Phase I Study of Panobinostat Plus Decitabine In Elderly Patients with Advanced MDS or AML.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1060-1060 ◽  
Author(s):  
Geoffrey L. Uy ◽  
Camille N. Abboud ◽  
Amanda F. Cashen ◽  
John F. DiPersio ◽  
Keith E. Stockerl-Goldstein ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Phase I ◽  
Disease Progression ◽  
Phase I Study ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
High Dose ◽  
Nonhistone Proteins ◽  
Synergistic Mechanism

Abstract Abstract 1060 Introduction: Panobinostat (LBH589) is pan-deacetylase inhibitor of both histones and nonhistone proteins such as HSP90 and HIF-α which are implicated in leukemogenesis. Panibinostat has demonstrated activity in a broad range of hematologic malignancies including AML with in vitro studies demonstrating synergistic mechanism of action with a number of agents including DNA hypomethylating agents. Methods: We conducted a phase I study of panobinostat plus decitabine in elderly patients with advanced MDS/AML. Patients age ≥ 60 years with advanced MDS (IPSS ≥ 1.5) or AML who had not been previously treated with a hypomethylating agent were eligible for the study. Decitabine 20mg/m2/d IV on days 1–5 was administered with panobinostat po 3x/wk on nonconsecutive days of a 28 day cycle for up to 12 cycles. panobinostat started at 10 mg/d and was escalated to a maximum of 40 mg/day in 5 cohorts using a 3+3 design. The 40 mg dose group was the highest allowed in the study based on anticipated cytopenias from both drugs in an elderly population. Results: Twenty-eight patients (21 AML/7 MDS) with a median age of 71 years (range 60–86), median WBC 12.7 (range 0.9–73.5) were treated in the Phase I study. Twelve of these patients had previously been treated with regimens that included 7+3 or high dose cytarabine (6 pts, 21%) or high dose lenalidomide (6 pts, 21%). The dose of panobinostat was escalated to a maximum of 40 mg 3x/wk. Of the first 27 evaluable patients there were 7/27 (22%) complete responses with 4 of 8 patients in the 30 mg/day cohort achieving a CR (1 CR, 3 CRi). Of the patients with a CRi, two had baseline cytogenetic abnormalities and both experienced disappearance of the abnormality at the time of response. These patients had persistent thrombocytopenia which may be a consequence of treatment rather than the presence of residual leukemia. Side effects included a dose-limiting asthenia (1 pt /each) which occurred in both the 30 mg and 40 mg/day cohorts. Disease progression was the most common reason for discontinuation of study treatment occurring in 8 pts (four of which occurred in the first cycle of therapy). These early cases of disease progression may suggest that “low-dose” therapies in patients should be avoided in patients with hyperproliferative disease. We conclude that the combination of panobinostat plus decitabine can be safely administered to patients with AML/MDS. The response rate observed at higher doses (’ 30 mg/d) is encouraging and warrants further investigation. Based on this phase I data which demonstrates encouraging evidence of clinical activity for the combination, a phase II cohort using a dose of panobinostat 40 mg po 3x/wk is currently being enrolled. Disclosures: Uy: Novartis: Research Funding. Off Label Use: Panobinostat for MDS/AML. Abboud:Novartis: Honoraria. Vij:Novartis: Honoraria; Eisai: Speakers Bureau. Westervelt:Novartis: Speakers Bureau.

Phase I Study of XK469R (NSC 698215), a Quinoxaline Phenoxypropionic Acid Derivative, in Patients with Refractory Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1952-1952
Author(s):  
Wendy Stock ◽  
Samir D. Undevia ◽  
Stefan Faderl ◽  
Olotoyosi Odenike ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Acid Derivative ◽  
Dose Level ◽  
Phase I Study ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Clinical Activity

