Phase 1 study with BIBW 2992, an irreversible dual tyrosine kinase inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) in a 2 week on 2 week off schedule

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3025-3025 ◽  
Author(s):  
C. H. Mom ◽  
F. A. Eskens ◽  
J. A. Gietema ◽  
K. Nooter ◽  
M. J. De Jonge ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Peak Plasma ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Ki 67 ◽  
Bibw 2992 ◽  
Skin Biopsies ◽  
Grade 3

3025 Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR and HER2. A phase 1 study of orally administered BIBW 2992 was performed to determine its safety, PK and PD. Methods: Patients (pts) with advanced solid malignancies received BIBW 2992 once daily (OD) for 2 weeks, in 4 week cycles. Adverse events were evaluated according to CTCv3.0 and tumor response according to RECIST. In cycle 1 and 2, BIBW 2992 plasma PK analysis was performed. Before and after cycle 1, biomarkers involved in EGFR activation were assessed in skin biopsies. Results: 38 pts received 10 mg (n=3), 20 mg (n=3), 30 mg (n=3), 45 mg (n=3), 70 mg (n=18), 100 mg (n=2) and 85 mg (n=6) OD. At 100 mg dose-limiting toxicities (DLTs) consisted of grade 3 skin rash (n=1) and grade 3 diarrhea despite loperamide (n=1). At the dose level of 85 mg, DLTs were seen in 2 pts (diarrhea in both). An additional 12 pts were subsequently enrolled at 70 mg. A total of 3 DLTs was seen in the 18 pts treated at 70 mg (all 3 diarrhea, in one case with additional grade 3 nausea and ALT increase). In other pts, diarrhea was controllable with loperamide, whereas skin events could be ameliorated with minocycline. The dose of 70 mg BIBW 2992 OD was therefore set as the recommended phase 2 dose. Exposure (AUC0-∞ and AUCτ,ss range 82–2080 ng·h/mL) and peak plasma concentrations (Cmax and Cmax,ss range 7–150 ng/mL) increased with increasing doses. High interpatient variability in all PK parameters was found, but was within the range expected for an orally administered drug. The volume of distribution (Vz/F) ranged from 800–2900 L, indicating high tissue distribution. Median tmax values ranged between 1–4 h. The gMean terminal t1/2 ranged between 13–32 h. Accumulation ratio based on AUC was between 2–2.9. Steady state was reached around day 8. After cycle 1, a >20% reduction in Ki-67 (range 20–83%), reflecting inhibition of keratinocyte proliferation, was seen in paired skin biopsies of 31 pts. Ki-67 positive cells (mean ± SD) decreased from 14 ± 4.5% pre-treatment to 7.9 ± 4.5% on day 13 (p<0.0001). SD lasting ≥4 cycles occurred in 8 pts. Conclusions: 70 mg BIBW 2992 OD can be safely administered in a 2 week on, 2 week off schedule. Further evaluation in phase 2 trials in warranted. [Table: see text]

