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.

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.

Combination Biologic Therapy as Initial Treatment for Follicular Lymphoma: Initial Results From CALGB 50701 - a Phase II Trial of Extended Induction Epratuzumab (anti-CD22) and Rituximab (anti-CD20)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 427-427 ◽  
Author(s):  
Barbara Grant ◽  
John P. Leonard ◽  
Jeffrey L Johnson ◽  
Lale Kostakoglu ◽  
Eric Hsi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Follicular Lymphoma ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Good Tolerability ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 427 Rituximab is effective as single agent therapy in the treatment of follicular lymphoma (FL), and when combined with chemotherapy has extended remissions and survival. Epratuzumab (Immunomedics), a humanized anti-CD22 monoclonal antibody, also has single agent activity in FL, and in combination with rituximab led to durable complete responses in the treatment of patients (pts) with relapsed and refractory indolent NHL. To evaluate the hypothesis that combining a second biological agent with rituximab might improve efficacy with good tolerability, the CALGB treated 60 previously untreated pts with epratuzumab and rituximab in a multicenter phase II trial and we report here the preliminary response and toxicity findings. Rituximab was administered at 375 mg/m2 iv weekly for four weeks, then every 8 weeks for four additional doses for a total of 8 doses over 9 months. Epratuzumab, was given at 360 mg/m2 two days before the first rituximab dose to assess toxicity. From week 2 on, epratuzumab was given before the rituximab on the same day for a total of 8 doses over 9 months. Fifty-seven evaluable pts were enrolled between May 2008 and September 2009. FLIPI scores at study entry were 13 (22%) low; 28 (47.5%) intermediate; and 18 (30.5%) high. Fifty-three pts completed all therapy through month 9. One pt was taken off therapy due to progression after month 5. One pt died during induction from line sepsis. Two pts were taken off study due to adverse events, 1 during induction (grade 4 thrombosis and MI), 1 following month 5 (dyspnea, hypoxia and pulmonary NOS). All other toxicities were grade 3 or lower, including fatigue (grade 3 3%, grade 2 17%), nodal pain (grade 3 5%, grade 2 8%), and cytokine release and pruritis (grade 2, 5% each). To date, there have been 19 CRs (33.3%), 29 PRs (50.9%)(ORR 84.2%); 9 (15.8%) had stable disease. All 19 CR patients completed all treatment. The mean time to CR was 9 months. Two patients progressed after a period of stable disease, and 25 of the 29 patients who achieved PR remain in response. All 19 CRs also remain in remission at this point with a median follow-up of 0.82 years (range 0.52 to 2.0). FLIPI score was not predictive of response. The CR rate in low risk pts was 31%, 44% in intermediate risk and 18% in high risk pts. There was a trend toward higher CR rate among patients with FcgR2A His (n=10, CR 60%) and to a lower CR rate among those with FcgR2A Arg (n=14, CR 14.3%). Correlations with PET scan at week 3, with tissue biomarkers and to statin use are being analyzed. Rituximab and epratuzumab is an effective and very well tolerated regimen with an ORR of 84% in previously untreated patients with follicular lymphoma. Disclosures: Off Label Use: Use of Epratuzumab, a humanized antiCD22 monoclonal antibody in treatment of follicular lymphoma. Leonard:BiogenIDEC: Consultancy; Genentech: Consultancy; Immunomedics: Consultancy. Jones:Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Cheson:Genentech: Consultancy.