Abstract XK469R is a quinoxaline phenoxypropionic acid derivative which possesses broad activity against murine and human tumors (including leukemia) and high activity against multidrug-resistant tumors. COMPARE analysis of cytotoxicity data from the NCI cell line screen suggested a unique mechanism. Phase I studies in patients with advanced solid tumors indicated that the dose-limiting toxicity (DLT) was myelosuppression, without other significant toxicities noted, at a fixed dose of 1400 mg/dose when given on a day 1,3,5 schedule every 21 days. Therefore, we conducted a phase I study to establish the DLT and maximally tolerated dose (MTD) of XK469R in patients with refractory hematologic malignancies, as well as to study the pharmacokinetics of XK469R in this patient population. XK469R was given as a straight dose as an IV infusion over 30 minutes-1 hour on days 1, 3, and 5 of a 21 day cycle. Because significant interpatient variability in drug clearance (associated with toxicity) was noted in prior studies, each dose cohort included a minimum of six patients. The dose levels studied were 1400 mg (n=6), 1750 mg (n=12), 2200 mg (n=14), and 2750mg (n=14). A total of 46 patients with relapsed/refractory leukemia have been treated and are evaluable for toxicity; 41 patients with AML, 4 ALL, and 1 CML-BC. The group consists of 26 males and 20 females with a median age of 53 (range 20–85). ECOG PS included 0 (n=19), 1 (n=21), and 2 (n=6). Median number of cycles received was 1; 10 patients received 2 cycles and 2 patients received 3 cycles. DLT was defined as any clinically significant grade 3 or 4 adverse nonhematologic toxicity other than prolonged myelosuppression, as defined by NCI criteria specific for leukemia. DLTs of colitis and mucositis were observed at the 2200 mg dose level, and mucositis and elevated bilirubin at the 2750 mg dose level. Other possibly related grade 1 and 2 toxicities noted were SGOT/PT elevations, nausea/vomiting, diarrhea, anorexia, indigestion, rash, and alopecia. The MTD, defined as the dose level at which <2/6 patients experience a DLT, was 2200 mg. Forty-two patients were evaluable for response and include CR (n=1, in 1750 mg cohort), HI (n=5), SD (n=21), and PD (n=15). Preliminary pharmacokinetic analysis revealed that plasma concentrations of XK469R decline in a biphasic manner. Half-life was long with a mean value of 48 h. Mean clearance was 206 ml/h with a coefficient of variation of 32%. Patients with lower clearance did not appear to be at greater risk of DLT. In conclusion, the recommended phase II dose of XK469R in patients with advanced leukemia is 1750 mg (day 1,3,5). Due to its novel mechanism of action, reasonable toxicity profile, and clinical activity in these high-risk patients, further exploration of XK469R, possibly in combination with other established agents, is warranted in patients with relapsed/refractory acute leukemia.

Phase I Study of IMGN901 in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3689-3689 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Mecide Gharibo ◽  
Sundar Jagannath ◽  
Nikhil C. Munshi ◽  
Kenneth C Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Minor Response

Abstract Background: IMGN901 (huN901-DM1) is a novel conjugate of the cytotoxic maytansinoid, DM1, with the humanized CD56-binding monoclonal antibody, N901. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of IMGN901. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of increasing doses of IMGN901 given for MM on a weekly schedule. Methods: Patients with relapsed or relapsed/refractory MM who have failed at least one prior therapy and have CD56-expressing MM received a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled in cohorts of 3 at each dose level, with DLT triggering cohort expansion. Results: Eighteen patients have received IMGN901 to date in this study - 3 patients each at 40, 60, 75, 90, 112, and 140 mg/m2/week. One patient experienced a DLT (grade 3 fatigue) on 140 mg/m2/week, and this cohort is being expanded to enroll up to 6 patients. No patients have experienced serious hypersensitivity reactions or evidence of presence of humoral responses against the huN901 antibody component (HAHA) or against the DM1 component (HADA). Preliminary PK results indicate an approximately linear relationship between dosing and observed maximal serum concentration. A confirmed minor response (MR) was documented in 3 heavily pretreated patients (1 patient each at 60, 90, and 112 mg/m2/week) using the European Bone Marrow Transplant criteria. Durable stable disease was reported at doses of 60, 90, 112, and 140 mg/m2/week. Of the 18 patients treated in the study, eight patients remained on treatment with IMGN901 for at least 15 weeks, five of these 8 patients remained on treatment for at least 24 weeks, and two of these 5 patients remained on treatment for at least 42 weeks. This phase I study provides preliminary evidence of safety as well as clinical activity of IMGN901 in patients with CD56-positive MM who have failed established MM treatments. Updated results of this ongoing study will be presented.

