Phase I study of bavituximab, a novel anti-phosphatidylserine monoclonal antibody in patients with advanced refractory cancer: Preliminary results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1080-1080
Author(s):  
N. K. Ibrahim ◽  
L. Wong ◽  
L. Rosen ◽  
J. Shan
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Study Endpoint ◽  
Preliminary Results ◽  
Fourth Dose ◽  
Grade 3 ◽  
Head And Neck Melanoma ◽  
To Receive

1080 Background: Aminophospholipid are normally expressed on damaged or apoptotic cells, as well as on the intravascular surface of EC of vessels feeding the tumor as a result of the tumor microenvironment (e.g., hypoxia, reactive oxygen species). Bavituximab (B), a novel monoclonal antibody against PS, has demonstrated preclinical anti-tumor activity by eliciting both innate and adaptive immune responses specific to tumor vasculature. Here we report preliminary results of the phase I study in patients (pts) with advanced solid tumors. Methods: This is a phase I, dose escalation, safety, tolerability and pharmacokinetic (PK) study, as well as to define DLT, MTD and/or maximum effective dose (MED) in pts with advanced refractory cancers. Planned cohorts of 6 pts, each were to receive 0.1, 0.3, 1 or 3 mg/kg. Escalation was permitted if mean cohort Cmax ≤ 65 mcg/mL and dose limiting toxicities (DLT) was observed in ≤ 1 of 6 pts. No premedication was planned or needed. DLT was defined as ≥ grade 3 drug-related adverse events (AE), ≥ grade 2 PT, or ≥ grade 3 aPTT. B was given as a 90 minute IV infusion (on days 0, 28, 35, 42 for the first two dose cohorts and 0, 7, 14, 21 for the third- and fourth-dose cohorts. Although not a study endpoint, tumor response was collected at day 56. Results: Data are available for the first 20 pts enrolled (10 breast, 3 colorectal, 2 pancreatic, 1 each of hepatocellular carcinoma, head and neck, melanoma, mesothelioma, and prostate cancer). Cohorts by dose: 0.1 mg/kg (8 pts), 0.3 mg/kg (6pts), and 1 mg/kg (6pts). Median age was 59 years and 70% of pts were females. (Q: see attached Excel file). No DLTs or drug-related severe AEs were reported. Common drug-related AEs were fatigue (7pts), nausea (6 pts), dry skin (3 pts), constipation (2 pts) and dyspnea (2 pts). All AEs were grade 1 or 2 and no dose relationship was observed. PK was dose proportional with mean serum Cmax of 2.3, 5.2 and 16.6 mcg/mL for the 0.1, 0.3 and 1 mg/kg groups, respectively. No accumulation of B was seen after multiple weekly dosing. Conclusions: Single agent bavituximab is well tolerated to date, with a predictable PK profile. Accrual of the last planned cohort is underway. MTD has not been reached. Final results will be available for presentation at the time of the Meeting. [Table: see text]

