Athos Gianella-Borradori

A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies

A phase I dose-escalation study of MSC1992371A, an oral aurora kinase inhibitor, was carried out in patients with hematologic malignancies. Patients received escalating doses either on days 1-3 and 8-10 (n=36) or on days 1-6 (n=39) of a 21-day cycle. The maximum tolerated doses were 37 and 28 mg/m(2)/day, respectively. Dose-limiting toxicities included severe neutropenia with infection and sepsis, mucositis/stomatitis, and diarrhea. Complete responses occurred in 3 patients. Four disease-specific expansion cohorts then received the dose and schedule dictated by the escalation phase but the study was prematurely discontinued due to hematologic and gastrointestinal toxicity at clinically effective doses.

Abstract C195: Phase I study of 2 dosing regimens of AS703569, an oral Aurora kinase inhibitor, in patients with solid tumors

Background and rationale: AS703569 is a novel, orally administered, potent ATP‐competitive, small molecule inhibiting aurora kinase A, B, and C as well as other kinases involved in cell proliferation and survival, including FLT3, ABL1, ABL1 (mut. T315I), JAK‐2, and FGFR3. In cell lines and tumor xenograft models AS703569 as single agent and in combination with standard‐of‐care anticancer agents has demonstrated strong inhibition of proliferation and induction of apoptosis leading to tumor regression and prolongation of animal survival. Methods: This is an open label, phase I, dose‐escalation study with the objective to determine the MTD of 2 regimens (R) of AS703569 in patients (pts) with advanced solid tumors. In R1 AS703569 is given once daily (QD) day 1 and 8 and in R2 QD day 1, 2, 3 every 21 days (q21d). The dose escalation followed a 3+3 design, separate for each R; pts were assigned to either one of the 2 R sequentially. Dose escalation was stopped when at least 2/3 or 6 pts experienced DLT in the first cycle and the MTD was defined as the dose level below. Results: In each regimen 8 dose levels (DL) were explored: 6, 12, 19.8, 30, 42, 55.8, 74 and 100 (R1) / 99 (R2) mg/m 2 (total dose per 21d cycle). In R1 42 pts were treated: 18 M/ 24 F, median age 60 (23–82); most frequent tumor types: 9 pts breast cancer (BC), 9 colorectal cancer (CRC), 4 lung and 4 prostate cancer (PC). Number of cycles per pt ranged between 1–16 (median 2), 90% of pts completed 2 cycles and 21% completed at least 4 cycles. DLTs in 2/6 patients occurred at 50mg/m 2 /d (total dose per cycle 100 mg/m 2 ), the MTD was established at 37mg/m 2 /d. In R2 39 pts were treated: 17 M/22 F, median age 62 (25–79); most frequent tumor types:10 pts had CRC, 7 PC, 3 cervix cancer. Number of cycles per pt ranged between 1–22 (median 2), 79% of pts completed 2 cycles and 23% completed at least 4 cycles. DLTs in 3/6 patients occurred at 33mg/m 2 /d (total dose per cycle 99mg/m 2 ), the MTD was established at 25mg/m 2 /d. For both R DLTs consisted of hematological toxicity (grade 4 neutropenia and thrombocytopenia). Non‐hematological adverse events (AEs) grade 3 reported in more than 10% of pts overall, in either R, were GI disorders (e.g. diarrhea, nausea, vomiting, intestinal obstruction). Non compartmental PK data of 81 pts (DL 1–8, both R) showed Cmax between 2–4 h (range 0.5–8 h). Cmax and AUC0‐24h increased with dose. Stable disease (SD) for more than 4 cycles occurred in 7 pts at the 3 highest DL. In R1 2 pts with BC (6–8 cycles), in R2 2 CRC / rectal cancer (5–6 cycles), 1 PC (8 cycles), 1 cervical cancer (5 cycles) and 1 neuroendocrine tumor (22 cycles). Conclusion: The objective of the study was achieved, the MTD for AS703569 day 1 and 8 q21d single agent in patients with solid tumors is 37mg/m 2 and for day 1,2,3 q21d it is 25mg/m 2 (same total dose per cycle). DLT is myelosuppression. Several pts experienced durable SD with tumor regression. Current investigations include testing a dose‐intensified regimen to further evaluate exposure, safety and anti tumor activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C195.

