Clinical activity and safety of the histone deacetylase inhibitor MGCD0103: Results of a phase I study in patients with leukemia or myelodysplastic syndromes (MDS)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6500-6500 ◽  
Author(s):  
G. Garcia-Manero ◽  
M. Minden ◽  
Z. Estrov ◽  
S. Verstovsek ◽  
W. M. Newsome ◽  
...  
Keyword(s):  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Median Number ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Tumour Suppressor Genes ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Dose Dependent

6500 Background: MGCD0103 is a novel inhibitor of human histone deacetylases (HDACs), with selectivity for the cancer-associated isoforms of class I HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumour suppressor genes leading to neoplastic transformation, and therefore inhibition of this enzyme may result in antineoplastic activity. Methods: To study the safety and activity of MGCD0103, we have developed a phase I open-label dose escalation study of MGCD0103 administered orally, three-times weekly in patients with leukemia or MDS, with the primary endpoints being the determination of the maximum tolerated dose (MTD) and the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MGCD0103. Eligibility criteria included appropriate performance status and renal and hepatic functions. Patients with relapsed/refractory leukemia or MDS and older patients with untreated AML/MDS were eligible. Results: Twenty patients have been enrolled at four dose levels (20, 40, 80 and 60 mg/m2) so far. Their characteristics are: median age 60 years (range 33–76); the majority of patients so far treated have AML; median number of prior therapies is 1 (range 0–3). Most patients had complex cytogenetics. MGCD0103 has been well tolerated at doses below 80 mg/m2. The MTD has been reached, with 3 out of 4 patients at a dose of 80 mg/m2 developing grade 3 toxicity, mainly fatigue, nausea, vomiting or diarrhea. Grade 2 toxicities include anorexia, constipation, dehydration. The median number of courses is 1 (range 1 to 6). As of January 2006, 7 patients are on study. PK evaluations show dose-dependent exposure. Analysis of peripheral blood cell HDAC activity indicates that HDAC inhibition occurs in all patients in a dose-dependent manner. Two patients with multiple relapsed/refractory acute myelogenous leukemia, and one with MDS have achieved a complete marrow response (blasts less than 6%). Of importance, maximal HDAC inhibition was observed in those patients at the time of best response. Conclusions: Single-agent MGCD0103 has clinical activity and is well tolerated at doses below 80 mg/m2 orally three times a week in patients with advanced leukemia. No significant financial relationships to disclose.

A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820 dimesylate in patients with advanced cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3001-3001 ◽  
Author(s):  
Matthew P. Goetz ◽  
Anthony W. Tolcher ◽  
Paul Haluska ◽  
Kyriakos P. Papadopoulos ◽  
Charles Erlichman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
P38 Mapk ◽  
Advanced Cancer ◽  
Phase I Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Dependent Manner ◽  
Dose Levels ◽  
Dose Dependent

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

Phase I/II Study of the Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor MGCD0103 in Combination with Azacitidine in Patients (pts) with High-Risk Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1954-1954 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Allen S. Yang ◽  
Francis Giles ◽  
Stefan Faderl ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Phase I ◽  
Hdac Inhibitor ◽  
Dna Methyltransferase ◽  
Performance Status ◽  
Single Agent ◽  
Substantial Reduction ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Older Patient

