Joyce Steinberg

Phase I and Biomarker Study of ABT-869, a Multiple Receptor Tyrosine Kinase Inhibitor, in Patients With Refractory Solid Malignancies

PURPOSEnTo determine the safety and tolerability of ABT-869 at escalating doses and its effects on biomarkers relevant for antiangiogenic activity in patients with solid malignancies.nnnPATIENTS AND METHODSnPatients with solid malignancies refractory to or for which no standard effective therapy exists were enrolled onto escalating-dose cohorts and treated with oral ABT-869 once daily continuously.nnnRESULTSnThirty-three patients were studied at doses of 10 mg/d, 0.1 mg/kg/d, 0.25 mg/kg/d, and 0.3 mg/kg/d. Dose-limiting toxicities in the first cycle (21 days) included grade 3 fatigue in a patient at 10 mg/d, grade 3 proteinuria and grade 3 hypertension in two separate patients at 0.25 mg/kg/d, and grade 3 hypertension and grade 3 proteinuria in two separate patients at 0.3 mg/kg/d, which was the maximum-tolerated dose. Other significant treatment-related adverse events included asthenia, hand and foot blisters, and myalgia. Oral clearance of ABT-869 was linear, with a mean of 2.7 +/- 1.2 L/h and half-life of 18.4 +/- 5.7 hours, with no evidence of drug accumulation at day 15. Two patients with lung cancer and one patient with colon cancer achieved partial response. Stable disease for more than four cycles was observed in 16 patients (48%). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed dose-dependent reduced tumor vascular permeability that correlated with drug exposure. By day 15 of treatment, circulating endothelial cells were significantly reduced (P = .007), whereas plasma vascular endothelial growth factor was increased (P = .004).nnnCONCLUSIONnABT-869 by continuous once-daily dosing was tolerable at doses </= 0.25 mg/kg/d. Biomarker evidence of antiangiogenic activity and DCE-MRI evidence of tumor antiangiogenesis were observed together with promising clinical activity.

Phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer

The objective of this study was to assess the efficacy and tolerability of YM155, a survivin suppressor, in combination with docetaxel, compared with docetaxel alone in patients with HER2-negative metastatic breast cancer. This phase II, multicenter, open-label, 2-arm study randomized patients (≥18xa0years) with histologically or cytologically confirmed stage IV HER2-negative metastatic breast cancer and ≥1 measurable lesion, to receive docetaxel alone or docetaxel plus YM155. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), time to response (TTR), biomarker assessment, and analysis of circulating tumor cells. Patients were women diagnosed with HER2-negative breast cancer; most had received prior drug therapies. The median PFS was 8.4xa0months with YM155 plus docetaxel (nxa0=xa050) and 10.5xa0months with docetaxel alone (nxa0=xa051; HR 1.53; 95xa0% CI 0.83, 2.83; Pxa0=xa00.176). No statistically significant differences were observed for secondary endpoints, although slightly greater OS (630 vs 601 days; Pxa0=xa00.768), CBR (84.3 vs 82.0xa0%; Pxa0=xa00.855), DOR, and TTR were observed with docetaxel alone compared with YM155 plus docetaxel, whereas ORR was similar (25.5 vs 26.0). The most common TEAEs observed with YM155 plus docetaxel compared with docetaxel alone were neutropenia (83.3 vs 84.3xa0%), alopecia (62.5 vs 52.9xa0%), fatigue (50 vs 41.2xa0%), and nausea (37.5 vs 41.2xa0%). Although YM155 is a novel drug that suppresses survivin, YM155 plus docetaxel exhibited no statistically significant differences in endpoints compared with docetaxel alone. The combination regimen was well tolerated.

Enzalutamide for the Treatment of Androgen Receptor–Expressing Triple-Negative Breast Cancer

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.

A phase 2, multicenter, open‐label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma

Survivin is a microtubule‐associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first‐in‐class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6‐month progression‐free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m2) in combination with YM155 (5 mg/m2 per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6‐month PFS rate. Secondary endpoints were objective response rate (ORR), 1‐year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty‐four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m2 and 56 patients received 75 mg/m2 of docetaxel. Six‐month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3–48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5–43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1‐year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6‐month PFS rate ≥20%) was not achieved.

Phase 2 study evaluating intermittent and continuous linsitinib and weekly paclitaxel in patients with recurrent platinum resistant ovarian epithelial cancer