Abstract 2746: A phase I, dose-escalation study of the Eg5-inhibitor EMD534085 in subjects with advanced solid tumors and lymphoma

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: EMD534085 is a potent and selective small molecule inhibitor of Eg5, a microtubule motor protein that is critical for proper spindle formation during mitosis. In preclinical studies EMD534085 causes mitotic arrest and cell death and has shown in vivo anti-tumor activity in several tumor types. Patients and Methods: A phase I dose escalation “3+3” study conducted in patients (pts) with advanced solid tumors and lymphoma. The objectives are to define the Maximum Tolerated Dose (MTD) based on the occurrence of Dose Limiting Toxicities (DLT), determine the pharmacokinetics (PK) and PD effects and obtain preliminary signals of anti-tumour activity. DLTs were defined as grade (Gr) 4 neutropenia of >5 days (d) or associated with fever ≥ 38.5C, Gr4 thrombocytopenia, dosing delay >14 d, Gr ≥ 3 non-hematological toxicity except alopecia, nausea and emesis. Dose increments were 100% until Gr 2 toxicity, 50% until the first DLT and 25% until >1 DLTs. The MTD level was defined as the DL below that at which >1/3 or >1/6 pts had a DLT in cycle 1 and a total of 12 pts were enrolled at the MTD. Starting dose level (DL1) was 2mg/m2 administered as a 1 hour intravenous infusion every 3 weeks. Results: Forty-four pts have been treated, 23M/21F, median age 60 range (28- 86) years. Tumor types: colorectal 8 pts, HNSCC 5 pts, sarcoma 5 pts, NHL 4 pts, mesothelioma 4 pts, NSCLC 4 pts, thymus carcinoma 3 pts, ovarian carcinoma 2 pts, other 9 pts. Eleven DLs have been evaluated: 2, 4, 6, 9, 14, 21, 32, 48, 72, 108 and 135mg/ m2. DLTs consisted of 1/6 pts Gr4 neutropenia of >5d at 108 mg/m2 and 1/6 Gr 4 neutropenia >5d and 1/6 Gr 3 coronary syndrome at 135 mg/m2. The MTD was therefore established at 108mg/m2. Relevant AE reported in cycle 2 included Gr 3 renal failure and Gr 3 coronary syndrome. Common adverse events were in general reversible and their severity was Gr≤2 for nausea, vomiting, dry mouth, asthenia, dysphagia, proteinuria and thoracic pain. Pharmacokinetic analysis was performed for the first 10 DLs. Increases in AUC0- and Cmax are dose-dependent without accumulation in the second cycle. At the MDT dose level (108 mg/m2), geometric mean PK values (n=6) were Cmax = 4731 ng/mL; AUC0- = 85263 ng.h/mL; t1/2 = 41 hrs; CL = 1.27 L/h/m2; and Vss = 72L/m2. Median number of cycles administered per pt was 3 (range 1-16). No tumor response has been reported so far, however disease stabilizations lasting more than 6cy (4 month) have been observed in 11 patients (25%) including SCCHN, messothelioma, thymus carcinoma: Conclusion: The primary objective of the study was achieved; the MTD is 108 mg/m2 i.v every 21 d. The AE profile is characterized by transient hematological toxicity and cardiac events. PK appears linear over the investigated dose range, analysis of pharmacodynamic markers is ongoing. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2746.

Abstract 2754: Phase I and pharmacokinetic (PK) study of two regimens combining the aurora kinase inhibitor AS703569 and gemcitabine in patients with advanced solid tumors

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: AS703569 is an orally available, ATP-competitive, small-molecule inhibitor of aurora kinases A, B, and C and other cancer-relevant kinases. AS703569 has shown in vitro and in vivo antitumor activity as a single agent and in combinations, including with gemcitabine (Gem). Phase I monotherapy studies in patients (pts) with solid tumors and hematologic malignancies are ongoing. Objective: To define the maximum tolerated dose (MTD) of 2 regimens (Rs) of sequential-combination [AS703569][1] and Gem (fixed dose 1000 mg/m2/day [d]). Methods: This multicenter, dose-escalation study with a 3+3 design was performed in pts with advanced solid tumors. R1: [AS703569][1] d2 and 9, Gem d1 and 8; R2: [AS703569][1] d1 and 8, Gem d2 and 9 of 21-d cycles. MTD definition: dose level (DL) below that at which >1/3 or >1/6 pts experienced a dose-limiting toxicity (DLT) in cycle 1. Secondary objectives included PK evaluations and antitumor activity. [AS703569][1] starting dose (DL1) was 10 mg/m2/d; other DLs assessed were 15, 21, 28, and 37 mg/m2/d (ongoing). Results: To date, 45 pts have been treated. R1 (19 pts): median (range) age 62 (31-75) years (y); 13 (68%) men; most common tumors: pancreatic (n=5), and lung, colorectal, and stomach (n=2 each); 1-16 cycles completed per pt. R2 (26 pts): median age 58 (20-80) y; 19 (73%) men; most common tumors: colorectal (n=5), liver (n=3), and lung, bladder, and pancreas (n=2 each); 1-10 cycles completed per pt. DLTs reported over the DLs studied to date: in R1, CTCAE Grade (Gr) 4 neutropenia ≥7 d and Gr 4 thrombocytopenia (37 mg/m2/d); in R2, Gr 4 neutropenia and septic shock (10 mg/m2/d), general status deterioration and asthenia (15 mg/m2/d), and Gr 4 neutropenia ≥7 d (28 and 37 mg/m2/d). Related treatment-emergent adverse events (TEAEs) ≥Gr 3 occurred in 13 pts (68%) in R1 and 19 pts (73%) in R2, most commonly neutropenia (R1 n=8; R2 n=13), lymphopenia (R1 n=11; R2 n=9), anemia (R1 n=4; R2 n=5), and thrombocytopenia (R1 n=2; R2 n=3). Other TEAEs ≥Gr 3 included nausea (R1 n=1), asthenia (R1 n=4; R2 n=2), and fatigue (R1 and R2 n=1). Two TEAEs led to deaths in R2 (10 mg/m2/d): 1 pt with Gr 4 neutropenia and septic shock; 1 pt with digestive hemorrhage. Preliminary PK data (n=34): peak [AS703569][1] plasma concentrations (DL 10-37 mg/m2/d) were mostly reached between 2-4 (range 1-8) h. Cmax and AUClast increased with dose. PK data are comparable to those from monotherapy Phase I studies. Stable disease (SD; >4 cycles) was seen in 11/33 pts; 1 pt with non-small-cell lung cancer had a partial response lasting 6 months. Conclusion: [AS703569][1] can be safely combined with standard-dose Gem. Most toxicities were hematologic and reversible. The MTD is being defined for both Rs and [AS703569][1] exposure seems unaltered by Gem coadministration. Some pretreated pts experienced tumor responses and long-lasting SD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2754. [1]: /lookup/external-ref?link_type=GEN&access_num=AS703569&atom=%2Fcanres%2F70%2F8_Supplement%2F2754.atom