Abstract Aberrant DNA methylation and histone code alterations are common in leukemia. The oral isotype-selective HDAC inhibitor MGCD0103 and the DNA methyltransferase inhibitor azacitidine have been shown to have synergistic antileukemia activity in preclinical models. Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). Based on this, we have developed a Phase I/II study of the combination in leukemia. Patients with relapsed/refractory MDS (10% or more marrow blasts) or AML, or untreated older patients with AML are eligible. Adequate performance status, renal and hepatic functions are required. Azacitidine is administered at its approved dose/schedule: 75 mg/m2 SC daily x 7 every 28 days. MGCD0103 was started on day 5 of azacitidine and was given as an oral dose 3 times a week without adjusting for body weight, without interruption. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. Three dose levels of MGCD0103 have been studied so far: 35, 60 and 90 mg. Twelve patients have been registered in this study. The median age is 61 (range 45–85). All, but 1 patient with MDS, had AML. All patients had relapsed or refractory disease. A total of 24 cycles have been administered, mean = 2.0 (range 1–4). Only 1 patient has experienced dose limiting toxicity: grade 3 vomiting at a dose of 90 mg of MGCD0103. Otherwise, the combination has been very well tolerated and the MTD has not yet been defined, with dosing currently ongoing at the approximate MTD of single agent MGCD0103: 110 mg orally three times a week without interruption. Preliminary PK data indicate that the t1/2 for azacitidine is less than 2 h, and does not appear to be affected by MGCD0103. Likewise, MGCD0103 pharmacokinetic characteristics do not appear to be affected by azacitidine. The majority of patients exhibited substantial reduction in HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. Two patients have achieved response: 1 complete remission after 4 courses of therapy (in an older patient in first relapsed AML with an initial CR duration of 11 months and multiple cytogenetic abnormalities). A second older patient with refractory AML achieved a complete marrow CR (marrow blasts less than 5%) but died from pneumonia (not drug-related) after the second course of therapy on day 28 before peripheral count recovery. In conclusion, the combination of azacitidine with MGCD0103 is safe in patients with advanced AML/MDS. The combination has encouraging safety, PK, and clinical activity profiles. The study continues at the MTD of single agent MGCD013 in combination with azacitidine. Once the MTD of the combination is documented, the study will continue as a phase II study in this patient population.

Preliminary Results of a Phase I/II Trial of BBR-2778 (Pixantrone) in Combination with Fludarabine, Dexamethasone, and Rituximab (FPD-R) in the Treatment of Patients with Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1324-1324 ◽  
Author(s):  
Luis Fayad ◽  
James Liebmann ◽  
Manuel Modiano ◽  
Gary I. Cohen ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Outpatient Basis ◽  
Significant Activity ◽  
Cardiac Events

Abstract Background: Fludarabine-mitoxantrone-dexamethasone-rituximab (FND-R) is a combination chemotherapy with significant activity in untreated and relapsed indolent B-cell lymphoma patients (pts). Pixantrone is a novel aza-anthracenedione that has no delayed cardiotoxicity in animal models and has single agent activity in NHL. We conducted an outpatient phase I/II trial, to define the recommended dose (RD) of pixantrone when substituting for mitoxantrone in the FND-R regimen, and the safety and efficacy of this regimen in pts with relapsed or refractory indolent NHL. Methods: Pts received pixantrone with fludarabine (25mg/m2/day, days 1–3), dexamethasone (20mg/day, days 1–5), and rituximab (375mg/m2/day on day 1) in a 28 day regimen (FPD-R). Based on previous single agent clinical studies, the starting dose of pixantrone was defined as 80mg/m². The RD was established to be 120mg/m2 and the protocol was amended to treat patients in the phase II part. Results: 9 pts (6 males) with a median age of 65 years (range 41–78) were included in the dose-finding part of the study. Following the protocol amendment, 23 pts (11 males) of WHO performance status 0–1, median age 61 (range 32–78) have been enrolled in the currently ongoing phase II part. Pathology included SLL/CLL, follicular grade I, follicular grade II, MALT, marginal cell, and other indolent B-cell lymphomas. All pts had received a prior anthracycline-containing regimen (median number 1, range 1–4). The study regimen was well tolerated; median number of courses received was 5 (range 2–8). Grade 4 toxicities were neutropenia in 10 pts, leukopenia in 5 pts, and thrombocytopenia in 1 pt. No clinically significant cardiac events or decreases in LVEF ≥20% were noted. However 4 pts went below 50% LVEF including 1 pt who was below 50% at baseline. Non-hematologic adverse events were primarily grade 1 or 2 in severity. Response rate was 75% for the 20 pts evaluable for response, with 11 (55%) complete remission [7 confirmed (CR), 4 unconfirmed (CRu)], and 4 (20%) partial remission (PR). Two responders went onto bone marrow transplant (BMT): one had a CRu and one a PR. A third patient was pending BMT after CR. At a median follow-up of 345 days, the median duration of response has not been reached, as only two pts have progressed: the first progression occurred at 113 days, and the second pt progressed at 699 days. The remaining pts are still in remission. Conclusions: The RD of pixantrone in the FPD-R regimen is 120mg/m2. The primary toxicity is hematologic. The regimen can be given on an outpatient basis, is associated with major responses, and is very well tolerated in relapsed and refractory indolent NHL pts.