scholarly journals Phase-1 Study of PF-114 Mesylate in CML Failing Prior Tyrosine Kinase-Inhibitor Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 790-790 ◽  
Author(s):  
Anna G Turkina ◽  
Olga Vinogradova ◽  
Elza Lomaia ◽  
Evgeniya Shatokhina ◽  
Oleg Shukhov ◽  
...  
Keyword(s):  
Tyrosine Kinase Inhibitor ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Skin Toxicity ◽  
Skin Lesions ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background: PF-114 mesylate is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCRABL1 isoforms including those with a BCRABL1T315I. We present data from a phase-1 study in subjects with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or who have BCRABL1T315I (NCT02885766). Methods: 3+3 dose-escalation design to determine maximum tolerated dose (MTD) followed by expanded cohorts for doses ≤MTD. The primary objective was to determine the MTD and identify dose-limiting toxicities (DLTs) during cycle 1 (28 days). Secondary objectives included safety and anti-CML activity based on hematological, cytogenetic, and molecular criteria. Adverse events (AEs) were assessed and graded using NCI-CTCAE v4.03. Results: 51 subjects were enrolled as of June 26, 2018. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given on a continuous QD schedule. Median age was 50 years (range, 29-82 years). Median interval from diagnosis to study-entry was 10 years (range, 0-23 years). Subjects had baseline ECOG performance scores <2. 13 subjects were reported to have BCRABL1T315I. Subjects were heavily pre-treated: 25 had received ≥3 prior TKIs; 5 subjects with BCRABL1T315I received 1 prior TKI. 600 mg was identified as the MTD with 1 of 6 subjects experiencing a DLT at this dose (Gr 3 psoriasis-like skin lesion). Similar grade-3 skin lesions were also identified at the dose of 750 mg in 2 subjects and at 400 mg in 1 subject. Therapy is ongoing in 23 subjects at doses 200, 300 and 400 mg with median duration of exposure of 5 (range, 1-21), 3 (range, 1-12) and 4 (range, 1-19) cycles. Other subjects discontinued because of progression (n=16), AEs (n=6) or other reasons (n=6). The most common of non-hematologic toxicity was skin toxicity, which was common at doses of ≥400 mg. Grade-3 skin toxicity occurred in 3 subjects on daily dose 750 mg, 4 subjects on dose 600 mg, 1 patient on dose 500 mg and 3 subjects on dose 400 mg. Skin lesions resolved rapidly upon drug discontinuation and topical therapy. No other drug related non-hematologic grade-3 toxicities except a single case of grade-3 hepatitis on dose 400 mg were observed. No deterioration of ankle-brachial index or vascular occlusive events were observed. A complete hematologic response was achieved in 8 of 19 evaluable subjects including 3 of 8 with BCRABL1T315I. Major cytogenetic response was achieved in 6 of 21 evaluable subjects including 3 of 7 with BCRABL1T315I. Major molecular response was achieved in 2 of 18 subjects completing ≥13 cycles. Most cytogenetic and molecular responses were achieved at doses 200 and 300 mg which were well-tolerated and will be considered for the phase-2 study. Conclusion: MTD of PF-114 is 600 mg with skin toxicity as the DLT. The best safety/efficacy ratio was seen at doses of 200 and 300 mg which are being studied in expanded cohorts and soon in a phase-2 study. Disclosures Turkina: Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations. Shukhov:Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Chelysheva:Bristol Myers Squibb: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations ; Novartis: Other: provided consultations and performed lectures. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Ottmann:Novartis: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Fusion Pharma: Consultancy, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Employment.

A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 986-993 ◽  
Author(s):  
Walter Fiedler ◽  
Hubert Serve ◽  
Hartmut Döhner ◽  
Michael Schwittay ◽  
Oliver G. Ottmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Dose Level ◽  
Short Duration ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Ki 67 ◽  
Acute Myeloid

AbstractFifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67+, phospho-Kit+, phospho–kinase domain–containing receptor–positive (phospho-KDR+), phospho–signal transducer and activator of transcription 5–positive (phospho-STAT5+), and phospho-Akt+ cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.

scholarly journals A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Advanced Acute Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 117-117 ◽  
Author(s):  
Hervé Dombret ◽  
Claude Preudhomme ◽  
Céline Berthon ◽  
Emmanuel Raffoux ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Normal Karyotype ◽  
Refractory Anemia ◽  
Phase 1 Study ◽  
Grade 3

