses of Pim than in non-Japanese pts with ST; due to a DLT at the lowest Pim dose the MTD could not be established in pts with HCC. Pim monotherapy did not warrant further investigation and the study was terminated early.

Abstract P3-14-10: Phase Ia/Ib study of taselisib (GDC-0032), a potent and selective phosphoinositide 3-kinase inhibitor, in Japanese patients with advanced solid tumors or hormone receptor-positive locally advanced or metastatic breast cancer (JO29196 study)

Abstract Background: Taselisib (GDC-0032) is an orally bioavailable, potent and selective phosphoinositide 3-kinase (PI3K) inhibitor. Preclinical data showed that taselisib had increased antitumor activity against PIK3CA (gene encoding the PI3Kα isoform) mutant tumors. This study aimed to investigate the safety, tolerability and pharmacokinetics (PK) of taselisib as monotherapy and in combination with fulvestrant in Japanese patients (pts). Materials and methods: A 3+3 design was used. In Phase Ia, pts with advanced solid tumors received taselisib tablet monotherapy (2, 4 or 6 mg once daily [QD]), and safety and PK were evaluated. In Phase Ib, pts with hormone receptor-positive locally advanced or metastatic breast cancer received taselisib (2 or 4 mg QD) in combination with fulvestrant (500 mg at a time), and safety and PK were evaluated. Maximal administered doses of 6 mg QD as a single agent and 4 mg QD in combination with fulvestrant were based upon prior clinical trial experience with taselisib (Juric D. et al. AACR 2013, Abstract LB-64; Juric D. et al. SABCS 2013, Abstract PD1-3). Results: As of 15 Mar 2015, 9 pts (PIK3CA mutant: 2 pts) were enrolled in Phase Ia and 3 pts in Phase Ib. Phase Ia dose-escalation study has been completed and Phase Ib is ongoing. In Phase Ia, no dose-limiting toxicity (DLT) was observed at any dose level tested (maximum administered dose of 6 mg QD). Common (≥3 pts) adverse reactions (ARs) were stomatitis (4 pts), rash (3 pts) and diarrhea (3 pts); the only Grade ≥3 AR was neutropenia (1 pt). Partial response was observed in 1 pt who received taselisib 4 mg and had a PIK3CA mutant breast tumor. Stable disease was observed in 4 pts. Cmax and AUC indicated a dose-proportional PK profile of taselisib within the dose range tested. Moreover, taselisib PK in Japanese pts was consistent with the PK reported from North American and European pts (Juric D. et al. AACR 2013, Abstract LB-64). In Phase Ib, 3 pts received taselisib 2 mg in combination with fulvestrant and no DLT was observed. Preliminary ARs were similar to those with monotherapy and no Grade ≥3 AR was reported. Confirmation of tolerability of taselisib 4 mg in combination with fulvestrant is under evaluation. Conclusion: Taselisib monotherapy was well tolerated in Japanese pts up to a dose of 6 mg, which is the recommended dose in non-Japanese pts. Promising preliminary activity of monotherapy was observed in advanced solid tumors, especially in a pt with PIK3CA mutant tumor. The combination of taselisib 2 mg with fulvestrant is well tolerated. Investigation of tolerability of taselisib 4 mg in combination with fulvestrant is ongoing. Final results of this study will be presented here at the Symposium this year. Citation Format: Kobayashi T, Nakano K, Tomomatsu J, Nara E, Ito Y, Kobayashi K, Fukada I, Araki K, Shimomura A, Shimoi T, Kodaira M, Yunokawa M, Yonemori K, Shimizu C, Nakamura K, Kotani N, Inatani M, Tamura K, Takahashi S. Phase Ia/Ib study of taselisib (GDC-0032), a potent and selective phosphoinositide 3-kinase inhibitor, in Japanese patients with advanced solid tumors or hormone receptor-positive locally advanced or metastatic breast cancer (JO29196 study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-10.