A Phase I Trial Of Anti-KIR Monoclonal Antibody IPH2101 and Lenalidomide For Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3181-3181 ◽  
Author(s):  
Don M. Benson ◽  
Adam D Cohen ◽  
Craig C Hofmeister ◽  
Munshi C Nikhil ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Nk Cells ◽  
Nk Cell ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Low Grade ◽  
Dosing Interval ◽  
Infusion Reactions

Abstract Introduction Multiple myeloma (MM) remains an essentially incurable plasma cell malignancy. MM utilizes specific immunoevasive strategies to avoid natural killer (NK) cell immune surveillance and cytotoxicity. Immunomodulatory agents such as lenalidomide (LEN) may exert indirect anti-MM efficacy via expansion and activation of NK cells. However, these favorable effects may be diminished when LEN is co-administered with high doses of dexamethasone (DEX). IPH2101 is a monoclonal anti-inhibitory KIR antibody which prevents negative signaling in NK cells and enhances NK cell recognition and killing of MM cells. A single-agent, phase I study of IPH2101 demonstrated full KIR blockade with encouraging safety and tolerability, and 34% of heavily pre-treated patients achieved disease stabilization (Blood 2012;120:4324-33). Preclinical data demonstrate that LEN and IPH2101 exert anti-MM effects via complementary NK-cell immunomodulatory mechanisms (Blood 2011;118:6397-91). Herein, data are presented from the first clinical experience with IPH2101 and LEN in combination in patients with MM. Methods A 3+3 phase I dose-escalation trial was conducted. Patients (age 18-80) with measurable, progressive MM were enrolled having received one or two prior lines of therapy. Prior LEN exposure was permitted unless resistance or intolerance was observed. Patients must have had ECOG performance status ≤ 2, creatinine clearance ≥ 60 ml/min, platelets ≥ 75,000/uL (or ≥ 30,000/uL if > 50% bone marrow plasma cells), absolute neutrophil count ≥ 1,000/uL, bilirubin < 1.5 ULN, and ALT / AST < 3 ULN. Patients must have adhered to standard prescribing guidelines for LEN. Three dose levels included: IPH2101 0.2mg/kg IV q 28 days + LEN 10 mg PO days 1-21; IPH2101 0.2 mg/kg + LEN 25 mg, and IPH2101 1mg/kg + LEN 25 mg for 4 cycles. Responding patients were allowed to receive 4 additional cycles. Patients completing all 8 cycles were maintained on LEN thereafter. No administration of DEX or other systemic corticosteroids was permitted. Dose reductions of LEN were permitted per prescribing information. The primary objective was to determine the safety and tolerability of IPH2101 + LEN, the secondary objectives included pharmacokinetics (PK) and pharmacodynamics (PD) of IPH2101 and biologic correlates with LEN as well as to determine clinical activity by standard IMWG uniform response criteria. Results 15 patients (10 M, 5 F, median age 60) were enrolled, 8 in first relapse and 9 in second relapse. 9 had prior LEN exposure. Cohorts 1 and 3 were expanded to n=6 patients respectively due to occurrence of possible dose-limiting toxicity. In both cases, a patient experienced a similar, apparent infusion reaction on cycle 1, day 1, characterized by fever, chills, cytokine release, and leucopenia. Events resolved with supportive care and both patients continued on trial without recurrence. The protocol was amended to include premedication with anti-histamine and acetaminophen,and no further infusion reactions were observed. Most other observed adverse events were of low grade and generally investigator-attributed as possibly or probably related to LEN. IPH2101 PD were not affected by co-administration of LEN. Full KIR occupancy was achieved in cohort 3 across the dosing interval. Five patients achieved a response (2 VGPR, 3 PR) with a median duration of 15+ months (3-26+). Conclusion The combination of IPH2101 + LEN appears to be a safe and well tolerated, and steroid-free combination in MM patients. Infusion reactions have not been observed since the addition of premedication prior to IPH2101 dosing. IPH2101 PD do not appear to be altered by co-administration of LEN, and full KIR blockade over the dosing interval has been achieved. Although the study is small, response rate and response duration are encouraging. These findings support further investigation of antiKIR therapy with LEN as the first, steroid-sparing, dual immunotherapy for MM. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without concomitant dexamethasone. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Caligiuri:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees.