Abstract Rationale: BET-bromodomain (BRD) proteins play a major role in the epigenetic regulation of gene transcription, notably of genes with superenhancer promoter regions including many oncogenes, such as MYC. OTX015 is a specific BRD 2, 3 and 4 inhibitor that blocks oncogene transcription, and triggers growth inhibition and apoptosis in acute leukemia cell lines and patient cells in vitro (Braun et al. ASH Annual Meeting 2013). Based on these findings, a Phase 1 study of OTX015 was designed for patients with advanced acute leukemia. Patients & Methods: Patients with various unselected relapsed/refractory leukemia subtypes for which no standard therapy options were available were enrolled in this ongoing Phase 1 study. Patients aged < 60 years had to have failed at least two lines of therapy and those aged >60 years at least one line. At least 5% bone marrow leukemic blasts were required at study entry. OTX015 was given orally, daily for 14 days of 21-day cycles (cy). The dose was escalated from 10 to 160 mg daily (QD) according to a standard 3+3 dose-escalation design, to determine the maximum tolerated dose (MTD) or biologically optimal dose. A BID schedule was tested at dose level (DL) 4 (40 mg x 2) and a continuous schedule at 120 mg. Pharmacokinetics was studied on day 1 and residual concentrations were measured on days 2, 8 and 15. Responses were assessed on blood and bone marrow aspirations at baseline, days 8, 22 and 43. Blasts at baseline and day 8 were stored for pharmacodynamic biomarker evaluation. Cytogenetic and molecular markers were collected based on center practice. Results: From January 2013 to June 2014, 36 patients were treated over 6 dose levels: 33 with acute myeloid leukemia (AML), 2 with acute lymphoblastic leukemia and 1 with refractory anemia with excess blasts. Median age was 70 years (range 19-85), 20 patients were male, 29 patients had ECOG 0-1, and 16 AML patients had normal karyotype. Patients had a median of 2 prior therapy lines (range 1-4). The median number of OTX015 cycles administered was 2 (range 1-14+), including 9 patients with >3 cycles. Among the 28 patients evaluable for dose limiting toxicity (DLT), no DLTs were observed through DL5 (120 mg QD). The MTD was exceeded at DL6 (160 mg QD) with one patient experiencing grade 3 diarrhea and another grade 3 fatigue and anorexia. The main toxicities were non-cumulative grade 1-2 gastrointestinal events (6 patients diarrhea, 3 dysgueusia, 3 abdominal pain, 3 nausea, 1 anorexia), hyperglycemia (3 patients), coagulation factor VII decrease (6 patients) and direct bilirubin increase (3 patients) (two latter AEs asymptomatic). These toxicities were mainly observed at QD doses above 80 mg and with 40 mg BID. Dose proportional plasma concentrations were observed and trough concentrations > 500 nM (in vitro active concentrations) were regularly observed from 80 mg/day. Clinically relevant activity was reported in 5 AML patients treated at 10, 40 and 80 mg, including one sustained CR from cy 4 to cy 12 (40 mg QD) and one CR with incomplete platelet recovery (CRp) from cy 2 to cy 5 (80 mg QD). Two patients (10 mg QD, 40 mg QD) had partial blast clearance (disappearance of peripheral blasts and decrease >50% in bone marrow blast percentage) and the remaining patient (40 mg BID) had gum hypertrophy resolution. Four of these 5 patients had secondary or therapy-related AML, 4 had normal karyotype and 2 had an NPM1 gene mutation. Conclusions: OTX015 single agent exhibits antileukemic activity over a wide range of DLs and plasma concentrations in patients with advanced AML. MTD is exceeded at 160 mg QD. The safe recommended dose and schedule is close to being identified. Central extensive molecular marker analysis is being performed and will be prospectively implemented in an expansion cohort. Updated data will be presented and will include correlations between regimen, pharmacokinetics, clinical activity and molecular profile. Table Dose (Schedule) N pts evaluable Evidence of activity DLT 10 QD (14/21) 3 1 20 QD (14/21) 3 40 QD(14/21) 4 1 (CR) 80 QD(14/21) 3 2 (1 CRp) 40 BID (14/21) 6 1 120 QD (14/21) 3 120 QD (21/21) 3 160 QD (14/21) 3 Diarrhea (1) Anorexia/fatigue (1) Disclosures Dombret: Oncoethix SA: Research Funding. Preudhomme:Oncoethix SA: Research Funding. Berthon:Oncoethix SA: Research Funding. Raffoux:Oncoethix SA: Research Funding. Thomas:Oncoethix SA: Research Funding. Vey:Oncoethix SA: Research Funding. Gomez-Roca:Oncoethix SA: Research Funding. Ethell:Oncoethix SA: Research Funding. Yee:Oncoethix SA: Research Funding. Bourdel:Oncoethix SA: Employee of study CRO Other. Herait:Oncoethix SA: CMO and Shareholder Other. Michallet:Oncoethix SA: Research Funding. Recher:Oncoethix SA: Research Funding. Roumier:Oncoethix SA: Research Funding. Quesnel:Oncoethix SA: Research Funding.