Abstract B179: Final results of a phase 1 study of cabozantinib (Cabo) in Japanese patients (pts) with expansion cohorts in non-small cell lung cancer (NSCLC) with defined molecular alterations

Abstract Background: Cabo inhibits tyrosine kinases including MET, VEGF receptors, AXL, and RET. The primary objective of this phase 1 study was to establish the recommended phase 2 dose (RP2D) of Cabo in Japanese pts; secondary objectives included assessment of safety, pharmacokinetics, and preliminary evidence of anti-tumor activity. Results from the dose escalation (DE) portion of the study have been previously reported. The final results of the study are presented, including data from expansion cohorts (ECs) in NSCLC with defined molecular alterations involving known driver oncogenes. Methods: Pts with advanced solid malignancies were enrolled in successive cohorts to receive escalating doses of Cabo orally once daily in a 3+3 design using capsule or tablet formulations. The RP2D was previously determined to be 60 mg qd tablet. Based on responses observed in pts with NSCLC, 3 molecularly defined NSCLC ECs were planned at the RP2D: EC1) pts with mutant EGFR and previous treatment with an EGFR inhibitor, EC2) pts with KRAS mutations, and EC3) pts with rearranged ALK (and previous treatment with an ALK inhibitor), RET, or ROS1. Tumor assessments per RECIST were performed on study day 29, and every 8 weeks thereafter until discontinuation of study treatment. Results: Forty three total pts were enrolled. Twenty three pts were enrolled in the DE cohorts, including 9 pts with NSCLC. Twenty pts were enrolled in the NSCLC ECs: 15 pts in EC1, 2 pts in EC2, and 3 pts in EC3 (n = 1 ALK+, n = 2 RET+). The median duration of treatment was 28.1 (3-156) weeks (wks) in the DE cohorts, and 13.3 (4-49) wks in the NSCLC ECs. Grade 3-4 AEs experienced by ≥3 pts were gamma glutamyl transferase increase (n = 4), hypertension (n = 3), and lymphopenia (n = 3) in the DE cohorts, and hypertension (n = 6), neutropenia (n = 5), alanine aminotransferase increase (n = 3), hand foot syndrome (n = 3), hypophosphatemia (n = 3), and dyspnea (n = 3) in the ECs. Serious AEs in ≥3 pts were dyspnea (n = 3), lung infection/pneumonia (n = 3), and pleural effusion (n = 3). The final PK analysis demonstrated that Cabo plasma exposures in Japanese pts were approximately 34% higher than reported previously in non-Japanese pts at the 60 mg tablet dose, and were within the range of inter-subject variability (%CV: 34% Japanese; 48% non-Japanese). Objective responses were observed in NSCLC pts: 4/9 NSCLC pts enrolled in the DE cohorts had a confirmed partial response (cPR) (2 pts ALK+, 1 pt RET+, 1 pt EGFR+), and 4/20 pts enrolled in the NSCLC EC cohorts had a cPR (all 4 pts were in EC1 [EGFR+]). Best change in sum of longest diameters (SLD) for all NSCLC pts with measureable disease (n = 28) ranged from 0 - 82% decrease (median = 24% decrease). For pts with a cPR, the time to initial response ranged from 4 - 20 wks and time from response to radiographic progression ranged from 4 - 64 wks. Conclusions: The RP2D of Cabo in Japanese pts was determined to be 60 mg. The safety and pharmacokinetic profiles are consistent with data from studies in non-Japanese pts. Antitumor activity with Cabo has been observed, including in pts with molecularly-defined NSCLC. Citation Format: Hiroshi Nokihara, Makoto Nishio, Noboru Yamamoto, Yutaka Fujiwawa, Hidehito Horinouchi, Shintaro Kanda, Asushi Horiike, Fumiyoshi Ohyanagi, Yifah Yaron, Anne Borgman, Tomohide Tamura. Final results of a phase 1 study of cabozantinib (Cabo) in Japanese patients (pts) with expansion cohorts in non-small cell lung cancer (NSCLC) with defined molecular alterations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B179.

THU0149 Efficacy and Safety of Baricitinib in Japanese Rheumatoid Arthritis Patients at 12 Weeks

BackgroundBaricitinib, a novel, oral inhibitor of JAK1/JAK2 in the JAK-STAT signaling pathway, was evaluated in a blinded Phase 2b study in Japanese patients (pts) with rheumatoid arthritis (RA) with an...