Final results of phase I and pharmacokinetic study of SJG-136 administered on a daily x 5 schedule

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13506-e13506 ◽  
Author(s):  
T. M. Kadia ◽  
S. Faderl ◽  
Z. Estrov ◽  
M. Konopleva ◽  
S. George ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Median Number ◽  
Clinical Activity ◽  
Vascular Leak ◽  
Ecog Performance Status ◽  
Acute Leukemias ◽  
Number Of Patients ◽  
Dose Levels

e13506 Background: SJG-136 is a pyrrolobenzodiazepine dimer that forms covalent DNA crosslinks in a sequence-specific manner in the minor groove. In vitro testing demonstrated a broad pattern of antitumor activity in sub-nmol concentrations. A phase I study in patients (pts) with solid tumors revealed clinical activity, defined MTD as 30 mg/m2/d administered on daily x 3 schedule, and confirmed manageable toxicity. Here we report the results of a CTEP-sponsored phase I trial of SJG-136 administered on a daily x 5 schedule in pts with relapsed or refractory (R/R) leukemias. Methods: Previously treated pts with R/R acute leukemias (AML, ALL, high risk MDS, CML blast phase) or R/R CLL with adequate organ function and ECOG performance status of ≤ 2 were eligible for the study. The starting dose level was 6 mcg/m2 given intravenously daily x 5 days on a 21 day cycle. Pts were sequentially enrolled in cohorts of 3 and the dose was escalated in a classic 3+3 schema at the dose levels: 6, 12, 24, and 36 mcg/m2. Repeat courses and intrapatient dose escalation were allowed. Results: Sixteen pts (11M, 5 F) were enrolled on the study. The median age of the patients was 53 (21–84). Thirteen (81%) pts had R/R AML, and 3 (19%) had R/R ALL of which 5 (31%) had diploid and 6 (38%) had adverse cytogenetics. Median number of prior therapies was 3 (2–6). Pts enrolled at each dose level (mcg/m2) were: 6 (3 pts), 12 (5 pts), 24 (4 pts), 36 (4 pts). The median number of cycles delivered was 1 (0–5). The dose of 36 mcg/m2 was found to be above the MTD, with the DLT being grade 3 soft tissue edema. Other manifestations of vascular leak including grade I, II hypoalbuminemia, edema, and pleural effusions were seen in a number of patients starting at dose level 24 mcg/m2 and above. Other non-dose limiting toxicities included nausea, dyspnea, fatigue, bloating, and insomnia. One pt had a PR, 8 pts had stable disease, and 6 had progression. Pharmacokinetic characteristics in this population will be reported. Conclusions: SJG-136 is safe and active in patients with advanced leukemias. Edema and other vascular leak syndromes are characteristic toxicities of the agent at higher dose levels. 24 mcg/m2 is the recommended phase II dose for the daily x 5 schedule. No significant financial relationships to disclose.

Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7062-7062 ◽  
Author(s):  
G. Garcia-Manero ◽  
A. S. Yang ◽  
V. Klimek ◽  
S. Luger ◽  
W. M. Newsome ◽  
...  
Keyword(s):  
Phase I ◽  
Hdac Inhibitor ◽  
Dna Methyltransferase ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Relevant Dose ◽  
Aberrant Dna Methylation ◽  
Dose Levels

7062 Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea & anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 & 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic & clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing. No significant financial relationships to disclose.