An open-label phase I dose escalation study of KRN951, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 1 in a 4 week on, 2 week off schedule in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
F. A. Eskens ◽  
A. Planting ◽  
L. Van Doorn ◽  
T. Isoe ◽  
K. Hayashi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Drug Exposure ◽  
Kinase Inhibitor ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Growth Factor Receptor ◽  
Pharmacokinetic Analysis ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Grade 3

2034 Background: KRN951 inhibits VEGF induced phosphorylation of VEGF receptors (VEGFR)2 and 1 (IC50 of 0.16 and 0.21 nM) and phosphorylation of c-Kit and Platelet Derived Growth Factor Receptor (PDGFR), (IC50 of 1.63 and 1.72 nM). Methods: The principal objectives of this study were (1) to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of KRN951 administered once daily (OD) for 28 days followed by 14 days off treatment, (2) to characterize safety and tolerability, (3) to characterize single and multiple dose pharmacokinetics, (4) to explore inhibitory effects on tumor blood flow, and (5) to look for evidence of antitumor activity. Results: 10 male and 5 female patients, median age 57 yrs (28–72) have been enrolled at dose levels of 1 mg (n=6), 2 mg (n=8), and 1.5 mg (n=1). The total number of courses given is 63 (1–15 per patient) At 2 mg DLT consisting of grade 3 asymptomatic proteinuria, grade 3 ataxia and grade 4 intracranial hemorrhage was seen in three patients. In the next-lower dose level of 1 mg one DLT (grade 3 fatigue) was seen. An intermediate dose of 1.5 mg is currently studied. Hypertension occurred in 14/15 patients but could be medically controlled. Pharmacokinetic analysis revealed dose dependent drug exposure and peak plasma concentrations. Plasma levels of sVEGFR2 decreased following exposure to KRN951. Exploratory analysis by means of Dynamic Contrast Enhanced MRI analysis indicated a decrease in tumorperfusion in selected patients. One confirmed partial response lasting more than 80 weeks in a patient with renal cell carcinoma was seen, and stable disease lasting more than 2 courses of treatment was seen in 6 patients. Conclusion: Once daily KRN951 can be administered safely when given for 28 days followed by 14 days off treatment. The recommended phase II dosing is currently being defined. No significant financial relationships to disclose.

Phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11514-11514
Author(s):  
Damon R. Reed ◽  
Sant P. Chawla ◽  
Bhuvana Setty ◽  
Leo Mascarenhas ◽  
Paul A. Meyers ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Ewing Sarcoma ◽  
Phase 1 ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Target Lesion ◽  
Tumor Shrinkage ◽  
Phase 2 ◽  
Phase 1 Trial ◽  
Grade 3