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]

Phase I Study of a New Humanized Anti-CD20 Monoclonal Antibody (LY2469298) in Japanese Patients (pts) with Relapsed or Refractory Follicular Lymphoma (FL) Pretreated with Rituximab-Containing Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3942-3942
Author(s):  
Michinori Ogura ◽  
Kensei Tobinai ◽  
Toshiki Uchida ◽  
Yukio Kobayashi ◽  
Takashi Oyama ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Half Life ◽  
Phase I Study ◽  
Volume Of Distribution ◽  
Clinical Activity ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 3942 Background: Pts with FL in whom position 158 on the FcγRIIIa (CD16) gene is heterozygous for valine/phenylalanine (V/F) or homozygous for phenylalanine (F/F) (F-carriers) have natural killer cells with lower binding affinity to IgG than valine homozygote (V/V) pts. These pts showed a lower response rate and shorter time to progression compared with V/V genotype pts after initial rituximab treatment. A humanized IgG1 anti-CD20 monoclonal antibody, LY2469298, was optimized through protein engineering in the Fc region to increase affinity with FcγIIIa and is expected to increase effector function in F-carriers. This phase I study was conducted to evaluate the safety, clinical activity, and pharmacokinetics (PK) of LY2469298 in Japanese pts with relapsed or refractory FL. Methods: Japanese pts with FL who relapsed or progressed after prior treatment, but not within 120 days of prior rituximab, received four infusions of LY2469298 at weekly intervals. The dose was assessed for safety, tolerability, and immunogenicity (HAHA) in 2 cohorts of 100 and 375 mg/m2. Dose-limiting toxicity (DLT) was evaluated from the day of the first infusion until two weeks after the last infusion. Response was evaluated according to the International Workshop Response Criteria (IWRC) at 9 and 21 weeks after the last dose. The PK of LY2469298 were assessed after the first and fourth dose by means of a non-compartmental analysis. Results: Ten pts (male/female: 5/5), median age 60.4 yrs (range: 39–75), were enrolled and treated in 2 cohorts: 3 pts at 100 mg/m2 and 7 pts at 375 mg/m2. The number of pts with stage I/II/III/IV at enrollment was 1/4/1/4, respectively. All pts received 1 or more treatment of prior rituximab alone or rituximab-containing regimen; 3/10 pts were refractory to the regimen. The median number of prior regimens was 2 (range: 1–9). Follicular Lymphoma International Prognostic Index (FLIPI) identified 4 pts at low risk, 2 at intermediate risk, and 4 at high risk. There was one V/V patient in the 375 mg/m2 cohort; all other pts were F-carriers. No DLT was observed in either cohort; therefore, the recommended phase II dose was determined to be 375 mg/m2. The most common adverse events (≥40% of pts) included hematological toxicities and infusion-related reactions: lymphopenia (n=10), pyrexia (8), leukopenia (7), chills (7), and neutropenia (5). Grade 3 or 4 hematological toxicities were lymphopenia (n=7) and neutropenia (2; no G-CSF required). There were no grade 3 or 4 infusion-related reactions; most reactions were limited to the first infusion. B-cell (CD19+) depletion in peripheral blood was rapid and sustained in all pts. B-cell recovery began in the 21-week observation period. LY2469298 was eliminated in a biphasic manner from pts' blood with a elimination half-life of 10 to 14 days. Clearance, elimination half-life, and volume of distribution were similar between the 2 doses. AUC and Cmax increased with dose. Of 10 evaluable pts, responses were observed in 5 pts (3 CR, 1 CRu, and 1 PR). Conclusions: Weekly doses of LY2469298 at 100 and 375 mg/m2 were well tolerated and resulted in evidence of clinical activity in pts with relapsed or refractory FL after prior rituximab alone or rituximab-containing regimens, although 9 of 10 pts were F-carriers. The PK characteristics of clearance, elimination half-life, and volume of distribution of the 2 LY2469298 doses were similar, both of which were eliminated in a biphasic manner. The promising results of this phase I study warrant further investigation of LY2469298 in pts with FL. Disclosures: Off Label Use: LY2469298 is an investigational agent. Matsue:Eli Lilly Japan KK: Employment. Cronier:Lilly UK: Employment. Wooldridge:Eli Lilly & Company: Employment. Koshiji:Eli Lilly Japan KK: Employment.