1708PD - Molecular Profile and Anti-Tumor Activity in Non-Small Cell Lung Cancer (NSCLC) Patients (PTS) in a Phase 1 Study of Cabozantinib (XL184) in Japan

ABSTRACT Background Cabozantinib is a potent targeted therapy that inhibits MET, VEGFR2, and RET. Anti-tumor activity in patients (pts) has been observed in a broad range of tumors including NSCLC. The primary objective of this phase 1 study is to determine the maximum tolerated dose (MTD) / recommended phase 2 dose in Japanese pts. Methods Pts with advanced solid malignancies are enrolled in successive cohorts to receive escalating doses of cabozantinib orally once daily in a 3 + 3 trial design. Dose limiting toxicities (DLTs) are determined using Cycle 1 data. Response is assessed using modified RECIST v1.0. Results: As of 1 June 2012, 14 pts were enrolled including 5 pts with non-small cell lung adenocarcinoma. Pts have been treated at 3 dose levels: 40, 60 and 80 mg. The NSCLC pts had a median of 4 prior regimens (range, 2 – 6). Four of the 5 NSCLC pts had a confirmed partial response (cPR) including a 51 yo female whose pre-treatment tumor sample lacked an EGFR activating mutation Analysis of tumor obtained pre-treatment and at progression demonstrated a KIF5B-RET fusion. Age Gender Smoking History Molecular Profile Treatment Duration (mos) Best Response 64 Female Never EGFR mutation 15+ cPR 51 Female Former EGFR wt, RET fusion positive 9 cPR 58 Female Never EGFR wt 10 cPR 43 Male Former ALK fusion positive 4 cPR 64 Female Never EGFR wt, ALK fusion negative 6.5 SD DLT of Grade 3 hypertension was reported in 2 pts. The MTD using a capsule formulation is 60 mg. Adverse events were generally mild to moderate and include hypertension, palmar-plantar erythrodysesthesia, diarrhea, mucositis, rash, edema and headache. Laboratory abnormalities include elevated AST/ALT, lipase and TSH; and neutropenia and thrombocytopenia. Preliminary PK analysis showed that dose-normalized exposure in Japanese pts is approximately 2-fold higher than in non-Japanese pts. Despite relatively higher exposures, cabozantinib 60 mg daily appears to be a well tolerated dose. Conclusions: Cabozantinib appears well tolerated. Signs of antitumor activity include response and prolonged stable disease in NSCLC pts. Accrual and additional molecular characterization is ongoing. Disclosure H. Nokihara: Taiho Pharmaceutical Co., Ltd, Merck Serono, Pfizer. N. Yamamoto: Chugai pharmaceutical co., ltd., Pfizer, Kyowa-Hakko Kirin co., ltd. Y. Yamada: Bayer, Yakult, AstraZeneca. J. Frye: Paid employee of Exelixis Exelixis stock ownership. A. Decillis: Paid Employee of Exelixis Exelixis Stock Ownership. T. Tamura: Chugai Pharmaceutical co., ltd., Daichi-Sankyo co., ltd., Boehringer Ingelheim, Abbott Japan Co., Ltd, Eisai co., ltd., Bristol-Myers Squibb, Kyowa-Hakko Kirin co., ltd. All other authors have declared no conflicts of interest.

A phase I study of dovitinib (TKI258) in Japanese patients with advanced solid tumors.

3088^ Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on responses observed in renal cell carcinoma, breast cancer, AML, melanoma, and multiple myeloma in clinical studies in the West, we investigated dovitinib in Japanese patients (pts). Methods: This multicenter phase I study determined the maximum tolerated dose (MTD) of dovitinib based on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in period, dovitinib was administered orally once daily on a 5-days-on/2-days-off schedule in 28-day cycles until disease progression or withdrawal. The planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic regression model based on the principle of escalation with overdose control was used to estimate the MTD. Results: In total, 28 pts received dovitinib: 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 7), 400 mg (n = 9), and 500 mg (n = 6). The median age was 58.5 years (range, 30-76); 16 of 28 pts (57%) were male. All pts had stage IV disease, with an ECOG performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort, cycle 19), 23 discontinued due to disease progression, and 4 discontinued due to adverse events (AEs). All DLTs were grade 3: anorexia (n = 1; 300 mg), nausea/vomiting (n = 1; 400 mg), liver function disorder (n = 1; 400 mg), and increased alanine transaminase (n = 1; 500 mg). The most common grade 3/4 AEs (occurring in >10% of pts) suspected to be related to study drug were lymphopenia (18%), neutropenia (14%), abnormal hepatic function (14%), decreased white blood cell count (14%), decreased appetite (14%), and hypertension (14%). Best responses were confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma, 400-mg cohort), stable disease in 9 pts (32%), and progressive disease in 10 pts (36%). No treatment-related deaths have been reported. Safety and PK parameters were comparable to those of non-Japanese pts in the global study. Conclusions: The study has completed enrollment. Dovitinib was found to be tolerable at doses up to 500 mg, which was declared as the MTD in Japanese pts.