A phase I study of AEE788, a multitargeted inhibitor of ErbB and VEGF receptor family tyrosine kinases, to determine safety, PK and PD in patients (pts) with advanced colorectal cancer (CRC) and liver metastases

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4065-4065 ◽  
Author(s):  
H. Q. Xiong ◽  
C. Takimoto ◽  
F. Rojo ◽  
D. Davis ◽  
J. Huang ◽  
...  
Keyword(s):  
Phase I ◽  
Liver Metastases ◽  
Phase I Study ◽  
Laser Scanning ◽  
Safety Data ◽  
Clinical Activity ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Dce Mri ◽  
Dose Dependent

4065 Background: AEE788 (AEE) is an oral inhibitor with potent activity against EGFR, ErbB2, and KDR. This phase I study was to assess the safety, PK, PD, and MTD/DLT of AEE in pts with CRC and liver metastases. Methods: AEE was given PO at 25, 50, 100, 250, 300 or 400 mg/day daily in 28-day cycles (C) to 3–6 pt cohorts. 24-hr PK was obtained on C1, days (D)1, 15 and 28. PK parameters of AEE and active metabolite, AQM674 (AQM) were computed by non-compartmental methods. PD markers were analyzed in skin (SK), and tumor (TU) biopsies pre- and post-treatment. Samples were evaluated by both IHC and Laser Scanning Cytometry (LSC). DCE-MRI was performed at baseline (BL), and on C1D2 and 28 and C2D28. Results: 22 pts were treated at doses of 25 (n=4), 50 (n=3), 100 (n=4), 250 (n=1), 300 (n=4), and 400 mg (n=6). No DLT was reported. The most common AE (> 15%): fatigue (55%), vomiting (46%), diarrhea (41%), nausea (36%), dyspnoea (23%), constipation (18%) pyrexia (18%) and rash (18%). 2 pts had reversible gr 3/4 LFTs. Serum concentration of AEE and AQM increases with dose and dose duration. 7 pts had stable disease at the end of C2. Median time on treatment was 56 days (range 7–168). In SK, at doses =100 mg, pEGFR, pMAPK and Ki67 were inhibited by an average of 51, 54 and 41%, respectively by IHC. In endothelial cell (EC) pKDR/KDR was significantly inhibited (4-fold) in the wound-induced SK in a dose-dependent manner by LSC. In TU, inhibition of pEGFR, pMAPK and Ki67 at 400 mg was 100%, 90% and 39%, respectively by IHC. EC pKDR decreased with dose, however, trend was not significant. 1 out 15 pts who had BL and end of C1 DCE-MRI had > 40% Ktrans reduction. Conclusions: A dose dependent inhibition of pKDR, pEGFR, and pMAPK in skin and tumor was observed. However, no significant effects were observed on Ki67 and apoptosis in TU. No dose dependent reduction in Ktrans from DCE-MRI was observed. These findings were consistent with the lack of clinical activity of AEE up to 400 mg in this patient population. The study has been discontinued without reaching DLT due to safety data from other phase I studies and in favor of different dosing schedules. No significant financial relationships to disclose.

Final Report of GFM-VOR2007 Study: a Phase I/II Study of Vorinostat and Low Dose Cytarabine (LDAC) for MDS Patients with Azacitidine (AZA) Failure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3825-3825 ◽  
Author(s):  
Thomas Prebet ◽  
Thorsten Braun ◽  
Odile Beyne-Rauzy ◽  
Eric Wattel ◽  
Francois Dreyfus ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Therapeutic Index ◽  
Median Number ◽  
Clinical Activity ◽  
Final Report ◽  
Sequential Administration