A Phase I Study of PRO131921, a Novel Anti-CD20 Monoclonal Antibody in Patients with Relapsed/Refractory CD20+ Indolent NHL: Correlation Between Clinical Responses and AUC Pharmacokinetics.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3742-3742 ◽  
Author(s):  
Jonathan W. Friedberg ◽  
Julie M. Vose ◽  
Brad S Kahl ◽  
Mark W. Brunvand ◽  
Andre Goy ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Research Funding ◽  
Phase I Study ◽  
Drug Exposure ◽  
Single Agent ◽  
Dose Cohort ◽  
Clinical Responses ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 3742 Poster Board III-678 PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody engineered to have significantly increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab as shown in in vitro models. In preclinical in vivo lymphoma models, PRO131921 has superior anti-tumor efficacy compared to rituximab. In this Phase I study, PRO131921 was administered as a single agent to patients (pts) with CD20+, relapsed or refractory indolent non-Hodgkin's lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The aim of the study was to determine the safety and tolerability of PRO131921, the maximum tolerated dose (MTD), its pharmacokinetics (PK), and to establish a Phase II dose. Pts were treated with PRO131921 by intravenous infusion (premedication with acetaminophen and anti-histamine) weekly for 4 weeks on days 1, 8, 15 and 22. The dose of the first infusion was approximately 50% that of subsequent infusions. The dose was escalated based on safety in a 3+3 design. PK samples were obtained pre- and post-infusion on days 1, 8, 15, and 22, and once each on days 2, 23, 29, 50, and 78 (and at later time points for up to a year). Twenty-four pts were treated with PRO131921 at doses from 25 mg/m2 to 800 mg/m2. Median age was 58 yrs (38-78). Histologies were follicular NHL (n=20), small lymphocytic lymphoma (n=3) or marginal zone NHL (n=1). Pts had received a median of 2 (range 1-6) prior regimens. PRO131921 was generally well-tolerated and no MTD was reached in the study. The most common adverse events were Grade 1 or 2 (CTCAE V3.0) chills, flushing, itching, fatigue, fever, nausea, dizziness, diarrhea, and hypotension, most of which were part of infusion-related reactions limited in general to the first infusion. These responded well to slowing or interruption of the infusion, and symptomatic treatment (including steroids). Grade 3 AEs (related and unrelated to study drug) included 3 episodes each of transient neutropenia and hypoxia, and single episodes of throat tightness, bronchospasm, syncope, fatigue, periarthritis, pneumonia, and deep venous thrombosis. There was 1 unrelated Grade 4 pulmonary embolism. Two pts did not receive all 4 doses of therapy due to DLTs. One dose limiting toxicity (DLT) was observed in the 200/400 mg/m2 dose cohort due to a significant infusion reaction, and a second was observed at the 300/800 mg/m2 dose cohort due to Grade 3 joint pain and fatigue after 2 infusions. Detailed PK studies of PRO131921 in all patients were broadly similar to rituximab with a dose-dependent increase in exposure, but with significant inter- and intra-patient variability. Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and both tumor shrinkage (p=0.049) and clinical response (p=0.034), consistent with the hypothesis that rapid drug clearance (e.g. by tumor in excess of drug) may result in decreased clinical efficacy. Best investigator-assessed responses to treatment in the 22 evaluable pts by day 78 or later were 6 PR, 13 SD, and 3 PD; 5/10 pts in the two highest dose cohorts responded. In conclusion, PRO131921 has shown clinical activity in rituximab-relapsed and refractory indolent NHL pts. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy. Disclosures: Friedberg: Genentech, Inc.: Honoraria, Research Funding. Vose:Genentech, Inc.: Consultancy, Research Funding. Kahl:Genentech, Inc.: Consultancy, Research Funding. Brunvand:Genentech, Inc.: Speakers Bureau. Goy:Genentech/Biogen IDEC: Consultancy, Speakers Bureau. Kasamon:Genentech/Biogen IDEC: Research Funding. Burington:Genentech, Inc.: Employment. Li:Genentech, Inc.: Employment. Ho:Genentech, Inc.: Employment. Cheson:Genentech, Inc.: Consultancy, Speakers Bureau.