Abstract C20: Phase I study of ombrabulin, a vascular disrupting agent (VDA), administered every 3 weeks to Japanese patients with advanced solid tumors.

Abstract Background: Ombrabulin, an analog of Combretastatin A4, is a vascular disrupting agent that destroys established tumor vasculature, causing blood perfusion shutdown and tumor necrosis. In Caucasian patients (pts), the recommended dose (RD) for ombrabulin single agent was established at 50 mg/m2 given every 3weeks. Recently, the existence of ethnic differences was pointed out in the effects and toxicities of some molecular targeted agents among Asians and Caucasians. Therefore, a phase I study of ombrabulin as a single agent administered every 3 weeks to Japanese pts with advanced solid tumors was performed. Objectives: The primary objective of this study was to determine the maximum tolerated dose (MTD) and the RD for Japanese pts. Secondary objectives were the assessment of the overall safety profile, the pharmacokinetic (PK) profile and the anti-tumor activity (RECIST). Methods: This was an open-label, sequential-cohort, dose-escalation study of ombrabulin administered every three weeks (ClinicalTrials.gov: NCT00968916). Cohorts of 3 or 6 pts were treated at 15.5, 25, 35 and 50 mg/m2 of ombrabulin given over a 30 min intravenous infusion. DLTs were to be evaluated during the first treatment cycle. RD was defined as the highest ombrabulin dose at which less than 33% of all evaluable pts experienced DLTs. PK parameters of ombrabulin and its major metabolite RPR258063 were measured at Cycle 1 on Day 1 and 2. Results: Fifteen Japanese pts were treated with ombrabulin (M/F, 6/9; median age, 62.0 [29–71]; and ECOG PS 0/1, 7/8). The most frequent tumor types were lung (6 pts), breast (2 pts) and muscle/soft tissue (2 pts). The median number of cycles was 2.0 (range 1-7). No DLTs were observed up to 35 mg/m2 and RD/MTD for Japanese pts was determined at 50 mg/m2 (maximum administered dose). One out of 6 pts treated at the RD experienced DLTs at Cycle 1: grade 2 hypertension and grade 3 diarrhea. Neither severe myelotoxicity nor abnormal elevation in cardiac markers was observed. The most frequent related AEs at RD were diarrhea (83.3%), nausea (83.3%) and hypertension (66.7%). No objective tumor response was observed; 33.3% (5/15 pts) of all pts had stable disease. Preliminary PK parameters were in the range of those observed in non-Japanese pts. Conclusions: In this study, treatment with ombrabulin given on Day 1 every 3 weeks was well tolerated with limited cardiovascular toxicity events; 33.3% of pts had stable disease. Results from this study in Japanese pts indicate that the ombrabulin RD is 50 mg/m2, the same as in Caucasians. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C20.

Abstract B54: Phase I study of ombrabulin in combination with cisplatin (CDDP) administered every 3 weeks to Japanese patients with advanced solid tumors.