A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10023-10023 ◽  
Author(s):  
M. Von Mehren ◽  
P. Reichardt ◽  
P. G. Casali ◽  
J. Blay ◽  
M. Debiec-Rychter ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Clinical Activity ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11

10023 Background: Nilotinib is a novel tyrosine kinase inhibitor (TKI) targeting KIT, PDGFR, and Bcr-Abl and inhibiting the proliferation of both IM-sensitive and -resistant cells in vitro. We report the results of a phase I study in GIST pts resistant to IM and other TKIs. Methods: Pts with progressive disease received nilotinib alone (400 mg p.o. bid) or escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) in combination with IM (400 mg p.o. bid), or nilotinib 400 mg bid plus IM 400 mg qd. Pharmacokinetic (PK) analyses were performed. Tumor assessments (RECIST) were done every 8 weeks. Baseline samples of 18 GISTs were analyzed for KIT and PDGFR mutations. Results: 53 pts received nilotinib, alone (n=18) or in combination with IM (n=35), for a median of 134 days (range 8 to 430 days). Thirty-nine pts (74%) had failed second-line therapies including sunitinib, AMG-706, dasatinib or RAD001. Most frequent adverse events were grade 1 (17% of pts) or 2 (51% of pts) including: skin toxicity, fatigue, myalgia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, hyperbilirubinemia and edema. Six pts experienced dose limiting hyperbilirubinemia or skin rash. One pt on nilotinib alone achieved partial response (PR) for > 6 months and 36 pts (68%)-13 on nilotinib alone-, had SD ranging from 6 weeks to > 6 months. Median progression-free survival was 134 days overall and 178 days for pts on nilotinib alone. Genotyping revealed mutations in KIT exon 9 (n=4) or 11 (n=11), and KIT WT (n=3). The single PR occurred in KIT exon 11 mutant GIST following previous adjuvant imatinib and intolerance to imatinib 800 mg. KIT was WT in 2 out of 8 pts with SD > 6 months. Conclusions: Nilotinib, alone and in combination with IM has promising clinical activity in pts with GIST resistant to prior TKIs. Tolerability is acceptable for both nilotinib 400 mg bid, alone and in combination with IM 400 mg qd, which are the recommended doses for future studies. No significant financial relationships to disclose.

Phase I study of OKT3 x hu3F8 bispecific antibody (GD2Bi) armed T cells (GD2BATs) in GD2-positive tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2533-2533 ◽  
Author(s):  
Maxim Yankelevich ◽  
Shakeel Modak ◽  
Roland Chu ◽  
Daniel W. Lee ◽  
Archana Thakur ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Phase I Study ◽  
Residual Disease ◽  
Ex Vivo ◽  
Autologous Blood ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Minor Response

2533 Background: With the proven success of anti-GD2 monoclonal antibodies in eradicating minimal residual disease in neuroblastoma (NB), exploiting antibody based anti-GD2 in T cell mediated strategies has potential to combat higher disease burden and improve patient outcome. We hypothesized that arming of ex vivo expanded and activated, autologous, blood derived T cells (ATC) with chemically heteroconjugated GD2Bi should redirect them to target NB. In vitro, ATC coated (armed) with 50 ng/106 cells of GD2Bi exhibited specific killing of NB and osteosarcoma (OS) cell lines. Methods: In this phase I study (NCT02173093), patients with GD2-positive tumors received 8, biweekly infusions of GD2BATs + daily low-dose IL-2 and biweekly granulocyte-macrophage colony stimulating factor (GM-CSF). The study followed the standard 3+3 design with dose levels of 40, 80, and 160 x 106 GD2BATs/kg/infusion. Results: Twelve patients (NB = 7, OS = 3, Desmoplastic Small Round Cell Tumor = 2) were enrolled from 11/2013 to 12/2017 and 9 completed therapy. Adequate ATCs could not be grown in one patient and two patients did not complete 8 infusions because of rapid disease progression. Infusions were given in outpatient settings. All patients developed a mild, dose-independent and manageable form of cytokine release syndrome with grades 2-3 fevers/chills, headaches and occasional hypotension for up to 48 hours after infusion. No patients developed significant pain. Maximum tolerated dose was not reached. Evidence of activity was seen in several patients including one patient with OS who had a PET response, one patient with NB who had complete bone marrow response (this patient had remained progression free for 2.5 years after completion of infusions), and another NB patient who had a minor response on MIBG scan. Four patients with NB are currently alive after additional therapies at 12, 14, 18, and 47 months post BAT infusions. Conclusions: Autologous T cells from heavily pretreated patients could be expanded ex vivo to large numbers, armed with GD2Bi, cryopreserved and thawed for safe IV administration up to total dose of 1.28x109/kg. Ongoing phase II arm of the trial will focus on evaluation of clinical activity of GD2BATs in patients with NB. Clinical trial information: NCT02173093.