Multicentre Phase I Study with an 8-Dose Regimen of Single Agent Anti-CD20 Monoclonal Antibody LFB-R603 in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2862-2862 ◽  
Author(s):  
Bruno Cazin ◽  
Stéphane Leprêtre ◽  
Bertrand Coiffier ◽  
Thérèse Aurran ◽  
Guillaume Cartron ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Stable Disease ◽  
Dose Regimen ◽  
Phase I Study ◽  
Single Agent ◽  
Safety Data ◽  
Advanced Stage ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 2862 Background: LFB-R603 is a next generation anti-CD20 monoclonal antibody (mAb) with an optimised glycosylation profile resulting in high antibody-dependent cellular cytotoxicity. A weekly × 4 dose regimen of LFB-R603 has been found to induce rapid, profound and sustained blood lymphocyte depletion in patients (pts) with advanced stage CLL in a multicentre first-in human dose-escalation phase I study*. Aims: A second part of the phase I study designed to evaluate a weekly × 8 dose regimen was initiated in April 2010. Objectives were to assess the safety, pharmacokinetics and potential efficacy of LFB-R603 in pts with CLL relapsing after at least one prior course of therapy with fludarabine. Methods: Twelve pts were included. A flat dose of LFB-R603 was administered once a week for 8 weeks consisting of an initial dose of 150 mg followed by 7 doses of 450 mg (total dose 3300 mg). Premedication consisted of allopurinol, dexchlorpheniramine and acetaminophen, combined with methylprednisolone 1mg/kg before the first two infusions. Results: Median age was 69.5 years [62–77], median time from diagnosis to inclusion was 10.4 years [4.0–23.6], number of prior therapies was 3 [1–8]. Seven pts received at least one prior rituximab-containing regimen (median number was 1 [1–3]). Two pts presented with 17p deletion. Bulky (>5cm) lymph node enlargement was observed in 4 pts, splenomegaly in 9 pts, and hepatomegaly in 4 pts. Median WBC count at baseline was 48.5×109/l [9.9–154.2], hemoglobin 11.9 g/dl [7.3–14.0] and platelets 102×109/l [13–193]. Median lymphocyte bone marrow infiltration was 85% [40–94]. Pharmacokinetic (PK) data showed an increase of mean Cmax, AUC¥ and t1/2 term from the first to the eighth infusion from 23.4 to 220.5 mg/L, 732 to 50, 760 mg.h/L, and 13.4 to 147.8 h, respectively whereas mean CL decreased from 424 to 38.6 mL/h. Median lymphocyte counts and relative circulating lymphocyte depletions from baseline at D8, D29, M2, M 4, and M 6 are presented in the table below. Response was evaluated at month 4 according to updated NCI-WG guidelines. Among 11 evaluable pts, overall response rate was 45% (5/11) corresponding to 5 pts in durable partial response (PR). Two additional pts were in PR at month 4 not confirmed 2 months later and 4 pts were in stable disease. Pts with 17p deletion and/or bulky tumor were in stable disease. All pts but one received the planned 8 infusions without any dose reduction. One patient was prematurely withdrawn from the study due to a concomitant secondary leukemia diagnosed after the 2nd infusion of LFB-R603. Interim safety data indicate that all pts presented with at least one drug-related adverse event (AE). Forty percent of the AEs were related to the first infusion, 18% to the second, and 21% to the subsequent infusions. The most frequent (> 10%) drug-related AEs were infusion related reactions (IRR) (75% of the pts, including 33% of pts with grade 3 (CT-CAE v3.0) IRR), neutropenia (58%; 33% with grade 3 and 25% with grade 4), grade 1–2 pyrexia (42%), grade 1–2 thrombocytopenia (42%), grade 1–2 infections (25%), chills (17%), asthenia (17%), and grade 3 hepatic cytolysis (17%). One pt experienced a grade 4 drug-related pancytopenia. All AEs were reversible spontaneously or with supportive care intervention. Conclusion: LFB-R603 induces a promising 45% of ORR in pts with advanced stage CLL at a relatively low dose regimen. PK data indicates that the dose and the schedule of administration could be optimized. Toxicity of LFB-R603 is manageable and makes possible a combination with chemotherapy. Disclosures: Cazin: LFB Biotechnologies: Honoraria. Leprêtre:LFB Biotechnologies: Honoraria. Coiffier:LFB Biotechnologies: Honoraria. Cartron:GSK: Honoraria; Roche: Consultancy, Honoraria; LFB: Honoraria. Sadoun:LFB Biotechnologies: Employment. Segaud:LFB Biotechnologies: subcontractor. Ribrag:LFB Biotechnologies: Honoraria, Research Funding.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

scholarly journals EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
Christine Fuller ◽  
Olivia Campagne ◽  
Tong Lin ◽  
Haitao Pan ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Single Agent ◽  
Pediatric Brain Tumor ◽  
Pi3k Pathway ◽  
Neurosurgical Procedures ◽  
Common Grade ◽  
Grade 3

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

Trisenox® (arsenic trioxide) in Patients with Myelodysplastic Syndromes (MDS): Preliminary Results of a Phase I/II Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1433-1433
Author(s):  
Norbert Vey ◽  
Francois Dreyfus ◽  
Agnes Guerci ◽  
Pierre Fenaux ◽  
Herve Dombret ◽  
...  
Keyword(s):  
Phase I ◽  
Arsenic Trioxide ◽  
Lower Risk ◽  
Single Agent ◽  
Clinical Activity ◽  
Molecular Response ◽  
Improvement Rate ◽  
Preliminary Results ◽  
Duration Of Response ◽  
Grade 3