11514 Background: Ewing sarcoma (ES), a rare bone and soft tissue sarcoma mainly of adolescents and young adults, is characterized by a chromosomal translocation resulting in a fusion oncoprotein. Lysine specific demethylase 1 (LSD1) has been shown to associate with the fusion oncoprotein and promote oncogenic transcriptional activity making LSD1 an attractive target for ES treatment. Seclidemstat is a novel, selective, reversible oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. This is the first report of an LSD1 inhibitor in a Phase 1 trial focused exclusively on ES. Methods: SALA-002-EW16 is a Phase 1 trial of single agent seclidemstat in patients (pts) with relapsed or refractory (R/R) ES. This report describes the completed monotherapy dose escalation. Pts > 12 years received oral SP-2577 twice daily in 28-day cycles under fasting conditions at the assigned dose level. The primary objective was safety and tolerability. Secondary objectives include to determine maximum-tolerated dose (MTD), recommended Phase 2 dose (RP2D), preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 27 pts with R/R ES were enrolled. Pts received escalating doses of SP-2577 at 75 (n = 1), 150 (n = 2), 300 (n = 4), 600 (n = 6), 900 (n = 8), or 1200 mg PO BID (n = 6). The median age was 25 years (range 15–68), 63% were male, and pts had received a median of 3 (range 2–12) prior systemic therapies. There were no treatment-related deaths. The most common ( > 5%) grade 3 treatment-related adverse events (TRAEs) were vomiting (15%), abdominal pain (11%), and hypokalemia (11%). One pt (4%) with grade 3 pancreatitis reported a grade 4 AE of elevated lipase. All remaining grade 3 TRAEs, including hematological TRAEs, were reported in only one pt each. Four pts discontinued study for an AE (weight loss, pancreatitis, vomiting, abdominal pain). Three pts had a dose reduction. The first cycle dose-limiting toxicities were gastrointestinal-related AEs observed in 2 pts at 1200 mg BID. Thus, the MTD/RP2D was established as 900 mg BID. Peak plasma concentrations occurred at a median of 4 hours (h) post-dose and median terminal half-life was 6 h; exposure was dose proportional through 900 mg BID. One pt at 600 mg BID achieved a reduction in target lesions starting at end of C2 with further target lesion tumor shrinkage through end of C4 and C6 (maximum 76% tumor shrinkage) with coincident new non-target lesion appearance at end of C2. Of pts evaluable for response at the end of C2 (12 pts), two additional pts (16.7%) at 600 mg BID and 900 mg BID had overall stable disease. Conclusions: Seclidemstat has a manageable safety profile with proof-of-concept preliminary activity in heavily pretreated pts with relapsed/refractory ES. These data support the planned Phase 2 expansion of seclidemstat as single agent and in combination with chemotherapy in ES and other sarcomas that share similar translocations. Clinical trial information: NCT03600649.

An Open-Label, Phase 2, Multicenter Study Of The Safety Of Long-Term Treatment With Siltuximab (an Anti-Interleukin-6 Monoclonal Antibody) In Patients With Multicentric Castleman’s Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1806-1806 ◽  
Author(s):  
Frits Van Rhee ◽  
Corey Casper ◽  
Peter M Voorhees ◽  
Luis E Fayad ◽  
Helgi van de Velde ◽  
...  
Keyword(s):  
Disease Control ◽  
Research Funding ◽  
Phase 1 ◽  
Extension Study ◽  
Development Research ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Equity Ownership ◽  
Grade 3 ◽  
Entire Treatment