Phase I Study of BB-10901 (huN901-DM1) in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3574-3574 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Sundar Jagannath ◽  
Robert L. Schlossman ◽  
Robert J. Fram ◽  
Richard M. Falzone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Phase I Study ◽  
Small Cell Lung Carcinoma ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Serious Adverse Events ◽  
Cell Lung Carcinoma ◽  
Myeloma Cells

Abstract Background: BB-10901 is a humanized monoclonal antibody that binds with high affinity to CD56 and is covalently linked to a novel cytotoxic maytansinoid DM1. Once bound to CD56, the conjugate is internalized and releases DM1. CD56 is expressed on a variety of tumor types such as small cell lung carcinoma, neuroendocrine tumors and hematological malignancies including multiple myeloma (MM) and acute leukemia. About 70% of MM patients have evidence of CD56 expression. Based on our preliminary results that BB-10901 has significant in vitro and in vivo anti-myeloma activity in a murine model, we have now initiated a phase I clinical study. Objectives: To determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and pharmacokinetics (PK) of BB-10901 given on a weekly schedule. Methods: Relapsed or relapsed/refractory MM patients who have failed at least one prior therapy and have CD56 expressing myeloma received a single IV infusion of BB-10901 on 2 consecutive weeks every 3 weeks. Subjects are enrolled in cohorts of 3 at each dose level. The starting dose was 40 mg/m2/week based on experience from a prior phase I trial in solid tumors. Results: Five patients have received BB-10901, 3 at 40 mg/m2/week and 2 at 60 mg/m2/week. No patients have experienced DLTs and no serious adverse events related to study drug were observed. In addition, no patients have experienced serious hypersensitivity reactions or evidence of HAHA or HADA formation. Our preliminary PK findings demonstrate that there is no evidence of accumulation of BB-10901. Detailed PK analysis and updated toxicity and efficacy data will be presented. Immunohistochemistry performed on marrow aspirates about 24 hours after huN901-DM1 infusion at 40 mg/m2 confirmed the presence of huN901-DM1 on myeloma cells in the marrow. Two patients treated at 60 mg/m2/week and who had failed multiple prior therapies including bortezomib, thalidomide and/or lenalidomide demonstrated anti-tumor response with a decrease in M proteins of 90% and 33%, respectively. Both patients received a fifth cycle of therapy and one continues on study. Conclusions: This phase I study provides preliminary evidence of safety and clinical activity of BB-10901 in patients with CD56-positive MM who have failed established MM treatments. Targeting of BB-10901 to myeloma cells in the marrow was confirmed. The MTD is not yet defined and enrollment is ongoing.

Evaluation of Pharmacokinetic-Pharmacodynamic (PKPD) Relationship of an Oral, Selective, First-in-Class, Potent IDH2 Inhibitor, AG-221, from a Phase 1 Trial in Patients with Advanced IDH2 Mutant Positive Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3737-3737 ◽  
Author(s):  
Bin Fan ◽  
Yue Chen ◽  
Fang Wang ◽  
Katharine Yen ◽  
Luke Utley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Phase I ◽  
Half Life ◽  
Phase I Study ◽  
Xenograft Model ◽  
Hematologic Malignancies ◽  
Plasma Exposure ◽  
Xenograft Mouse Model