Abstract Introduction: Single-agent Trisenox® (arsenic trioxide) induces high hematologic and molecular response rates leading to prolonged survival in patients with relapsed/refractory acute promyelocytic leukemia. Arsenic trioxide exhibits multifaceted mechanisms of action, including induction of tumor cell differentiation, apoptosis, and angiogenesis inhibition. Recent reports have documented the clinical activity of arsenic trioxide in MDS patients, leading to improvements in hematologic parameters and to transfusion independence or reduction. We report preliminary results of an ongoing European multicenter phase I/II study of arsenic trioxide in MDS patients. Patient eligibility includes all FAB categories with <30% blasts. Final results of the study will be reported. Methods: Arsenic trioxide is given as a 1-hr IV infusion, loading dose of 0.30 mg/kg/day for 5 days, and maintenance with 0.25 mg/kg/day 2X a week for >15 weeks. Disease assessments are every 8 weeks, by modified IWG response criteria. Patients: 105 patients have been enrolled: median age is 67 years (range 31–89), median time from diagnosis to 1st dose is 10.9 months (range 0.2–117.6). 101 patients have received drug and have been evaluated (78M/23F). 39 patients have IPSS lower-risk (LR: low and Int-1) and 62 have higher-risk (HR: high and Int-2) MDS. FAB categories are RA (9 patients), RARS (11), RAEB (62), RAEB-t (13), and CMML (6). 86 patients were transfusion dependent at baseline. Results: Responses were observed in 27 evaluable patients (27%). They include 1 CR (1%), 20 major Hematologic Improvements (HI: 20%) and 6 minor HI (6%). Responses were seen across the 3 lineages: major HI-Erythroid: 11; major HI-Neutrophil: 8 (including 2 also HI-E); and major HI-Platelet: 6 (including 3 also HI-E). The hematologic improvement rate among LR patients was 9/39 (23%) and among HR patients, 18/62 (29%, including the CR). 14 patients became transfusion independent and an additional 7 patients had transfusions reduced by ≥50%. Responses were seen after 1–3 months of treatment, and median duration of response is 4+ months at this time. The true duration of response is not yet known, as 20 patients were still responding at their most recent assessments. Arsenic trioxide toxicity was manageable and mostly mild; 4 patients had treatment-related grade 3 febrile neutropenia and 1 patient each experienced grade 3 and grade 4 thrombocytopenia. One had grade 4 neutropenia; the only other grade 4 toxicity was 1 pulmonary edema. An additional 14 patients each had a different grade 3 event. QTc prolongation was reported in only 1 patient, who had 2 isolated episodes that were considered clinically insignificant and did not result in treatment delay. No patient had alopecia or severe nausea or vomiting. Summary and Conclusions: These preliminary results indicate that arsenic trioxide is generally well tolerated, even by elderly patients, and that it induces responses in all three hematopoietic lineages, in similar proportions of patients with higher risk and with lower risk MDS. 14 of 86 transfusion-dependent patients became transfusion independent. Final results of the study will be presented.

Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancers (NCI protocol 7156 supported by NCI grant UO1 CA062461)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3549-3549 ◽  
Author(s):  
D. S. Hong ◽  
L. Camacho ◽  
C. Ng ◽  
J. Wright ◽  
R. A. Newman ◽  
...  
Keyword(s):  
Phase I ◽  
Skin Rash ◽  
Dose Escalation ◽  
Phase I Study ◽  
Mapk Pathway ◽  
Synergistic Effects ◽  
Single Agent ◽  
Unknown Primary ◽  
Advanced Cancer Patients ◽  
Grade 3

3549 Background: The Ras and Raf kinases are sequential signaling proteins in the MAPK pathway and inhibition of both targets may confer synergistic effects, particularly in tumors with activation of either kinase through mutation or other mechanisms. Therefore, we sought to combine sorafenib, a multikinase inhibitor (Raf, VEGFR, PDGFR) and tipifarnib an inhibitor of farnesyltransferase that is critical for Ras activity in a phase I study to determine the safety, pharmacokinetics (PK), and tumor response. Methods: The trial was a phase I trial of advanced cancer patients(pts) with a conventional dose escalation design. Each cycle consisted of 28 days of sorafenib and 21 days of tipifarnib. Dose levels are listed in the table . Results: To date, a total of 27 pts have been enrolled (median age 54.5 yrs, M:F 1:1. 3 RCC, 3 breast, 4 sarcoma, 4 melanoma, 3 CRC, 4 thyroid, 2 H&N, one thymic, one adrenal cortical, one SCC of the lung, and one unknown primary SCC). Two pts developed grade 3 DLT-skin rash on the first dosing level (tipifarnib at 100 mg po BID and sorafenib at 400 mg po BID). Dose escalation was modified as per table below. At dose level 4, 2/5 pts entered experienced a DLT of grade 3 rash and grade 3 drug fever, therefore MTD has been determined to be tipifarnib 100 mg BID, sorafenib 400 mg qam, 200 mg qpm. The most common treatment related toxicities included lymphopenia (18), hyperglycemia (17), and skin rash (14). Currently, 19 of the 27 pts are evaluable; 13 pts had SD (8–44 weeks); 2 RCC pts for 32 weeks, an adrenal cortical ca pt for 32 weeks, one melanoma pt for 44 weeks. PK analysis suggested findings similar to single agent PK profiles, no PK interactions were apparent. Conclusions: Significant toxicity with the combination of these two agents, even doses well below single agent maximum levels were observed. The MTD was determined to be tipifarnib at 100 mg BID, sorafenib at 400 mg qam, 200 mg qpm. PK analysis, to date show,no pharmacokinetic interaction between tipifarnib and sorafenib. [Table: see text] [Table: see text]