Abstract Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disease driven by interleukin (IL)-6 overproduction. There is no established standard of care for MCD, and patients are usually managed by a variety of strategies with only modest success. Treatment with siltuximab, an anti-IL-6 mAb, demonstrated clinical and radiologic responses in MCD patients in a phase 1 study (Kurzrock et al. Clin Cancer Res 2013;19:3659-70). A phase 2 extension study to assess the safety of long-term treatment with siltuximab in MCD patients is currently ongoing. We report the interim analysis results based on 19 patients who had sustained disease control on siltuximab in the phase 1 study and continued to receive siltuximab 11 mg/kg q3w IV in the phase 2 extension study. Safety monitoring focused on infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, and liver function based on the potential risks from the mechanism of action of IL-6 blockade. Investigator assessed disease control and survival status were also collected. When these 19 patients started the phase 1 study, median age was 44 (range 18, 76) yrs, 63% were male, median disease duration was 4.8 mos (37% newly diagnosed), 53% had hyaline vascular and 47% had plasmacytic histological type, all were HIV- and HHV-8-negative, 32% were therapy-naïve, and 68% had prior therapy (including 21% with prior cancer-related surgery and 63% with prior systemic therapy for MCD). At the data cutoff for this interim analysis of the extension study (January 2013), patients had received in total a median of 81 doses (maximum 129) of siltuximab during a median treatment duration of 5.1 (range 3.4, 7.2) yrs, with 74% of patients treated >4 yrs. All 19 patients are alive and continuing siltuximab treatment. Over the entire treatment duration (ie, both studies), upper respiratory tract infection (89%); nausea (63%); vomiting (58%); diarrhea (53%); hypercholesterolemia (47%); hypertriglyceridemia, pain in extremities, headache, rash, and hepatic function abnormal (each 42%) were most commonly reported. The incidence of AEs reported in the different system-organ classes was similar or lower in the treatment periods of 2 to 4 yrs and more than 4 yrs compared with the treatment period of 0 to 2 yrs. 63% of patients reported at least one grade ≥3 AE (mostly grade 3, none grade 5) during the entire treatment period, most commonly in the following system-organ classes: gastrointestinal (32%); infections (26%); and blood/lymphatic system disorders or general disorders/administration-site conditions (each 21%). Grade ≥3 hypertension was reported in 3 patients; grade ≥3 nausea, cellulitis, and fatigue in 2 patients each; other grade ≥3 AEs were reported in single patients. Two patients had at least one serious infection during phase 1, and none were reported during phase 2 extension study (overall incidence 0.0226 per pt-yr). Eight patients had low-grade hypertriglyceridemia in phase 1, with no additional cases reported during extension study (overall incidence 0.1250 per pt-yr). No patient had grade ≥3 thrombocytopenia, and only 1 patient had grade ≥3 neutropenia during the entire treatment period (overall incidence 0.0103 per pt-yr). Only 1 case of grade ≥3 abnormal hepatic function was reported (in phase 1). No GI perforations occurred. No patient developed infusion-related reactions during the extension study. Only 3 patients had SAEs during the extension study, including unrelated syncope and dyspnea. One patient developed grade 3 polycythemia (Hb 18.8 g/dL), which was controlled without complications. Based on independent radiologic review of images from the phase 1 study, 1 patient had CR, 11 had PR, and 7 had SD at initiation of extension study. All 19 patients have sustained disease control (SD or better) by investigator assessment, including 8 patients who had their dosing interval increased to q6w after established prolonged PR/CR (median q6w treatment duration 11 mos). After a median follow-up of 5.1 yrs, the OS rate in these 19 patients is 100%. In conclusion, the 19 patients with MCD in this extension study have received siltuximab for a prolonged period of time (median 5.1 yrs, up to 7.2 yrs). All patients are alive and maintain disease control. Prolonged siltuximab treatment is well tolerated, with no evidence of new or cumulative toxicity or treatment discontinuations and with a low rate of serious adverse events including serious infections. Disclosures: Van Rhee: Janssen Research & Development: Research Funding. Casper:Janssen Research & Development: Research Funding. Voorhees:Janssen Research & Development: Research Funding; Abbott: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Membership on an entity’s Board of Directors or advisory committees; MedImmune: Membership on an entity’s Board of Directors or advisory committees. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qin:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qi:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Tromp:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Kurzrock:Janssen Research & Development: Research Funding.

Hydrogen sulfide as an endogenous regulator of vascular smooth muscle tone in trout

2004 ◽  
Vol 286 (4) ◽  
pp. R678-R685 ◽  
Author(s):  
Ryan A. Dombkowski ◽  
Michael J. Russell ◽  
Kenneth R. Olson
Keyword(s):  
Hydrogen Sulfide ◽  
Rainbow Trout ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Sulfide Concentration ◽  
Phase 2 ◽  
Phase 3 ◽  
Relaxation Phase ◽  
Channel Inhibition