Abstract 4433: A Phase I study of two dosing regimens of oral AS703569, an inhibitor of aurora kinase and other kinases, in patients with hematologic malignancies

Background: AS703569 is a novel, orally available, ATP-competitive, small-molecule inhibitor of aurora kinases A, B, and C and several other kinases relevant in hematologic malignancies (HM), including FLT3, ABL1, ABL1 (mutation T315I), JAK-2, and FGFR3. AS703569 has shown potent antitumor activity in preclinical in vitro and in vivo studies as monotherapy and in combination. Objectives: To determine the maximum tolerated dose (MTD) and evaluate safety, pharmacokinetics, and antitumor activity of 2 regimens (Rs) in patients (pts) with advanced HM. Methods: Phase I, 2-arm, dose-escalation study. Pts were sequentially assigned to either AS703569 on days (d) 1-3 and 8-10 (R1) or d 1-6 (R2) of a 21-d cycle. Starting dose: 3mg/m 2 /d (18mg/m 2 /cycle); dose escalation followed a 3+3 design with 12 pts at the MTD, defined as dose level (DL) below that at which >1/3 or >1/6 pts had a dose-limiting toxicity (DLT) in cycle 1. Results: DLs assessed in both Rs: 3, 6, 10, 15, 21, 28, 37, and 47mg/m 2 /d. R1 (36 pts): median age 67 (35-83) years (y); 22 (61%) men; diagnosis: acute myeloid leukemia (AML n=24; 67%); myeloproliferative disorder (MPD n=4), myelodysplastic syndrome (MDS n=3), chronic myeloid leukemia (CML n=3), Ph+ acute lymphocytic leukemia (ALL n=1), and non-Hodgkin9s lymphoma (n=1); 0-9 cycles were completed. MTD was 37mg/m 2 /d; DLTs occurred in 2/3 pts at 47mg/m 2 /d (diarrhea, hyponatremia, sepsis). R2 (39 pts): median age 70 (22-82) y; 25 (64%) men; diagnosis: AML (n=30; 77%), MPD (n=3), MDS (n=2), CML (n=2), and ALL (n=2); 0-6 cycles were completed. MTD was 28mg/m 2 /d; DLTs occurred in 3/6 pts at 37mg/m 2 /d (mucositis, neutropenic infection, diarrhea). AS703569-related adverse events ≥Grade 3 occurred in 26 pts (72%) in R1 and 24 pts (62%) in R2; mainly diarrhea (R1 [n=5] 37 and 47 mg/m 2 /d; R2 [n=4] 28-47 mg/m 2 /d), stomatitis/mucositis (R1 [n=1] 37 mg/m 2 /d; R2 [n=8] 28-47 mg/m 2 /d), and sepsis (R1 [n=3] 21 and 37 mg/m 2 /d; R2 [n=1] 28 mg/m 2 /d). Peak drug plasma concentrations (n=74) were mostly reached between 1-4 (range 0.5-8) hours across all DLs in both Rs; C max and AUC 0-24 increased with dose (3-47mg/m 2 /d). Best response was complete remission (CR) in 2/54 pts with AML (R2: 37 and 47mg/m 2 /d), and in 1 pt with Ph+ ALL (R1: 37mg/m 2 /d). Evidence of activity also included blasts reduction to Conclusion: The primary objective was achieved: the MTD of AS703569 is 37mg/m 2 /d (222mg/m 2 /cycle) for R1 and 28mg/m 2 /d (168mg/m 2 /cycle) for R2. DLTs were mainly gastrointestinal toxicity or severe neutropenia with associated infections/sepsis. CR was seen in pts with AML and Ph+ ALL, and disease regression in other HMs (MDS and CML). These results support the ongoing disease-specific expansion study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4433.