Abstract Background: Ombrabulin, an analog of Combretastatin A4, is a vascular disrupting agent that destroys established tumor vasculature, causing blood perfusion shutdown and tumor necrosis. However, a narrow rim of tumor cells remains at the tumor periphery after single agent ombrabulin therapy that necessitates its combination with other anticancer therapy (ies). Ombrabulin in combination with platinum derivatives has shown synergistic activity in animal models. Dramatic decrease of tumor blood perfusion was shown by DCE-US in a clinical study when ombrabulin was given in combination with CDDP to patients (pts) with solid tumors. In Caucasian pts, the recommended dose (RD) was established at 25 mg/m2 for ombrabulin and 75 mg/m2 for CDDP, given every 3 weeks. Phase II studies in combination with taxanes and platinum salts in lung and ovarian cancers, and a Phase III study with cisplatin in advanced soft tissue sarcoma are ongoing. Objectives: The primary objective of the study was to determine the recommended dose (RD) and the dose-limiting toxicities (DLTs) of ombrabulin in combination with cisplatin in Japanese pts with advanced solid tumors. Secondary objectives were the assessment of the overall safety profile, the pharmacokinetic (PK) profile and preliminary anti-tumor activity (RECIST). Methods: This was an open-label, sequential-cohort, dose-escalation study of intravenous ombrabulin administered immediately followed by a CDDP infusion every 3 weeks (ClinicalTrials.gov: NCT01021150). Cohorts of 3 or 6 pts were treated at 15.5 and 25 mg/m2 of ombrabulin in combination with 75 mg/m2 of CDDP (fixed dose). DLTs were to be evaluated during the first treatment cycle. RD was defined as the highest ombrabulin dose at which less than 33% of all evaluable pts experienced DLTs. PK of ombrabulin, its metabolite RPR258063 and total/ultrafilterable CDDP were measured at Cycle 1 on Day 1, 2, 3. Results: Ten pts (4 at 15.5 mg/m2 and 6 at 25 mg/m2) were treated (M/F, 5/5; median age, 49.5 [31–67]; and ECOG PS 0/1, 8/2). The most frequent tumor types were breast (3 pts) and esophagus (2 pts). The median number of cycles was 4.0 (range 1–6). Neither DLT nor serious cardiovascular adverse events (AE) were observed. The RD was defined at ombrabulin 25 mg/m2 and CDDP at 75 mg/m2. No grade 3/4 AE were observed at RD other than neutropenia, which occurred in 3/6 pts. The most frequent treatment-related AEs observed at RD were neutropenia (83.3%), decreased appetite (83.3%), hiccups (83.3%), constipation (83.3%), nausea (83.3%) and fatigue (83.3%). One patient (carcinoma of unknown primary) had a partial response and 5 pts had a stable disease as per RECIST. Preliminary PK parameters of ombrabulin, RPR258063 and total/ultrafilterable CDDP were in the range of those observed in non-Japanese pts. Conclusions: In this study, ombrabulin in combination with CDDP was well tolerated in line with results of prior studies. Based on the results from this study, the RD for Japanese pts was defined as 25 mg/m2 of ombrabulin and 75 mg/m2 of CDDP, identical to the one in Caucasian pts. Antitumor activity was observed in different tumor types and at different ombrabulin doses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B54.

Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2. Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1). Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented. Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text]

A Phase II Study (FINDER 2) Comparing Three Dosing Regimens of Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer.

Abstract Background: The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive (ER+) advanced breast cancer (FINDER) 2 study investigated the efficacy, safety, and pharmacokinetic (PK) profile of 3 fulvestrant dosing regimens in postmenopausal women with ER+ advanced breast cancer, recurring/progressing after prior endocrine therapy.Objectives: Primary: to evaluate the objective response rate (ORR). Secondary included assessment of: time to progression (TTP), clinical benefit rate (CBR), duration of response (DOR), tolerability, and PK parameters.Methods: This randomized, double-blind, parallel-group, multicenter, Phase II study, evaluated patients (pts) randomized 1:1:1 to different doses of fulvestrant: 250 mg (approved dose [AD]; given on Days 0, 28 and every 28 days thereafter), 250 mg plus loading dose (LD; 500 mg on Day 0, then 250 mg on Days 14, 28 and every 28 days thereafter), and 500 mg (high dose [HD]; Days 0, 14 and 28 and every 28 days thereafter). Treatment continued until disease progression, or until any other criterion for discontinuation was met.Results: In total, 144 pts were randomized from 34 centers in 8 countries and 143 received treatment: fulvestrant AD (n=47); LD (n=50); HD (n=46). ORRs were: 8.5% (95% confidence interval [CI] 2.4-20.4%), 5.9% (1.2-16.2%), and 15.2% (6.3-28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI 19.1-47.1%), 47.1% (32.9-61.5%), and 47.8% (32.9-63.1%) for the AD, LD, and HD arms, respectively. Median TTP was numerically longer for the HD (6.0 months) and LD (6.1 months) arms vs the AD arm (3.1 months). The low number of responders in all treatment arms prevented DOR assessment. The incidence of adverse events (AEs) was similar in all groups (76.6% AD, 72.0% LD, 69.6% HD); few pts experienced serious AEs (4 pts AD, 9 LD, 4 HD) with no clustering of event type. AEs with an incidence of ≥10% (in any arm) were back pain, arthralgia, fatigue, injection-site pain, nausea, dyspnea, cough, and hot flash. Concentrations in the AD arm approached steady state in the 3rd month of dosing and within the 1st month for LD and HD. Exposure (AUC, Cmin and Cmax) appeared to be linear across the dose range studied and, for the 250mg arms, similar to that previously reported in Western populations (Studies 9238IL/0020 & 0021).Conclusion: No statistically significant differences in efficacy could be proven between AD, LD and HD given the widely overlapping CIs for median TTP. The tolerability profile was similar across the three dosing regimens. Steady-state concentrations were achieved earlier with LD and HD. A parallel study in Japanese pts will be used for comparisons of fulvestrant efficacy and tolerability in Japanese and non-Japanese pts. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4095.