Abstract Abstract 3825 INTRODUCTION: AZA is the standard of care for patients (pts) treated for high risk MDS. Outcome of patients with AZA failure is poor with no standard treatment currently available (Prebet, JCO, 2012), and alternative strategies are required for this population. Vorinostat is a histone deacetylase inhibitor with clinical activity in MDS and leukemia, although response rate remains low when used as single agent (Garcia-Manero Blood 2008). By contrast, combinations with cytotoxic or targeted therapies seem promising. METHODS: In this study (clinicaltrials.gov NCT00776503), we combined LDAC (10mg/m2/d in the first cycle, then 20 mg/m2/d) for 14 days SC every 28 day cycle and escalating doses of vorinostat. Two schedules of vorinostat, (400mg/day orally) beginning on day 1 (arm A) or on day 14 (arm B), were tested in 3 cohorts receiving escalating treatment duration (7days, 10 days and 14 days per cycle) with a classical 3+3 phase I schedule. 7 additional pts were included at the dose level recommended by the DSMB for each cohort (arm A and B). Inclusion criteria were age >18, MDS or AML with 20–30% blasts, IPSS≥1.5, prior failure of AZA. Toxicity was assessed using CTCAE V3. Patients with clinical benefit could continue on therapy after cycle 3 until progression. RESULTS: A total of 42 pts were included and 40 were treated, 23 pts in arm A and 17 pts in arm B. 2 pts died before the beginning of treatment. Median age was 74 years (range 46– 88), median number of previous treatments was 2 (1–3), and median number of cycles of previous AZA treatment was 11 (range 1–25). All pts were IPSS Int-2 (n=21) or High risk MDS (n=19). A total of 137 cycles of treatment was administered with a median number of 3 cycles/pt and 11 pts received more than 3 cycles (28%). The recommended dose was determined for arm A at 10 days of vorinostat and for arm B at 14 days. During cycle 1, dose limiting toxicities were grade 3 fatigue (n=2), grade 4 bilirubin (n=1), and grade 4 infection (n=2), all in arm A. The most frequent non-limiting toxicities were myelosuppression (37/40), infections (8/40) moderate fatigue (23/40) and mild GI toxicities (25/40). Response was centrally reviewed according to IWG 2006 criteria. Overall response rate was 17% in 35 evaluable pts including 2 CRi, 2 HI and 2 marrow CR. Median duration of response of 3 months (range [2–6+]). There were 2 responders in arm A (1 in the 7 day cohort and 1 in the 14 day cohort) and 4 responders in arm B (1 in the 7 day cohort, 2 in the 10 day cohort, 1 in the 14 day cohort) including the 2 CRi. 18 pts remained stable without HI and 11 progressed during treatment. Median overall survival of the cohort was 9.2 months and 1-year probability of survival was 36%. CONCLUSIONS: Our results show that 400 mg/day vorinostat can be combined to LDAC and given for 10 days (arm A) to 14 days (arm B) with acceptable side effects. It also suggests that the sequential administration might be associated with an increased therapeutic index since longer vorinostat therapy duration could be tolerated. Response rate remains modest but survival compared favorably with conventional care in this group of patients with dismal outcome. Disclosures: Fenaux: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Safety and Efficacy Results from a Phase I Trial of Single-Agent Lumiliximab (Anti-CD23 Antibody) for Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2503-2503 ◽  
Author(s):  
John C. Byrd ◽  
Susan O’Brien ◽  
Ian Flinn ◽  
Thomas J. Kipps ◽  
Mark A. Weiss ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Patient Characteristics ◽  
Outpatient Setting ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Treatment Regimens

Abstract The CD23 antigen is expressed at high density on the cell surface of certain B-cell malignancies, including chronic lymphocytic leukemia (CLL). Lumiliximab (L-mab), a macaque-human chimeric anti-CD23 monoclonal antibody, has been reported to have antitumor activity against CLL in preclinical studies. In this Phase I multicenter study, the safety, efficacy, and pharmacokinetics of single-agent L-mab were evaluated in 46 patients with relapsed or refractory CLL. Therapy consisted of intravenous L-mab given as 6 regimens: (1) 125 mg/m2/wk for 4 weeks; (2) 250 mg/m2/wk for 4 weeks; (3) 375 mg/m2/wk for 4 weeks; (4) 500 mg/m2/wk for 4 weeks; (5) 500 mg/m2 for 3 doses during Week 1, then 500 mg/m2/wk during Weeks 2 to 4; and (6) 500 mg/m2 three times a week for 4 weeks. Patient characteristics were as follows: median age of 62 years (range 47 to 80 years), 93% Caucasian, 72% male, 54% fludarabine-refractory, 48% Rai stage III/IV, and 78% WHO Performance Status 1. At study entry, patients had progressive CLL after 1 to 13 prior treatment regimens (median = 4 prior regimens). Antibody infusions, administered over 2 hours in an outpatient setting, were well tolerated. Study-related adverse events (probable, possible, or unknown relationship to study treatment) were reported in 40 of 46 patients (87%). The majority of events were Grade 1 or 2; the most common were headache, constipation, nausea, and cough. Grade 3 or 4 study-related adverse events were reported in 7 of 46 patients (15%) and included neutropenia and dyspnea. Evidence of clinical activity consisted of reductions in absolute lymphocyte counts (ALC) and lymphadenopathy. Decreases in ALC were observed in 42 of 46 (91%) patients, and decreases ≥ 50% were observed in 11 of 40 (28%) patients enrolled at 375 mg/m2/week or higher. Of 37 patients evaluated for change in lymphadenopathy, reductions were observed in 22 (59%). Flow cytometry revealed that L-mab saturated CD23 sites on CLL cells at doses above 375 mg/m2/week without down regulating CD23 expression. These results suggest that single-agent L-mab can be administered safely with evidence of clinical activity in patients with heavily pretreated CLL. Ongoing clinical studies are assessing the potential of L-mab in combination with rituximab and fludarabine-based chemotherapy.