A humanized anti-CD3 monoclonal antibody, visilizumab, for treatment of severe steroid-refractory ulcerative colitis: Preliminary results of a phase I study

2003 ◽  
Vol 124 (4) ◽  
pp. A7 ◽  
Author(s):  
Scott E. Plevy ◽  
Bruce A. Salzberg ◽  
Miguel Regueiro ◽  
William Sandborn ◽  
Stephen B. Hanauer ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Monoclonal Antibody ◽  
Phase I ◽  
Phase I Study ◽  
Preliminary Results ◽  
Steroid Refractory

A phase I study of IMC-11F8, a fully human anti-epidermal growth factor receptor (EGFR) IgG1 monoclonal antibody in patients with solid tumors. Interim results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3024-3024 ◽  
Author(s):  
B. Kuenen ◽  
E. Witteveen ◽  
R. Ruijter ◽  
A. Ervin-Haynes ◽  
M. Tjin-A-ton ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Stable Disease ◽  
Phase I Study ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Igg1 Monoclonal Antibody ◽  
Initial Cohort ◽  
To Receive

3024 Background: This ongoing phase I study is being conducted to determine the safety profile and recommended dose of IMC-11F8, a fully-human IgG1 monoclonal antibody that targets the EGFR. Methods: Patients (pts) with advanced solid tumors who are refractory to or have no available standard therapy are eligible to receive IMC-11F8 intravenously either weekly or every other week for 6 weeks (1 cycle). The initial cohort of patients will receive 100 mg of IMC-11F8. In the absence of a dose-limiting toxicity (DLT), dose escalation will be 200, 400, 600, 800, and 1000 mg in successive cohorts. Prior to the initial cycle, pts receive one IMC-11F8 infusion at their assigned cohort followed by a 2-week pharmacokinetic (PK) period. Pts with stable disease or better after cycle 1 are eligible to receive additional cycles of IMC-11F8. Results: 31 of 40 pts have been enrolled in the 100-, 200-, 400-, 600-, and 800-mg cohorts. Pt characteristics are M/F 20/11, median age 58 years (37 - 76), median ECOG score 1 (0–2). No DLTs have been observed. Only grade 1/2 skin rashes were reported. The most frequent adverse events were nausea, vomiting, fatigue, and headache. No infusion reactions were observed. 2 pts (1 confirmed) have achieved a PR, 1 pt with melanoma in the 200-mg cohort with 39+ weeks of weekly IMC-11F8 treatment and 1 pt with rectal cancer in the 400-mg cohort with 20+ weeks of IMC-11F8 administered every other week. 5 pts in the 200- to 600-mg cohorts have stable disease and have received from 11+ to 35+ weeks of IMC-11F8 treatment. A noncompartmental analysis of 20 pts demonstrated that IMC-11F8 exhibits nonlinear PK. As IMC-11F8 escalated from 100 to 600 mg, T1/2 increased from 67 to 84 hrs, Cmax increased from 30 to 368 μg/mL, AUCinf increased from 1753 to 67295, and CL decreased from 57.0 to 8.9 mL/hr. Conclusions: These interim results indicate that IMC-11F8 is well tolerated in this patient population. Although a maximum tolerated dose has not been established, IMC-11F8 has shown activity at two different dose levels. [Table: see text]

Results of a phase I study of clofarabine (CLO) plus cyclophosphamide (CY) in adult patients (pts) with relapsed and/or refractory acute lymphoblastic leukemia (ALL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7020-7020
Author(s):  
S. Faderl ◽  
D. A. Thomas ◽  
V. Gandhi ◽  
X. Huang ◽  
G. Borthakur ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Lymphoblastic Leukemia ◽  
Nyha Class ◽  
Single Agent ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Infectious Complications ◽  
Acute Leukemias ◽  
Grade 3