Hydrogen sulfide (H2S) is an endogenous vasodilator in mammals, but its presence and function in other vertebrates is unknown. We generated H2S from NaHS and examined the effects on isolated efferent branchial arteries from steelhead (stEBA) or rainbow (rtEBA) trout. H2S concentration was measured colorimetrically (CM) and with ion-selective electrodes (ISE) in rainbow trout plasma. NaHS produced a triphasic response consisting of a relaxation (phase 1), constriction (phase 2), and relaxation (phase 3) in both unstimulated vessels and in stEBA precontracted with carbachol (Carb). Phase 1 and phase 3 in stEBA were decreased and phase 2 increased in unstimulated vessels by K+ATP channel inhibition (glibenclamide), or a cocktail of inhibitors of cyclooxygenase, lipoxygenase, and cytochrome P-450 (indomethacin, esculetin, and clotrimazole). Inhibition of soluble guanylate cyclase with ODQ or NS-2028 inhibited phase 3 in stEBA, although NaHS decreased cGMP production by rtEBA. stEBA phase 2 contractions were partially inhibited by the myosin light chain kinase inhibitor, ML-9, but unaffected by L-type calcium channel inhibition (methoxyverapamil), whereas contraction in rtEBA was partially inhibited by nifedipine or removal of extracellular calcium. Phase 3 relaxations were more pronounced in stEBA precontracted with Carb and norepinephrine (NE) than those contracted by KCl or K2SO4. stEBA phase 2 and phase 3 responses were dose dependent (EC50 = 1.1 ± 1.2 × 10-3 M and 6.7 ± 0.9 × 10-5 M, respectively; n = 7). NaHS was also vasoactive in steelhead bulbus arteriosus, celiacomesenteric arteries, and anterior cardinal veins. Rainbow trout plasma sulfide concentration was 4.0 ± 0.3 × 10-5 M, n = 4 (CM) and 3.8 ± 0.4 × 10-5 M, n = 9 (ISE); similar to phase 3 EC50. Because NaHS has substantial vasoactive effects at physiological plasma concentrations, we propose that its soluble derivative, H2S, is a tonically active endogenous vasoregulator in trout.

Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients: pharmacokinetics and recommended phase 2 dose

2015 ◽  
Vol 33 (4) ◽  
pp. 942-953 ◽  
Author(s):  
Karthik Venkatakrishnan ◽  
Tae Min Kim ◽  
Chia-Chi Lin ◽  
Lim Soon Thye ◽  
Wee Joo Chng ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
East Asian ◽  
Aurora A Kinase ◽  
Phase 2 ◽  
Aurora A ◽  
Phase 1 Study

Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor: Preliminary results from a phase 1 study in patients with advanced malignant solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3552-3552 ◽  
Author(s):  
W. A. Messersmith ◽  
S. Krishnamurthi ◽  
B. A. Hewes ◽  
C. M. Zacharchuk ◽  
R. Abbas ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Solid Tumors ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Human Tumor ◽  
Dependent Manner ◽  
Phase 1 Study ◽  
Once Daily ◽  
Grade 3

3552 Background: Bosutinib (SKI-606) is a potent, low molecular weight, orally active, competitive inhibitor of both Src and Abl tyrosine kinases. Elevations of Src kinase activity occur in a variety of human tumor types and are correlated with aggressiveness. We conducted a phase 1 study in patients (pts) with advanced solid tumors to assess tolerability, safety, pharmacokinetics (PK), and preliminary antitumor activity of bosutinib. Methods: Patients in cohorts of 3–6 received 50, 100, 200, 300, 400, 500 or 600 mg bosutinib orally on study day 1 and then once daily beginning on day 3. Timed blood samples were collected on days 1–3, 15 and 16 for PK analysis. Tumor assessments (modified RECIST criteria) were made at baseline and the end of every third cycle (21 days/cycle). Collection of tissue samples for analysis of Src biomarkers was optional. Results: Preliminary data are presented for 51 pts (median 57 years, 57% women). Three pts who received 600 mg bosutinib/day had drug-related dose-limiting toxicity of grade 3 diarrhea (2 pts) and grade 3 rash (1 pt). Gastrointestinal (GI) toxicity was reported among 6 pts in the 500-mg maximum tolerated dose (MTD) lead-in cohort so that 400 mg was selected as the MTD. Drug-related adverse events (AEs), any grade, occurring in =25% of pts were nausea (67%), diarrhea (55%), anorexia (45%), vomiting (43%), asthenia (41%). The only grade 3 drug-related AE occurring in =5% of pts was diarrhea (14%). After oral administration, bosutinib exposure increased in a dose-dependent manner. Multiple-dose exposure was nearly 2- to 3-fold higher than single-dose exposure. Mean elimination half-life was approximately 17 to 21 hours, supporting a once-daily dosing regimen. Six pts had stable disease >15 weeks (2 pts each with breast, colorectal cancer, non-small cell lung cancer [NSCLC]) and 1 pt had stable disease >52 weeks (pancreatic cancer). Conclusions: Bosutinib was generally well tolerated with predominantly gastrointestinal AEs. Accrual and evaluation of an expanded cohort restricted to patients with colorectal, pancreatic, and NSCLC tumors is ongoing. The patient with pancreatic cancer has had stable disease >52 weeks. No significant financial relationships to disclose.