Abstract B48: A phase 1 study of an antisense oligonucleotide against survivin (LY2181308) in Japanese patients with solid tumors

Abstract Background: Survivin is a protein known to regulate apoptosis and cell division and highly expressed in various types of cancers. The inhibition of survivin is expected to normalize the cell cycle and selectively eradicate tumor cells. LY2181308 is a second generation antisense oligonucleotide (ASO) designed to complementarily bind to human survivin mRNA and to inhibit the gene/protein expression, which in turn should restore the normal apoptotic pathway in cancer cells. To evaluate the tolerability, pharmacokinetics (PK), and anti-tumor effect of LY2181308 in Japanese patients (pts) with solid tumors, a phase 1 dose-escalation study was conducted. Methods: The primary objective of this study was to evaluate the tolerability of LY2181308 up to 750 mg. The secondary objectives included evaluation of PK and anti-tumor response. Dose-escalation cohorts include 3–6 pts starting at 400 mg with sequential escalations to 600 and 750 mg. The treatment schedule consisted in a loading dose of 3 consecutive daily intravenous infusions over 3 hours, followed by a maintenance weekly intravenous infusion over 3 hours. Results: A total of 14 pts (11 male /3 female) were enrolled into 3 cohorts (4 at 400 mg; 4 at 600 mg; 6 at 750 mg): median age = 60 (44–73). The median treatment period was 2.0 cycle (1–4). Of the 14 pts, 12 pts were evaluable for dose limiting toxicities (DLTs, 3 at 400 mg; 3 at 600 mg; 6 at 750 mg); 2 pts each at 400 mg and 600 mg were excluded due to early disease progression. Only 1 pt at 750 mg reported DLTs; Grade 3 elevations in ALT/AST/ -GTP. All 14 pts were evaluable for safety and PK. The most frequent adverse events (AEs) were hyperhidrosis, prothrombin time ratio increased, and pyrexia. Most AEs were CTCAE Grade 1 or 2. No deaths or study discontinuations due to any adverse events were reported. One serious AE (Grade 3 blood bilirubin increased) was observed in 1 pt with pancreatic cancer (600 mg); this toxicity was not judged to be causally related to the study drug due to disease progression. Abnormalities of blood coagulation values, commonly observed with second generation ASOs, were reported in most pts; they were all Grade 1. The plasma PK profile primarily illustrated tissue distribution, and only a small percentage of the plasma exposure (∼7%) was eliminated under the terminal elimination t½. The terminal elimination t½ was ∼21 days. The geometric mean AUC0-∞ and Cmax following 750-mg dose on Day3 were 324000 ng*h/mL and 66700 ng/mL, which were comparable with those of non-Japanese pts. The terminal t½ was derived from a 4-compartment model which was found to fit adequately the data. Consistent with the long terminal t½, the PK analyses showed that the clearance to tissue and elimination clearance were low to moderate (i.e ∼2 L/h and ∼30 L/h, respectively) and that the volume of distribution was high (>10000 L). Of the 14 pts, 12 pts who had target lesions were evaluable for anti-tumor response. Eleven pts were Progressive Disease, and 1 pt was Stable Disease. Conclusions: LY2181308 monotherapy in doses of up to 750 mg was confirmed to be tolerable for Japanese pts with solid tumors. LY2181308 showed very long half-life and was considered to be extensively distributed into tissues based on the rapid decrease of plasma LY2181308 concentration after the administration. Further investigations in combination with other anti-tumor drugs are ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B48.