A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by 24 Hour Infusion Every 2 Weeks to Patients with Myeloid Malignancies and Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2654-2654 ◽  
Author(s):  
Gautam Borthakur ◽  
Susan O’Brien ◽  
Farhad Ravandi-Kashani ◽  
Francis Giles ◽  
Aaron D. Schimmer ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Ambulatory Setting ◽  
Clinical Activity ◽  
Qtc Prolongation ◽  
Grade 3

Obatoclax is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It activates apoptosis and has clinical activity in CLL (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. This Phase I trial was designed to evaluate the potential of prolonged infusions to minimize these toxicities while maintaining biological and clinical activity. We enrolled 14 patients at doses ranging from 7–40 mg/m2 over 24 hours every 2 weeks utilizing a modified accelerated titration design with 3–6 patients per cohort and doubling of the dose until 28 mg/m2. Cycle 1 was administered in a clinical research unit to accommodate PK sampling but subsequent cycles were administered in the ambulatory setting using portable infusion pumps. Median age was 62 (range 56–82) and 10 patients were male. The following diagnoses were included: myelodysplatic syndromes (MDS; 8, 4 secondary), refractory acute myelogenous leukemia (AML; 5) and CLL (1). A total of 51 infusions were administered. At doses ≤28 mg/m2, adverse events (AE) of Grade 1 dizziness (2/9), headache (2/9), euphoric mood (2/9) and Grade 2 somnolence (2/9) were of lesser frequency and intensity then at equivalent dose levels previously administered with a 3 hour infusion. At the 40 mg/m2 dose level, dose-limiting toxicities of Grade 3 QTc prolongation with no accompanying arrythmias were reported in 2/5 patients who both had QTc prolongation at baseline. Other toxicities included Grade 2 somnolence (4/5), Grade 1 euphoric mood (3/5), Grade 1 anxiety (2/5) and single reports of Grade 1 dizziness, dysarthria, dysphasia, confusion, hallucination and disorientation. The pharmacokinetics (PK) of obatoclax following a 24-hr IV infusion is dose proportional for both Cmax and AUC24h. Induction of apoptosis was monitored quantitatively with serial determinations of plasma concentration of histone-oligonucleosomal DNA (ODNA) complexes. An early release of ODNA greater than 4-fold occurred in 10/14 patients by the midpoint of the infusion and was sustained to the end of the infusion. The rapid elimination of the plasma obatoclax concentration immediately following the end of infusion was associated with a decline of the plasma oligonucleosomal DNA level; however multiple additional peaks of oligonucleosomal DNA concentrations occurring over days following the infusion were still detected in 9 of 14 patients. 3/8 patients with MDS showed hematological improvement with red blood cell or platelet transfusion independence. Bone marrow blasts were reduced from 14% to 4% in another patient with secondary MDS. Conclusions: Single agent obatoclax is well tolerated when administered as a 24 hour continuous infusion, with abrogation of previously noted infusional CNS toxicities. Biological and clinical activity are retained. Further prolongation of the infusion may lead to more robust activity and will be explored. Phase II single agent trials using 28 mg/m2 over 24 hours every 2 weeks have been initiated in patients with myelofibrosis and previously untreated MDS with anemia and/or thrombocytopenia to further evaluate the potential for hematological improvement in response to obatoclax.

Sign in / Sign up

Export Citation Format

Share Document