Phase I study of OPB51602, a small molecule inhibitor of STAT3 phosphorylation, in patients with refractory solid malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3002-3002 ◽  
Author(s):  
Boon C. Goh ◽  
Andrea LA Wong ◽  
Ross A. Soo ◽  
Li-Ren Kong ◽  
Ying Kiat Zee ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase I ◽  
Small Molecule ◽  
Phase I Study ◽  
Mononuclear Cells ◽  
Small Molecule Inhibitor ◽  
Clinical Activity ◽  
Molecule Inhibitor ◽  
Stat3 Phosphorylation ◽  
Grade 3

3002 Background: STAT3 is constitutively activated by growth signaling pathways in many malignancies; in many cell lines inhibition of STAT3 leads to cell death. OPB51602 is a small molecule inhibitor of STAT3 phosphorylation (Tyr705) and activation. Methods: A phase I study of OPB51602 administered for 2 weeks every 3 weeks was initiated to determine the maximum tolerable dose (MTD), evaluate pharmacokinetics (PK), and assess pharmacodynamics effects on STAT3 in peripheral blood mononuclear cells (PBMCs). The starting dose was 2mg/day, and dose escalations to 5mg/d, 10mg/d, 20mg/d, were planned. Single dose PK was done on the first day of administration for 4 days. Dose escalation was based on the “3+3” design, MTD was defined as the dose with at least 2/6 dose limiting toxicities (DLTs) in the first cycle and toxicities were graded by NCICTCv4.0. Results: 32 patients (pt) were treated at doses of 2mg/d (n=7), 4mg/d (n=18), 5mg/d (n=7). The main toxicities observed included nausea/vomiting, diarrhea, peripheral neuropathy and fatigue. 5 mg/d was the MTD, where cycle 1 DLTs of grade 3 diarrhea/dehydration and hyponatremia occurred in 1 patient respectively. One pt developed grade 3 peripheral neuropathy at 4mg/d cohort. PK showed maximal drug levels 2-3 hours after administration, bi-exponential decay, with mean oral clearance of 316.5 +/- 638.9 L/h and long terminal mean half-life of 61.8 +/- 15.9 h on day 17. STAT3 phosphorylation in PBMCs assessed in 6 pts receiving 4mg/d was reduced from 67.4 +/- 17.4% at baseline to 53.0 +/- 18.1% (p=0.001) after administration on day 1. Interestingly, reduction in tumor metabolism by PET CT on day 15 was observed in 4/8 pts receiving 4mg/d. A pt with heavily pretreated adenocarcinoma of lung at 5mg/d dose had partial response; another pt with metastatic endometrial cancer at 4mg/d dose experienced stable disease for 6 cycles. Conclusions: OPB51602 has an MTD of 5mg/d on this schedule, demonstrates inhibition of STAT3 phosphorylation, and evidence of clinical activity. Further proof of concept studies of OPB51602 are warranted.

First in human phase I study of MK-2461, a small molecule inhibitor of c-Met, for patients with advanced solid tumors

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 14657-14657 ◽  
Author(s):  
L. H. Camacho ◽  
S. L. Moulder ◽  
P. M. LoRusso ◽  
G. R. Blumenschein ◽  
P. J. Bristow ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Small Molecule ◽  
Phase I Study ◽  
Small Molecule Inhibitor ◽  
Advanced Solid Tumors ◽  
Molecule Inhibitor

Phase I Study of Clofarabine Plus Idarubicin and Clofarabine Plus Idarubicin Plus Cytarabine (ARA-C) in Patients (PTS) with Relapsed and Primary Refractory Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1809-1809 ◽  
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajolil ◽  
William Wierda ◽  
Srdan Verstovsek ◽  
Farhad Ravandi-Kashani ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Acute Leukemias ◽  
First Remission ◽  
First Relapse ◽  
Grade 3

Abstract Phase I and II clinical studies demonstrated activity of Clofarabine in acute leukemias. In previous studies we have investigated clofarabine, plus ara-C combinations and reported a CR rate of 24% in relapsed AML and 52% in previously untreated AML ≥ 50 years (yrs) with acceptable toxicity profile. Anthracyclines are active in AML. To explore clofarabine further in AML combinations we conducted a phase I study of clofarabine with idarubicin with or without ara-C in pts with relapsed AML, MDS, and CML. Considered as dose-limiting toxicities (DLT) are ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) will be determined by “3+3” dose escalation scheme. On the clofarabine (C)/idarubicin (I) combination (CI), 9 AML pts are enrolled (2 primary refractory, 7 first relapse). Median age: 58 yrs (range 24–71). Median first remission duration (CRD1): 3.1 mos. (0–7.6). For the first dose level, C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d. Among the first 6 pts, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation of C to 15mg/m2 i.v. daily x 5 and I 8mg/m2 i.v. daily x 3. Among 3 pts, 1 ≥ gr.3 toxicity (↑ bili) was observed. No responses occurred. On the CI + ara-C arm (CIA), 7 AML pts are enrolled (1 primary refractory, 6 first relapse). Median age: 58 yrs. (24–78). Median CRD1: 11.2 mos. (0–13.1). First dose level: C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d. Of 3 pts, 2 developed ≥ gr.3 toxicities (↑ bili, diarrhea) leading to the following de-escalation: C 15mg/m2 i.v. daily x 5d, I 6mg/m2 i.v. daily x 3d, A 0.75g/m2 i.v. daily x 5d. Of 4 pts (1 ≥ gr. 3 rash, ↑ bili), 3 pts achieved CR. The phase I study is ongoing until determination of DLT and MTD for each arm. Our preliminary results indicate clinical activity of CIA even at the low dose level.