Abstract Introduction: Isocitrate dehydrogenase (IDH) is a critical enzyme in the citric acid cycle, catalyzing the oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (a-KG). The mutant IDH are not catalytically inactive enzymes, but rather possess novel enzymatic activities, catalyzing the reduction of α-KG to the ‘oncometabolite' 2-hydroxyglutarate (2-HG), which has been found to be elevated in patients with several tumor types, including acute myelogenous leukemia (AML). AG-221 is an oral, selective, first-in class, potent inhibitor of the IDH2 mutant protein. The compound has been demonstrated to reduce 2-HG levels by >90% and reverse histone and DNA hypermethylation in vitro, and to induce differentiation in leukemia cell models. In vivo pharmacokinetic/pharmacodynamic (PK/PD) studies in a U87MG IDH2 (R140Q) xenograft mouse model demonstrated robust plasma 2-HG lowering, and the correlation between PK (AG-221 exposure) and PD (the inhibition of 2-HG production) was used for human efficacious exposure projection. The PK/PD correlation was further confirmed in a primary human AML xenograft model in mice. These results are compared to early PK/PD results from the ongoing first-in-human Phase I study of AG-221 in patients with advanced IDH2 mutant positive hematologic malignancies [NCT01915498]. Methods: This first-in-man Phase I study of oral AG-221 was designed to evaluate the safety, PK, and PD, including 2-HG levels, as well as clinical activity. AG-221 was administered orally once (QD) or twice (BID) per day in continuous 28-day cycles. Sequential cohorts of patients were enrolled at higher dose levels. Patients included in this analysis were enrolled to doses of 30, 50, 75 mg BID and 100 mg QD (total N=21). Patients bearing the two dominant IDH2 mutations, R140Q (85.7%) or R172K (14.3%), were enrolled in the Phase I study. Blood was collected at multiple time points for determination of the PK and PD effects of AG-221. The concentrations of AG-221and 2-HG in plasma samples were determined using a qualified LC-MS/MS based method. PK and PK/PD analyses were performed using WinNonLin®. In addition, PK/PD relationships and efficacy of AG-221 was evaluated in a U87MG IDH2-R140Q xenograft mouse model and a primary human AML xenograft mouse model carrying the IDH2-R140Q mutation following oral doses. Results: Preliminary analysis of PK demonstrated excellent oral AG-221 exposure in humans. The mean plasma half-life is greater than 40 hours. Plasma 2-HG concentrations decreased rapidly; substantial and constant plasma 2-HG inhibition was achieved following multiple AG-221 doses in patients, and the inhibition was dose and drug exposure dependent. Based on exposure-response analyses with R140Q patients, the AG-221 AUC0-10hr value of 47.1 hr•ug/mL is estimated to result in sustained 90% plasma 2-HG inhibition in human (Figure1) which is associated with IC90 of 66 ng/mL. This is consistent with an in vivo IC90 in an AML xenograft model, U87MG IDH2-R140Q. In addition, up to 50% plasma 2-HG inhibition was observed in limited number of patients with R172K mutation. Figure 1. AG-221 plasma exposure and 2-HG inhibition correlation in patients with IDH2-R140Q mutation Figure 1. AG-221 plasma exposure and 2-HG inhibition correlation in patients with IDH2-R140Q mutation Conclusions: The pharmacokinetic profile for AG-221 supports QD dosing based on the high plasma exposure and long half-life observed in this study. AG 221 suppressed the production of 2-HG in plasma to the normal range found in healthy volunteers. 2-HG inhibition in R140Q mutation was translated well from mice to humans as well as from in vitro to in vivo. Disclosures Fan: Agios Pharmaceuticals: Employment, Stockholder Other. Chen:Agios Pharmaceuticals: Employment, Stockholder Other. Wang:Agios Pharmaceuticals: Employment, Stockholder Other. Yen:Agios: Employment. Utley:Agios Pharmaceuticals: Employment, Stockholder Other. Almon:Agios Pharmaceuticals: Employment, Stockholder Other. Biller:Agios Pharmaceuticals: Employment, Stockholder Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. Yang:Agios Pharmaceuticals: Employment, Stockholder Other.