Results of a randomized phase II trial of amrubicin (AMR) versus topotecan (Topo) in patients with extensive-disease small cell lung cancer (ED-SCLC) sensitive to first-line platinum-based chemotherapy

8028 Background: SCLC presents as ED-SCLC in 60%-70% of patients (pts). AMR, a synthetic anthracycline, is approved for these pts in Japan. We compare the efficacy and safety of single-agent AMR vs topotecan in non-Japanese pts with 2nd-line ED-SCLC sensitive to 1st-line platinum-based chemotherapy. Methods: This phase II, open-label, multicenter study enrolled pts with ED-SCLC sensitive to 1st-line platinum-based chemotherapy (recurrence or progression ≥90 days from 1st-line treatment). Pts aged ≥18 years with ECOG performance status (PS) ≤2 and only 1 prior therapy were eligible. Pts were randomized (2:1) to receive IV AMR 40 mg/m2/d (d, 1–3) or IV topotecan 1.5 mg/m2/d (d 1–5) and treated every 21 days until progression, unacceptable toxicity, or withdrawal. The primary endpoint, overall response rate (ORR, complete + partial response), used RECIST criteria. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: In all, 76 pts were randomized to AMR (n=50) or topotecan (n=26) with AMR given for a median of 6 cycles (range 1–16) and topotecan 3 cycles (1–16). AMR significantly improved ORR rates vs topotecan (p<0.012; Table ). Median PFS/OS was 4.3 months (95% CI 2.0, 6.1)/9.3 months (95% CI 5.7, 12.0) with AMR vs 3.5 months (95% CI 2.1, 6.3)/8.9 months (95% CI 4.8, 13.8) with topotecan. There was a higher proportion of ECOG PS 2 pts in the AMR group (n=6) vs the topotecan group (n=2). A trend towards improved OS was observed in the ECOG 0–1 subgroup of 68 pts: median OS was 10.5 months with AMR vs 9.7 months with topotecan. The most common grade ≥3 adverse events with AMR vs topotecan were neutropenia (53% vs 74%), thrombocytopenia (31% vs 52%) and leukopenia (27% vs 30%). Three AMR pts (6%) and 1 topotecan pt (4%) died of neutropenic infection. Conclusions: AMR significantly improves ORR and has acceptable tolerability as 2nd-line treatment in pts with sensitive ED-SCLC. [Table: see text] [Table: see text]

Tolerability and safety of oral neratinib (HKI-272) in Japanese patients with advanced solid tumors

e14505 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. In non-Japanese pts, neratinib was found to have clinical activity against solid tumors and dose-limiting toxicity (DLT) of diarrhea. The maximum tolerated dose (MTD) was 320 mg daily and the recommended dose (RD) was 240 mg because of the diarrhea. In this phase 1 study, the MTD was determined and safety and preliminary efficacy were assessed in Japanese pts with advanced solid tumors. Methods: Pts (3- 6/cohort) received 80, 160, 240, or 320 mg oral neratinib. Each pt participated in only 1 dose group and received single doses of neratinib followed by 1 wk of observation; pts then received daily continuous administration at the same dose. DLTs were assessed from the first single dose to the end of 14 days of continuous treatment. Pharmacokinetics (PK) will be analysed via a noncompartmental method. Tumor measurements were made at screening and at the end of every 8 weeks (2 cycles) by RECIST. Results: Preliminary data for 21 pts as of 30 Oct 2008 are presented. Pts had a median age [range] of 61 yrs [39–78], were 62% male, and had all received ≥2 prior chemotherapy regimens. Tumor types at primary diagnosis were advanced colorectal (81%), breast (14%), and gastric (5%) cancer. Median duration of neratinib treatment [range] was 10 wks [3–29].Two patients at the 320-mg dose had DLTs of diarrhea plus anorexia. Therefore the MTD was determined to be 240 mg. Neratinib-related AEs, any grade in ≥25% of pts included diarrhea (95%), fatigue (67%), anorexia (43%), nausea (43%), abdominal pain (38%), decreased hemoglobin (38%), increased AST (33%), and rash (29%). Neratinib-related AEs, grade ≥3 in ≥1 pts were anorexia (3 pts) and diarrhea (2 pts). Two pts had partial response (PR), 8 pts had stable disease (SD) ≥8 wks, 2 had SD≥16 wks, 9 had progressive disease. The 2 pts with PR had ErbB-2+ advanced breast cancer. PK analysis is still ongoing. Conclusions: In Japanese pts, the MTD for neratinb was determined to be 240 mg and the RD will be confirmed as 240 mg. Neratinib is tolerable and demonstrates preliminary antitumor activity in pts with solid tumors. [Table: see text]

Phase I and Pharmacokinetic Study of Inotuzumab Ozogamicin (CMC- 544) as a Single Agent in Japanese Patients with Follicular Lymphoma Pretreated with Rituximab.