Rapid Mobilization of Long Term Repopulating Hematopoietic Stem Cells (HSC) with AMD15057, a Small Molecule Inhibitor of VLA4; Synergism with AMD3100 and G-CSF

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 615-615 ◽  
Author(s):  
Pablo A. Ramirez ◽  
Michael Rettig ◽  
Matthew Holt ◽  
Julie Ritchey ◽  
John F. DiPersio
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Small Molecule ◽  
Mononuclear Cells ◽  
Optimal Dose ◽  
Small Molecule Inhibitor ◽  
Jurkat Cells ◽  
Hematopoietic Stem ◽  
Molecule Inhibitor

Abstract Background: Hematopoietic stem cells (HSC) interact with stromal cells, osteoblasts and matrix proteins in the hematopoietic niche. This interaction plays an important role in HSC trafficking, proliferation and differentiation. Significant data support the roles of both the SDF-1/CXCR4 and the VCAM1-VLA-4 axes in stem cell homing and mobilization. Two recent reports have shown that Natalizumab, an anti-VLA-4 monoclonal antibody used in the treatment of Multiple Sclerosis, induces mobilization of CD34+ HSC over several days. In the present study we tested the specificity and efficacy of a novel VLA-4 small molecule inhibitor, AMD15057, in murine preclinical studies of normal HSC mobilization. Methods: Fibronectin adhesion assays were performed with Jurkat cells to test the specificity of AMD15057. Ninety-six well plates were coated with fibronectin or BSA and the inhibition of Jurkat cell (VLA-4 +) adhesion by AMD15057 was determined in the presence or absence of PMA activation. To evaluate the mobilization of HSC progenitors, 8 week old 129/B6 F1 mice (n=6 per group, 3 experiments) were left untreated (unmobilized) or treated with AMD15057 (0.1,1,3 mg/kg iv or 3,5,7 mg/ kg sc), AMD3100 (1,3 mg/kg iv or 1,3,5 mg/kg sc), G-CSF (250 mg/kg/d × 5 d) or combinations. Total WBC and CFU-GM were determined at different time points for each mobilization regimen. For long-term competitive repopulation cell assays (LTRC), PBMCs from 3 Ly5.2+ unmobilized or mobilized mice (700uL PB each) were pooled, mixed with 5×105 Ly5.1+ BM mononuclear cells (MNC) (3:1 ratio) and injected into lethally irradiated Ly5.1+/Ly5.2+ compound heterozygote recipient mice. Chimerism was evaluated monthly for 6 months by flow cytometry. Secondary transplants to evaluate long term repopulation activity was performed by injecting lethally irradiated heterozygotes with 106 BM pooled MNC from the primary recipients. Results: The adhesion of untreated and PMA treated Jurkat cells to fibronectin coated wells was decreased by 62% (3.2 SD) and 69% (3.4 SD) (p<0.001) respectively, upon the addition of 1ug/ml AMD15057 compared to vehicle control. In vivo, a single iv or sc injection of AMD15057 resulted in maximum mobilization of CFU-GM within 0.5–0.75 hr. This effect was dose dependent for both sc and iv administrations. Maximum and comparable peak mobilization (13-fold iv; 9-fold sc, pNS) and kinetics of murine HSC mobilization was seen in mice receiving 1mg/kg iv and 5mg/kg sc AMD15057. In contrast, iv dosing of a small molecule inhibitor of CXCR4, AMD3100 (3mg/kg optimal dose) resulted in more rapid peak mobilization (10-fold) in <1hr compared to 3hr peak mobilization (20-fold) after sc dosing (5mg/kg optimal dose). Combination of AMD15057 (1mg/kg iv) with AMD3100 (5mg/kg sc) resulted in synergistic mobilization of CFU-GM (60-fold) when compared to each agent alone (p<0.01). In addition, when AMD3100 and AMD15057 were administered to mice after 5 days of mobilization with G-CSF (17-fold), a dramatic, rapid and reversible mobilization of CFU-GM was observed (200-fold) which was significantly higher than G-CSF+AMD3100 (90-fold) and G-CSF+AMD15057 (90-fold). LTRC assays confirmed that both AMD3100 and AMD15057 induced the rapid mobilization of short and long term repopulating cells and that this effect was synergistic when both agents were co-administered and exceed the LTRC seen after G-CSF mobilization. Secondary transplants confirmed the long term repopulating capacity of HSC mobilized with AMD15057. Conclusions: The VCAM1/VLA-4 axis is involved in HSC trafficking. AMD15057 is effective in blocking the interaction between VLA4 and its ligand fibronectin. AMD15057 induces rapid and reversible mobilization of normal progenitors and HSC which have the long term repopulating capacity. Finally, a dramatic synergistic effect was observed when AMD15057 was combined with AMD3100, G-CSF and the combination. The results provide a plausible foundation for replacing G-CSF with small molecule inhibitors of CXCR4 and VLA-4 for rapid and reversible HSC mobilization in humans.

Prevention of chemotherapy-induced peripheral neuropathy by the small-molecule inhibitor Pifithrin-mu in a mouse model

2015 ◽  
Vol 49 ◽  
pp. e25-e26
Author(s):  
K. Krukowski ◽  
C.H. Nijboer ◽  
X. Huo ◽  
M. Maj ◽  
A. Kavelaars ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Mouse Model ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor
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