Phase I Study of AVE1642 Anti IGF-1R Monoclonal Antibody in Patients with Advanced Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1166-1166 ◽  
Author(s):  
Philippe Moreau ◽  
Cyrille Hulin ◽  
Thierry Facon ◽  
Mario Boccadoro ◽  
Dominique Mery-Mignard ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Phase I ◽  
Phase I Study ◽  
Clinical Activity ◽  
Diabetic Patients ◽  
Human Antibody ◽  
Synergistic Activity ◽  
Open Label

Abstract Rationale: CD221 (IGF-1R) is aberrantly expressed in multiple myeloma (MM) and is associated with disease severity (Bataille et al, Haematologica2005;90:706). IGF-1R is thus an attractive therapeutic target in patients with advanced disease. Patients and methods: We have conducted an open-label dose escalation phase I study of AVE1642, anti IGF-1R monoclonal antibody, in patients with advanced MM. The primary objective was to determine the selected dose of AVE1642 administered every 3 weeks (q3w) based on pharmacokinetic (PK), pharmacodynamic (PD) parameters and dose limiting toxicities. The secondary objectives were to assess the safety profile, the biological activity (saturation of receptors) on peripheral granulocytes, the potential immunogenicity and preliminary clinical activity of AVE1642. Results: 14 patients have been treated with AVE1642 as IV infusion administered q3w (day 1 = day 22) at 3 different dose levels: 3 (n = 4), 6 (n = 6) and 12 mg/kg (n = 4). A median number of 2 infusions (1–8) were administered. AVE1642 was well tolerated, except reversible grade 3 hyperglycemia observed in 2 diabetic patients. No hypersensitivity during infusion was reported. No human antibody anti AVE1642 was detected. One patient with Bence-Jones MM experienced a decrease in proteinuria and relief of bone pain. Based on PK/PD results, the dose of 12 mg/kg of AVE1642 has been selected for further clinical evaluation in MM patients. Based on the in vitro synergistic activity of AVE1642 + bortezomib (Descamps et al, ASH2006, 845a), we have started a combination trial of AVE1642, 12 mg/kg q3w + bortezomib (1.3 mg/m2 at d1, d4, d8 and d11 q3w) in patients with advanced MM.

Prolonged Low Dose Therapy with a Pan-Deacetylase Inhibtor, Panobinostat (LBH589), in Patients with Myelofibrosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 794-794 ◽  
Author(s):  
John Mascarenhas ◽  
Alice Mercado ◽  
Amelyn Rodriguez ◽  
Min Lu ◽  
Carla Kalvin ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Disease Process ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Deacetylase Inhibitor ◽  
Clinical Responses ◽  
Systemic Symptoms ◽  
Recommended Phase Ii Dose

Abstract Abstract 794FN2 LBH589 is a novel pan-deacetylase inhibitor (DACi) that has demonstrated clinical activity in phase I/II studies in patients with a variety of hematologic malignancies. Our group has previously presented preliminary results of a phase I study of LBH589 in patients with myelofibrosis (MF) (Mascarenhas et al, ASH 2009, a308) while a phase II trial using higher doses of LBH589 has also been reported (DeAngelo et al, ASH 2010,a630). Both studies identified reversible thrombocytopenia as the DLT and reported evidence of clinical responses. The final results of our phase I study and the effects of extended treatment with LBH589 are reported here. We enrolled 18 patients at 3 dose levels. Fifty-five percent of these patients had PMF, 28% Post-PV MF and 17% Post ET MF; all were intermediate/high risk based on Lille classification. Twenty-five mg PO TIW was determined to be the recommended phase II dose. All patients experienced resolution of their systemic symptoms and 10/11 patients with baseline palpable splenomegaly, who were evaluable after 1 month of therapy, had a median reduction of 30%, range 0–100%. Five patients entered into an extension phase of the trial and received > 6 months of therapy with a mean dose of 20mg PO TIW at time of optimal response (Table 1). Of these patients, 2 were initially enrolled in the 20 mg PO TIW cohort, 1 in the 30 mg PO TIW cohort and 2 in the 25 mg PO TIW cohort. Both patients at the lowest dose achieved clinical improvement (CI) by IWG-MRT response criteria at 6 months as did one patient at the 25 mg dose. The remaining 2 patients had SD at 30 and 25 mg. A mean reduction in palpable splenomegaly at 3 and 6 months of 55% and 83%, respectively, was observed in this group. Two of these patients had marked and durable improvement in anemia (patients 1 and 4). Patient 4 achieved a near CR at 16 months with resolution of palpable splenomegaly, elimination of peripheral blood dacrocytes and leukoerythroblastosis, a 4g/dL increase in hemoglobin, improvement in overall marrow cellularity and megakaryocyte atypia with an increase in erythroid precursors and a significant reduction of reticulin/collagen fibrosis. Patient 1 was heavily transfusion dependent requiring RBC transfusions weekly to maintain a mean hemoglobin of 6.5g/dL and after 6 months on LBH589 achieved >50% reduction in transfusion dependence maintaining a mean hemoglobin of 9g/dL. Patient 2 had resolution of palpable splenomegaly and leukoerythroblastosis by cycle 6 and the bone marrow at cycle 26 was characterized by a reduction in marrow fibrosis from grade 4 to 1. A phase II study is ongoing, 14 patients are currently enrolled, with a planned goal of 22 patients. Pharmacokinetic and pharmacodynamic studies as well as cytokine profiling of the phase I patients are being analyzed and will be presented at the meeting. We conclude that low doses of LBH589 delivered for greater than 6 months in patients with MF are capable of ameliorating symptoms, improving clinical features and reversing pathologic marrow changes. Disclosures: Off Label Use: Oral histone deacetylase inhibitor that targets epigenetic changes in malignant myelofibrosis cells with an goal to modify the disease process.