Phase I Study of RO5072759 (GA101) in Patients with Relapsed/Refractory CD20+ Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1704-1704 ◽  
Author(s):  
Gilles Salles ◽  
Franck Morschhauser ◽  
Thierry Lamy ◽  
Noel Milpied ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Single Agent ◽  
Treatment Phase ◽  
End Of Treatment ◽  
Cd20 Antibody ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 1704 Poster Board I-730 Background RO5072759 (GA101) is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials. In vitro data show GA101 exhibits increased antibody-dependent cytotoxicity (ADCC) and strongly enhanced direct cell death compared to rituximab. Methods In this first Phase I study, GA101 was administered i.v., as a single agent to patients with CD20+ NHL for whom no therapy of higher priority was available. On days 1, 8 and 22 and subsequently every 3 weeks for a total of 9 infusions, flat doses between 50 mg to 2000 mg were given in a safety-driven, dose escalation, 3 × 3 design. The aim was to determine the safety, tolerability, dose-limiting toxicity (DLT), and the pharmacokinetics of GA101. Preliminary phase I data were reported on the first 12 NHL patients (Salles et al, ASH 2008). Here, we present the definitive results of this phase I on 21 NHL patients. Their median age was 64 yrs (39-83) with the following histologies: follicular (n = 13), mantle cell (n = 4), and diffuse large B-cell, Waldenstrom's macroglobulinemia, small lymphocytic, lymphoplasmocytoid (1 each). Patients had previously received a median of 4 (range 1-7) prior regimens [time from last treatment to study entry 12 months], with 95% of patients exposed to prior rituximab and 10/21 (48%) of patients with prior stem cell transplantation. Results GA101 was well tolerated with no DLTs, no dose reductions and no GA101-related Grade 4 toxicities (CTCAE V3.0). Four patients experienced at least one SAE. The most common adverse events were Grade 1 or 2 infusion related reactions essentially limited to the first infusion. Tumor lysis syndrome (Grade 3) was observed in 1 patient. Related Grade 3 hematological toxicities were neutropenia (n = 2; no G-CSF required), anemia (1) and thrombocytopenia (1) and 11/21 patients reported Grade 1-2 infections. No significant change in complement fractions (C3, C3a, C4a, C5, C5a, Bb) was observed. Measurement of plasma cytokines during and immediately after the 1st infusion showed an increase in IL6 and IL8 with a smaller increase in IL10, TNFa and IFN-γ, with recovery by Day 8. Median T-cell (CD3, CD4 and CD8) sub-sets and NK counts were low in all patients prior to therapy. Concurrent to cytokine increase, a further decrease in these lymphocyte sub-sets was observed after the first infusion, recovering thereafter, with median values returning to baseline values by end of treatment. In contrast, B-cell (CD19+) depletion was rapid and sustained in the majority of patients \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(1921\) \end{document}. End of treatment B-cell recovery has been observed in 3 of the responding patients [recovery ranging from 410-532 days after first dose]. No significant changes from baseline immunoglobulin levels were observed. GA101 pharmacokinetics were characterized by two clearance components, one linear component and one time-dependent saturable component consistent with target-mediated disposition, also observed with rituximab. Whilst the plasma concentrations demonstrate a dose-dependent increase, there was significant inter- and intra-patient variability. The time-dependent clearance component is consistent with a reduction in target-mediated antibody clearance with increasing duration of treatment. Responses occurred at all dose levels, and across all FcγIIIRA (158F/V polymorphism) genotypes, with best overall response of 5 CR/CRu, 4 PR (ORR=43%) (all responding patients had histology of fNHL, their median measurable baseline lesions=3295mm2, and 6 patients had prior ASCT), 5 SD, 6 PD & and 1 non-evaluable (premature death unrelated to GA101). Of those 9 responses, 8 responses occurred during the treatment phase. One of the responding patients progressed during the treatment phase and in the follow-up phase one patient with a CR progressed after responding for 5.5 months. Six patients have an ongoing response [4 CR, 2 PR] [response duration ranging from 7.5+ to 17+ months] and in addition, one patient with SD has converted to PR in the follow-up phase [SD for 17 months and PR for 4+ months]. Conclusion GA101 is a next generation anti-CD20 antibody that has shown promising efficacy in this difficult-to-treat patient population. GA101 is currently being explored as a single agent in phase II in relapsed/refractory indolent/aggressive NHL and B-CLL and in combination with chemotherapy in a phase Ib study. Disclosures Salles: Roche: Honoraria. Morschhauser:Roche: Honoraria. Bieska:Roche: Employment. Carlile:Roche: Employment. Cartron:Roche: Honoraria.