BACKGROUNDnLinsitinib, an oral, dual inhibitor of insulin-like growth factor-1 receptor and insulin receptor, in combination with weekly paclitaxel, may improve clinical outcomes compared with paclitaxel alone in patients with refractory or platinum-resistant ovarian cancer.nnnPATIENTS AND METHODSnThis open-label phase 1/2 clinical trial (NCT00889382) randomized patients with refractory or platinum-resistant ovarian cancer (1:1:1) to receive either oral intermittent linsitinib (600mg once daily on Days 1-3 per week) combined with paclitaxel (80mg/m2 on Days 1, 8, and 15; Arm A) or continuous linsitinib (150mg twice daily) in combination with paclitaxel (Arm B), or paclitaxel alone (Arm C). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety/tolerability.nnnRESULTSnA total of 152 women were randomized to treatment (n=51 Arm A; n=51 Arm B, n=50 Arm C). In combination with paclitaxel, neither intermittent linsitinib (median PFS 2.8months; 95% confidence interval [CI]:2.5-4.4) nor continuous linsitinib (median PFS 4.2months; 95% CI:2.8-5.1) improved PFS over weekly paclitaxel alone (median PFS 5.6months; 95% CI:3.2-6.9). No improvement in ORR, DCR, or OS in either linsitinib dosing schedule was observed compared with paclitaxel alone. Adverse event (AE) rates, including all-grade and grade 3/4 treatment-related AEs, and treatment-related AEs leading to discontinuation, were higher among patients receiving intermittent linsitinib compared with the other treatment arms.nnnCONCLUSIONnAddition of intermittent or continuous linsitinib with paclitaxel did not improve outcomes in patients with platinum-resistant/refractory ovarian cancer compared with paclitaxel alone.

Abstract A165: Result of a phase 1 (dose-escalation stage), first-in-human study of ASP5878, an oral FGFR inhibitor, in patients with advanced solid tumors

Background: ASP5878 is an orally available, novel Fibroblast Growth Factor Receptor (FGFR) inhibitor against FGFR 1, 2, 3, and 4. It demonstrated potent in vitro and in vivo inhibitory effects on a variety of human tumor cell lines and xenograft models with FGFR alterations. Deregulated activation of FGFR signaling has been implicated in several human cancers. Method: This first-in-human phase I study consists of dose escalation (P1a) and expansion (P1b) stages. The primary objectives of P1a are to determine the safety and tolerability and to establish dose limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended P1b dose (RP1bD). The secondary objectives are to determine pharmacokinetics (PK) and pharmacodynamics (PD) of ASP5878. The exploratory objective is to determine antitumor activity of ASP5878. ASP5878 was orally administered on Cycle 0 (a single oral dose once daily followed by 2 days interruption), Cycle 1 and subsequent cycles (continuous daily dosing once (qd) or twice daily (bid)) consist of 28 days each. Dose escalation was planned in a step-wise manner, by using the Bayesian Continual Reassessment Method. Three to four patients (pts) with advanced solid tumors (unselected for FGFR alteration) were planned to be enrolled per cohort in P1a. Results: As of 12 March 2015, 25 pts with advanced solid tumors (lung cancer, hepatocellular carcinoma, etc.) had received at least 1 dose of ASP5878 in 7 dose cohorts (0.5 - 2.0 mg qd, 2.0 - 10.0 mg bid continuous dosing). Twenty three (92.0%) pts experienced at least a single AE. AEs reported by 20 (80%) pts were considered to be study-drug related by the investigators. SAEs were reported in 3 pts (grade 3 hepatic dysfunction in the 1.0 mg qd cohort, grade 3 dyspnea in the 2.0 mg bid cohort and grade 3 urinary tract infection (UTI) in the 2.0 mg bid cohort). Of these, only the UTI was considered to be possibly related to ASP5878 exposure. No DLT was observed, up to the 10u2009mg bid cohort. Common possibly or probably drug-related AEs (mostly grade 1/2) were hyperphosphatemia (HP) (12/25, 48%), serous retinal detachment (SRD) (8/25, 32%), and diarrhea (8/25, 32%). HP was transient and reversible, and was mostly manageable by appropriate measures (e.g.; low phosphate diet, oral phosphate adsorbent, and/or temporary study drug interruption). The vast majority of SRD did not cause any affect on visual perception and resolved after brief study drug interruption. Preliminary PK analyses revealed that plasma concentrations of ASP5878 were increased in a dose proportional manner with median t max of 1-3 hr and median t 1/2 of 2-6 hr. Preliminary data on 3 pts enrolled at a 20mg bid dose indicate that HP was observed in all 3 pts with 2 of the 3 patient9s HP considered a DLT by the investigators/sponsor. One partial response was observed in a bladder cancer patient with an FGFR gene alteration in the 20 mg bid cohort. In the presentation, further updates will be presented. Conclusions: ASP5878 was well tolerated with manageable, mostly grade 1/2 AEs. Tumor shrinkage was observed in a bladder cancer patient with an FGFR gene alteration. RP1bD has not yet been established. Further dose exploration is ongoing (NCT02038673). Citation Format: Toshio Shimizu, Toshihiko Doi, Noboru Yamamoto, Haruyasu Murakami, Junji Furuse, Koji Kawai, Hiroyuki Nishiyama, Satoshi Morita, Shunji Takahashi, Erkut Bahceci, Joyce Steinberg, Howard A. Ball, Futoshi Kunieda, Kentaro Takeda, Aya Kita, Shigeru Takeshita. Result of a phase 1 (dose-escalation stage), first-in-human study of ASP5878, an oral FGFR inhibitor, in patients with advanced solid tumors. [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 A165.