Full Dose Bendamustine (Treanda ®) Can Be Safely Combined with Rituximab, Etoposide and Carboplatin (TREC): Results of a Phase I Trial in Patients with Relapsed or Refractory Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3650-3650
Author(s):  
Lihua Elizabeth Budde ◽  
Shustov R Andrei ◽  
Gooley Ted ◽  
Tara L Chen ◽  
Edward N. Libby ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Research Funding ◽  
Phase I Trial ◽  
Clinical Activity ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Multi Agent ◽  
Refractory Lymphoma ◽  
Stage 1

Abstract Abstract 3650 Background: Traditional salvage strategies for relapsed lymphoma are less effective when disease recurs after modern front line therapies (e.g. R-CHOP, BEACOPP). Furthermore, typical multi-agent regimens require inpatient hospitalization and carry the risk of significant non-hematologic toxicity from drugs such as ifosfamide, high-dose cytarabine, and cisplatin. Bendamustine (Treanda ®, T) has both broad spectrum clinical activity in lymphoma and a moderate side effect profile, though limited data exist on the utility of this agent as part of a dose-intense rescue approach. We, thus, hypothesized that bendamustine could safely supplant ifosfamide within the RICE regimen yielding a feasible, effective, outpatient multi-agent salvage strategy (TREC) for patients with relapsed or refractory lymphoma. Methods: Eligibility included: relapsed/refractory lymphoma (untreated T-NHL or MCL was allowed during stage 1), age ≥18 years, performance status of 0–2, measurable disease, no active CNS involvement, ANC 3 1,500/μL, platelets 3 100,000/μL, adequate hepatic and renal function, no active arrhythmias, and no known HIV. The primary objective of the study was to define a maximally tolerated dose (MTD) of bendamustine associated with a dose limiting toxicity (DLT) rate of ≤25%. A DLT was defined as any related non-hematologic grade ≥4 adverse event (AE), or inability to complete one full cycle of therapy due to toxicity. Therapy was delivered in the outpatient setting and consisted of bendamustine ranging from 60 mg/m2 to 120 mg/m2 daily on days 1 and 2 in combination with carboplatin (AUC = 5 on day 1), etoposide (100 mg/m2 on days 1 to 3) and rituximab (375 mg/m2, for CD20+ disease only on either day 2 or 3) every 21 days for up to 2 cycles with G-CSF support. Single patient dose escalation occurred until a DLT was observed, followed by cohorts of 4 patients up to a maximum dose of 120mg/m2 × 2. Response was measured by standard criteria (Cheson 2007). AEs were graded using the CTCAE v4.0 Results: Twenty-four patients were treated, 4 in stage 1, and 20 in stage 2 with no DLTs observed. Baseline features included median age = 58 (range 18 – 72) years, median prior therapies = 1 (range 0 – 2), and refractory to last regimen = 16 (of 22 evaluable, 73%). All B-NHL patients had disease progression following prior rituximab. Histologies included Hodgkin lymphoma (HL, n = 8), diffuse large B-cell (DLBCL, n = 9), mantle cell (n = 2), T-NHL (n = 2), follicular (n = 2), and lymphoplasmacytic lymphoma (n = 1). Twenty-three patients received 2 cycles and one received 1 cycle due to disease progression. All cycles were given in the outpatient settings. Thirteen non-hematologic AEs ≥ grade 3 (SAEs) were observed in 9 patients. The most common related SAEs were dehydration (2), and febrile neutropenia (2). Responses were observed in 16 patients (67%) with 9 CR, and 7 PR. Response rates in HL and DLBCL were 88% (6CR, 1PR), and 56%. Mobilization of peripheral blood stem cells (PBSC) was successful in all 15 attempts immediately following the second cycle of T(R)EC (median yield: 5.58×106CD34/kg, range 3.96 – 11.68). At the last update with a median follow up of 8 (range 2 – 18) months, 19 (79%) patients are alive, and 13 (54%) are progression free, including 10 of 12 who subsequently underwenttransplant. Conclusions: This multicenter phase I trial confirms the ability to safely replace ifosfamide with 120mg/m2 × 2 of bendamustine, yielding the TREC regimen for patients with relapsed/refractory lymphoma. The outpatient administration, manageable toxicity profile, effective use for PBSC mobilization, and preliminary response data are encouraging. These data support future evaluation of TREC, including our ongoing expansion cohorts further investigating outcomes in patients with DLBCL and HL. Disclosures: Budde: Teva: Research Funding. Gopal:TEVA: Research Funding.