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.

First Interim Results of a Phase I/II Study of Lenalidomide in Combination with Anti-PD-1 Monoclonal Antibody MDV9300 (CT-011) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1838-1838 ◽  
Author(s):  
Yvonne A. Efebera ◽  
Ashley E Rosko ◽  
Craig Hofmeister ◽  
Joe Benner ◽  
Courtney Bakan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
T Cell ◽  
Partial Response ◽  
Phase I ◽  
Nk Cells ◽  
Disease Progression ◽  
Stable Disease ◽  
Nk Cell ◽  
Grade 3

Abstract Introduction: Multiple myeloma (MM) is associated with profound and widespread disarray of both the adaptive and innate arms of the immune system including loss of effector T cell function, humoral immune deficiency, and natural killer (NK) cell immunity. This immunosuppressive milieu is crucial to promoting disease progression. Standard treatment options (immunomodulators (IMIDs) and proteosome inhibitors, radiation, and high-dose corticosteroids) offer modest benefit, but also contribute to further immune suppression. Little is known regarding the mechanisms by which immune dysfunction and immunoevasion occur. Our group has characterized an important role for the programmed death receptor-1 (PD-1) / PD-L1 signaling axis in these processes. MDV9300 (formerly CT-011 / Pidilizumab) is a novel IgG1 humanized monoclonal antibody (mAb) that modulates the immune response through interaction with PD-1. Lenalidomide (Len) an IMID exerts efficacy in MM in part through enhancement of NK cell versus MM effect - an effect likely mediated through T cell production of interleukin (IL)-2. In our in-vitro study, pretreatment of NK cells with MDV9300 with or without Len enhanced immune complex formation between NK cells and MM tumor targets and also augmented NK cell activation and cytotoxicity against MM. We sought to determine the safety, tolerability and any early signs of efficacy in relapsed or refractory MM patients using MDV9300 in combination with Len. Methods: In the phase I portion, the primary endpoint is to determine the maximum tolerated dose (MTD) of the combination. Key eligibility criteria are relapsed or refractory disease but not progressed on Len 25 mg; ≥2 prior lines of therapy, absolute neutrophil count ≥ 1000/µL; Platelets ≥60,000/µL; and creatinine clearance of ≥ 40ml/min. Patients are treated with escalating doses of MDV9300 and Len utilizing a 3x3 escalation design (Table 1). If stable disease is the best response after 4 cycles, patients have the option of adding dexamethasone (20-40mg weekly). Len dose may be modified independently of MDV9300. Patients can receive a maximum of 12 cycles of therapy. Results: Twelve patients are evaluable to date. The median age was 68.5 (range 49-82) and the median time from diagnosis 4.98 years (range 1.54-12.62). At study entry, 67% had high risk cytogenetics (del 17p, complex karyotype, gain 1q) and the median number of prior treatment lines was 2 (range 2-11). 100% of patients had received prior Len, bortezomib and Dex, 50% alkylating agents (cyclophosphamide, oral melphalan, bendamustine), 75% autologous stem cell transplant, 25% pomalidomide and 33% carfilzomib. MDV9300 infusion has been well tolerated with only one grade 2 infusion related toxicity with sore throat. The patient received hydrocortisone with no further reaction observed. Grade 3/4 Anemia, neutropenia, and thrombocytopenia attributable to therapy have been seen in 25%, 23%, and 34% of patients, respectively. Other common grade 2-3 therapy related adverse events are fatigue (50%), anorexia (17%), and hypophosphatemia (17%). There has been no grade 3 or higher infection and no worsening of neuropathy from baseline. Len dose was reduced in 3 patients (25%) and increased in one. There has been no dose reduction in MDV9300. Dex 20 mg or less was added in 2 patients for muscle cramps and < PR after 3 cycles. To date 7 patients are off therapy; 1 due to grade 3 fatigue and 6 due to disease progression. Five patients continue on therapy at respective 12, 11, 9, 5 and 3 months. Responses to date have been 3 Very good partial response,1 partial response, 2 minimal response and 2 stable disease. Conclusion: The combination of steroid sparing MDV9300 and Len regimen has demonstrated an acceptable toxicity profile to date with evidence of anti-myeloma activity. This is the first reported combination anti-PD-1 based immune therapy for MM. Updated results will be presented at the meeting including the MTD dose for phase II. Table 1. MDV9300- mg/kg Intravenously given on day 3 every 28 days Lenalidomide- mg orally days 1-21 every 28 days DLT Evaluable DLTs Cohort 1 1.5 15 6 Grade 3 fatigue. Cohort extended to 6 Cohort 2 3 15 3 none Cohort 3 3 25 3 none Cohort 4 6 25 0 Acknowledgments: Drug has been provided by Medivation; The study is sponsored by the American Cancer Society Disclosures No relevant conflicts of interest to declare.