7020 Background: CLO is a second generation nucleoside analog with FDA approval for children with ALL relapse. Single agent CLO in adult ALL was less active so that combinations of CLO with other active agents are pursued. As CLO inhibits DNA repair following exposure to DNA damaging agents, we designed a phase I study of the combination of CLO with CY. Methods: Pts ≥ 21 years (yrs) with primary refractory or relapsed ALL, NYHA class < 3, and a cardiac ejection fraction ≥ 45% were eligible. The continual reassessment method (CRM) was used to determine the maximum tolerated dose (MTD) from 4 pre-defined dose levels. The starting dose level was CLO 40 mg/m2 i.v. daily x 3d and CY 200 mg/m2 i.v. q12h x 3d. For cohort 2, CY was 300 mg/m2 and cohorts 3 and 4 maintained these doses with the treatment duration extended to 4 and 5 days, respectively. Results: Thirty pts have been enrolled. Median age was 28 yrs (range 21–72). Twenty-one pts had pre-B ALL, 5 pts pre-T/T ALL, 1 pt mature B ALL, and 3 pts biphenotypic acute leukemias. Karyotype was diploid in 10 pts and 2 pts had Ph+ ALL. Median number of prior regimens was 2 (1–5). Seven (23%) pts were primary refractory. Among the remainder, preceding median remission duration was 8.6 mos (1–39 mos). Five pts were treated in cohort 1 and 25 in cohort 2. One (20%) pt in cohort 1 and 9 (36%) in cohort 2 experienced DLTs (≥ grade 3) including transaminase elevations, diarrhea, hyperbilirubinemia, and (1 pt each) elevation of creatinine/renal failure, lipase elevation, rash, nausea/vomiting. Evaluable for response were 28 pts: 3 CR (one pt in cohort 1) and 1 marrow CR (OR 14%). All pts had pre-B ALL. One pt had Ph+ ALL, and one was primary refractory to HCVAD. Three early deaths due to infectious complications occurred (all in cohort 2). Conclusions: The MTD for this combination is CLO 40 mg/m2 i.v. daily x 3d and CY 200 mg/m2 i.v. q12h x 3d. DLT are mainly GI-related. A phase II extension is ongoing and will focus on efficacy data. [Table: see text]

Phase I study of sunitinib (SU) in combination with pemetrexed (Pem) in patients (pts) with advanced solid tumors (ST)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14630-e14630
Author(s):  
K. Nakagawa ◽  
I. Okamoto ◽  
T. Shimizu ◽  
M. Miyazaki ◽  
J. Tsurutani ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Japanese Patients ◽  
Fixed Dose ◽  
Solid Malignancies ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor ◽  
To Receive

e14630 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSR-1, and shows antitumor activities in several types of solid malignancies. Non-small-cell lung cancer (NSCLC) xenograft data indicate SU enhanced the antitumor activity of Pem. This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of combination therapy with the oral SU and Pem for Japanese patients with advanced ST. Methods: Pts with ST refractory to standard therapy were randomly assigned to receive either oral SU 50 mg/day for 2 weeks followed by 1 week rest (Schedule 2/1, S-2/1) or SU 37.5 mg continuous daily dose (CDD). Fixed-dose Pem (500mg/m2 IV) was administered on day1 every 21 days. A standard “3+3” design was employed in both treatment schedules and treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. Results: A total of 12 pts (med. age 63 years, range 49–69; 10 Male/ 2 Female) have been enrolled (6 pts in the S-2/1 arm and 6 pts in the CDD arm). The most common cancer is NSCLC (9 pts, 75%). All patients completed their first cycle for DLT evaluation, and no DLTs were observed in either treatment arm. The most common toxicities were fatigue (n=8), anorexia (n=6), and thrombocytopenia (n=12). Treatment-related ≥ grade 3 adverse events (AEs) included fatigue (n=1), hypertension (n=1), neutropenia (n=4), leucopenia (n=3), thrombocytopenia (n=2), lymphopenia (n=2), and increased ALT (n=1). Three pts (S-2/1: 2, CDD: 1) required dose reduction of SU due to G3 toxicities. All toxicities were clinically manageable and reversible. One pt with NSCLC had a documented PR with cavity formation inside the tumor. Conclusions: SU 37.5 mg/day (CDD schedule) plus Pem 500mg/m2 every 21 days, and SU 50 mg/day (S-2/1 schedule) plus Pem 500mg/m2 every 21 days were well tolerated and associated with encouraging antitumor activity. [Table: see text]

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