Phase I/pharmacokinetic study of thioguanine administered as a 48-hour continuous intraperitoneal infusion.

1988 ◽  
Vol 6 (4) ◽  
pp. 696-700 ◽  
Author(s):  
S Zimm ◽  
S M Cleary ◽  
C N Horton ◽  
S B Howell
Keyword(s):  
Steady State ◽  
Phase I ◽  
Peritoneal Cavity ◽  
Pharmacokinetic Study ◽  
High Performance ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
High Dose ◽  
Chemical Peritonitis

Thioguanine (TG) is an antimetabolite with established antileukemic activity. The most pharmacologically rational manner of TG administration is continuous infusion. Intraperitoneal (IP) delivery of TG provides the opportunity to definitively test the concept of high-dose, long-term antimetabolite administration. The high systemic clearance and in vitro activity of TG against ovarian carcinoma suggested that it would be an excellent candidate for IP administration as a prolonged infusion. TG was administered as a 48-hour continuous IP infusion in this phase I/pharmacokinetic study. TG infusions were administered using a portable, programmable pump (Pancretec Provider Model 2000; Pancretec, Inc, San Diego). Twenty-five patients were treated. At a dose of 900 mg/m2/48 h, TG produced unacceptably severe myelosuppression. The dose-limiting toxicity was granulo-cytopenia. Other toxicities were mild: emesis, alopecia, skin rashes, and photosensitivity reactions. IP TG did not produce chemical peritonitis, hepatotoxicity, or mucositis. The pharmacokinetics of IP TG were determined in 16 patients. TG levels were measured by reverse-phase high-performance liquid chromatography (HPLC). At steady state, the mean peritoneal to plasma TG ratio was 1,800 at the maximum tolerated dose (MTD). Steady-state TG levels in the peritoneal cavity and plasma were 2 mmol/L and 1.1 mumol/L, respectively, at a dose of 744 mg/m2. The elimination half-life of TG from the peritoneal cavity was one hour. TG exhibited linear pharmacokinetics over the dosage range investigated. Encouraging clinical activity was seen with IP TG. There was one partial response (PR) and four minor responses (MR). TG can be safely administered by the IP route. The recommended dose for phase II testing is 744 mg/m2/48 h. IP TG has a favorable pharmacokinetic advantage and has demonstrated encouraging clinical activity. Further studies of IP TG infusions are warranted.

Sign in / Sign up

Export Citation Format

Share Document