scholarly journals Phase 1 Study of the IDH1m Inhibitor FT-2102 As a Single Agent in Patients with IDH1m Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1453-1453 ◽  
Author(s):  
Justin Watts ◽  
Maria R. Baer ◽  
Jay Yang ◽  
Shira Dinner ◽  
Sangmin Lee ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Human Tissue ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Grade 3

Abstract Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Herein, we present preclinical and clinical data from an ongoing Phase 1/2 study of single-agent (SA) FT-2102 in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: Extensive pre-clinical evaluations were performed on FT-2102, including CYP interactions in-vivo in rat and in-vitro in human tissue and in-vivo QTc toxicology in monkeys. The clinical Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion phases. FT-2102 was administered daily until disease progression or unacceptable toxicity. Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors, and no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: Evaluation of FT-2102 in in-vivo rat and in-vitro human tissue indicated hepatic metabolism by CYP enzymes (CPY3A4, 2C9, 1A1) as the major route of excretion. Animal toxicology studies predicted the threshold for QTc risk occurred at exposures >5.5 fold higher than the murine exposure at which 90% 2-HG reduction was observed. In the clinical study, at the time of the data cutoff, 31 patients (pts) had been treated with SA FT-2102, with a median of 3 mo. on treatment (range: 0.2 to 20 mo.). Of the 31pts treated, 25 had AML (22 R/R; 3 TN) and 6 had MDS (4 R/R; 2 TN). The median number of prior anti-leukemia therapies was 2 (range: 0-9) for AML pts and 1 (range: 0-4) for MDS pts. FT-2102 doses were: 150 mg QD (n=8), 300 mg QD (n=4), 150 mg BID (n=16), and 100 mg QD with food (n=3). Eighteen pts discontinued treatment, most commonly due to death (n=5), progressive disease (n=5), HSCT (n=3), or lack of response (n=3). Severe (≥Grade 3) AEs occurring in >5% of pts included thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), pneumonia (13%), neutropenia (7%), hypokalemia (7%), pyrexia (7%) and leukocytosis (6%). Three pts had differentiation syndrome (IDH-DS), which resolved with temporary interruption of FT-2102, treatment with dexamethasone, hydroxyurea, and supportive care in all three. One pt had transient QTcF prolongation (Grade 3) which resolved with temporary interruption of FT-2102 and cessation of suspected concomitant medications. Eight pts died on treatment or within 28 days of the last dose, with no deaths considered related to FT-2102. No DLTs were observed during dose escalation. Selection of FT-2102 150 mg BID as the RP2D was supported by PK and PD data. Durable steady-state (Css) achieved by Week 2 was well below the threshold for QTc risk predicted by preclinical studies. The predicted IC90 was confirmed with prompt and durable 2-HG reduction to normal levels by C2D1 at the RP2D. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been observed from 1 to 6 months on treatment, with stable disease observed beyond 6 months; 42% of the patients remain on treatment. Conclusions: FT-2102 preclinical evaluations suggest a low risk of clinically significant CYP-mediated drug-drug interaction and QTc prolongation. SA FT-2102 is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Significant clinical activity has been observed in heavily pre-treated and in TN patients, both in AML and MDS. FT-2102 continues being investigated at a dose of 150 mg BID in a Phase 2 study. Three SA Phase 2 cohorts are currently open for enrollment in R/R AML, AML/MDS with CR/CRi (i.e., with MRD), and in pts with R/R MDS/AML with prior exposure to an IDH1m inhibitor. Data updates will be available at the time of presentation. Disclosures Lee: LAM Therapeutics: Research Funding; Karyopharm Therapeutics Inc: Consultancy; AstraZeneca: Consultancy; Clinipace: Consultancy; Amgen: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Ferrell:Incyte: Research Funding. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

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