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]

Phase I study of imatinib in combination with gemcitabine and capecitabine

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13523-e13523
Author(s):  
R. C. Ramaekers ◽  
J. Elkahwaji ◽  
E. Reed ◽  
A. Ganti ◽  
J. Wang ◽  
...  
Keyword(s):  
Phase I ◽  
Stable Disease ◽  
Renal Cell ◽  
Phase I Study ◽  
Growth Factor Receptor ◽  
Dose Schedule ◽  
Unknown Primary ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Tumor Types

e13523 Background: Imatinib-mediated inhibition of platelet-derived growth factor receptor lowers tumor interstitial pressure allowing for improved intratumoral antineoplastic drug concentration. A phase I study of imatinib (Im) with the synergistic combination of gemcitabine (Gem) and capecitabine (Cape) was undertaken. Methods: Eligibility requirements included refractory solid tumors, ECOG 0/1 and adequate organ function. A 3-week treatment cycle was used with the dose levels (DL) 0 and -1 as outlined in the table. Dose limiting toxicity (DLT) was defined as occurring within the first 2 cycles of therapy. Patients remained on therapy unless DLT occurred or disease progression. Results: Twelve patients with a median age of 59.5 (range 44 - 77) were evaluable. Baseline characteristics included ECOG PS 0/1: 6/6; prior systemic therapies: median 3 (range 1–6); tumor types: renal (4), melanoma (2), prostate, esophageal, pancreatic, small cell lung, breast, unknown primary. At DL 0, 2 of 6 patients experienced DLT (gr. 3 thrombocytopenia; gr. 4 leucopenia). At DL -1, 1 of 6 patients experienced DLT (gr. 3 thrombocytopenia). No patient missed a dose; one patient in DL -1 completed only 1 cycle. Median cycles administered was 2 (range, 1 - 19). At cycle 2 evaluation, 7 pts had stable disease, 4 had progressive disease and 1 was not evaluable. Grade 3 or 4 toxicity included thrombocytopenia, leucopenia, hyperglycemia and weakness. All hematologic grade 3/4 toxicity was seen in patients having received ≥3 cytotoxic regimens previously. Most common grade 1/2 toxicities included anemia, nausea/emesis and fatigue. One patient with renal cell had stable disease (SD) for 15 cycles and one patient with melanoma had SD for 19 cycles. Conclusions: Im in combination with Gem and Cape is well tolerated in patients without extensive exposure to cytotoxic therapy. Activity is seen in various tumor types particularly melanoma and renal cell. The suggested dose for phase II studies is Im 400 mg/d, Gem 400 mg/m2 and Cape 400 mg/m2 in the dose schedule as described above. [Table: see text] [Table: see text]

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