Introduction: Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapeutic agent composed of a monoclonal antibody which targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor antibiotic. Since CD22 is expressed on more than 90% of B-lymphoid malignancies, CMC-544 may be useful for treating patients (pts) with B-cell non-Hodgkin lymphoma (B-NHL). In a phase I study in the US and EU, CMC-544 showed definite clinical activity in pts with relapsed/refractory B-NHL (both follicular and diffuse large) with clinically manageable thrombocytopenia as the main toxicity. In this phase 1 study, the safety, tolerability, efficacy and pharmacokinetics (PK) of CMC-544 was evaluated in Japanese pts with relapsed or refractory B-cell NHL.Methods: CMC-544 was administered IV once every 28 days ± 2 days (1 cycle). A dose escalation was planned using 1.3 mg/m2 and 1.8 mg/m2, the maximum tolerated dose (MTD) which was previously determined in non-Japanese pts. Pts were allowed to enroll in the study if they had relapsed or refractory CD22+ B-NHL. Tumor responses were evaluated by investigator's assessment according to the International Workshop Criteria for NHL.Results: Enrollment for this study is complete and included 13 pts (6 women, 7 men, median age [range] of 49 yrs [43–72]). All of the 13 pts who were enrolled had follicular lymphoma and had received at least one regimen of rituximab alone or rituximab-containing chemotherapy in their prior treatments. The median number of prior treatment regimens was 1 (range: 1–13). In dose escalation, no pts had dose limiting toxicities and the tolerability in the MTD previously determined in non-Japanese pts (1.8mg/m2) was confirmed for Japanese pts. 3 pts and 10 pts were treated with 1.3 mg/m2 and 1.8 mg/m2 of CMC-544, respectively. The median number of CMC-544 treatment cycles was 3 (range: 2–8). The most common drug-related adverse events (AEs, all grades ≥ 35% pts) included thrombocytopenia (100%), leukopenia (92%), neutropenia (85%), elevated AST (85%), anorexia (85%), lymphopenia (85%), nausea (77%), elevated ALT (54%), malaise (46%), and headache (46%). Grade 3/4 AEs ≥ 15% pts were: thrombocytopenia (54%), lymphopenia (31%), neutropenia (31%), and leukopenia (15%). 7 pts discontinued treatment due to AEs; 1 pt because of grade 2 rash, 1 pt because of grade 2 urticaria and 5 pts because of AEs which required treatment delays of >3 wks (2 pts with prolonged thrombocytopenia, 1 pt with prolonged thrombocytopenia and neutropenia, 1 pt with neutropenia and elevated alkaline phosphatase, and 1 pt with prolonged neutropenia and elevated total bilirubin). PK analyses demonstrated that maximum serum concentration (Cmax) and area under the curve (AUC) of CMC-544 increased in a dose dependent manner. Both parameters increased with the second dose in the second cycle. At all dose levels, terminal half-life (t1/2) was prolonged, and total clearance (CL) was decreased in the second cycle. Overall, the PK profile was similar to that of the previous study with non-Japanese pts. 7 pts had CRs (CR + CRu), 4 pts had PRs, and 2 pts had stable disease. The objective response rate (ORR) was 85% (11/13).Conclusions: The tolerability of CMC-544 for Japanese pts with relapsed or refractory follicular B-NHL who had been pretreated with rituximab was confirmed at 1.8 mg/m2 administered once every 28 days. This is the same dose level as the MTD for non-Japanese pts. The PK profile of CMC-544 in Japanese pts was similar to that in non-Japanese pts. Based on the acceptable safety profiles and a high preliminary ORR, CMC-544 should be considered for further investigations in Japanese pts with relapsed or refractory B-NHL who have been pretreated with rituximab.