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.

Evaluation of Oral Azacitidine Using Extended Treatment Schedules: A Phase I Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 603-603 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Steven D. Gore ◽  
Christopher R. Cogle ◽  
Elias J. Jabbour ◽  
M. Renee Ward ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Research Funding ◽  
Phase I Study ◽  
Treatment Schedule ◽  
Employment Equity ◽  
Transfusion Independence ◽  
Clinical Responses ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 603 Parenteral azacitidine (AZA) is approved for administration on days 1–7 of a 28-day treatment schedule. Based on the short plasma half-life of AZA, S-phase restricted incorporation into DNA, and rapid re-methylation of DNA, it is possible that chronic daily exposure could enhanced its clinical activity. An oral formulation would be convenient and allow evaluation of lower doses administered on extended schedules. The initial phase I study of oral AZA, administered daily on a 7-day schedule demonstrated that it was bioavailable, safe, and clinically active in patients with MDS and AML (Garcia-Manero G, et al. Blood 2009;114:A117). Here, we report the results of a multicenter phase I exploration of extended oral AZA schedules, including dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary response data. Patients aged ≥ 18 years with MDS, CMML or AML (not candidates for other therapies) were enrolled in the study. Inclusion criteria were a hemoglobin level of ≤ 9.0 g/dL, and/or platelet count of ≤ 50 × 109/L, and/or be RBC transfusion-dependent; prior azanucleoside therapy was not permitted. Patients received oral AZA daily (QD) or twice daily (BID) on 14- or 21-days schedules, with starting at a dose of 300 mg for QD dosing and 200 mg for BID dosing. Patients were enrolled into cohorts of 6 and evaluated for DLTs at the end of Cycle 1. Patients were monitored continuously for adverse events (AEs) and assessed for disease response at the end of every second cycle. During Cycle 1, on the first and last day of treatment, PK parameters were derived from AZA concentrations in the plasma after the first dose of the day. PD samples were collected during the first 2 cycles and DNA methylation changes were evaluated using a LINE-1 assay. To date, 25 patients (median age 68 years [range 44–87]; 14 male and 11 female) with MDS (n = 13), AML (n = 7 de novo and n = 3 transformed), and CMML (n = 2) have received oral AZA on extended treatment schedules. Two DLTs, grade 3 nausea and grade 3 vomiting, occurred in 1 of 6 DLT-evaluable patients treated at 14-days QD (n = 7). No DLTs were observed on the 21-day QD (n = 6) or 14-day BID (n = 6) schedules; safety evaluation for the 21-day BID schedule is ongoing (n = 6). The maximum tolerated dose has not been reached on these schedules; no patient has received > 300 mg per dose. Overall rates of all grades nausea, vomiting, diarrhea, constipation, and abdominal pain with the extended schedules were similar to those observed with the oral 7-day schedule. The rate of febrile neutropenia (all grades) was higher in the 21-day QD cohort. This was observed in 4 patients with baseline ANC < 500 and/or AML diagnosis. Most common grade 3/4 AEs in the QD schedules were febrile neutropenia (14-day, 1/7; 21-day, 4/6), anemia (14-day, 1/7; 21-day, 0/6), thrombocytopenia (14-day, 1/7; 21-day, 1/6), diarrhea (14-day, 0/7; 21-day, 1/6), nausea (14-day, 1/7; 21-day, 0/6), and vomiting (14-day, 1/7; 21-day, 0/6). Extended BID schedules are under evaluation. PK data have been generated for 19 of 25 patients. For the 300 mg 14-day QD, 300 mg 21-day QD, and 200 mg 14-day BID schedules, using mean AUC (first and last day) results, extrapolated cumulative exposures per cycle were ~28%, 42% and 26%, respectively, compared with historical exposure observed following subcutaneous administration. AZA exposure increased with increasing dose, but was not dose-proportional. Clinical responses were observed for MDS/CMML patients on both extended QD schedules, with assessment ongoing for BID schedules (Table). In summary, extended (14- and 21-day) dosing of oral AZA is generally well tolerated, with no AZA accumulation, and promising clinical responses were observed, including complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Table. Parameter, n (%) Oral AZA Treatment Schedule MDS/CMML Responders/Evaluable patients, (%) 14-day QD 21-day QD Overall response* (CR, mCR, any HI) 5/6 (83) 3/3 (100) CR 0/6 2/3 (67) mCR 0/6 3/3 (100) HI 5/6 (83) 3/3 (100) HI-erythroid 3/5 (60) 1/1 (100) HI-platelet† 2/5 (40) 3/3 (100) HI-neutrophil 0/1 0/1 Transfusion independence 3/4 (75) 1/2 (50) RBC 1/2 (50) 1/1 (100) Platelet 2/2 (100) 0/1 * International Working Group 2006 criteria, patients only counted once for overall response, but may be counted more than once in individual response categories. † Includes patients achieving partial (≥ 50%) or complete platelet transfusion independence. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Cogle:Celgene: Research Funding, Speakers Bureau. Ward:Celgene: Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment. Giordano:Celgene: Employment, Equity Ownership. Kantarjian:Celgene: Research Funding. Skikne:Celgene: Employment.

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]

scholarly journals A Phase I Study of Lenalidomide and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2318-2318
Author(s):  
Elizabeth A. Griffiths ◽  
William Brady ◽  
Wei Tan ◽  
Carlos E Vigil ◽  
James E. Thompson ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase I Study ◽  
Response Rate ◽  
Single Agent ◽  
Grade 3 ◽  
Acute Myeloid ◽  
Intermediate Dose

Abstract Background: Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Although cytarabine arabinoside (AraC) is the most active drug, constituting the backbone of a majority of r/r regimens, the benchmark response to therapy remains a dismal 17 to 20% (Burnett, Wetzler et al. JCO, 2011.). The immunomodulatory drug lenalidomide (Len), is approved by the Food and Drug Administration for multiple myeloma and myelodysplasia and has demonstrated activity as a single agent in AML at doses as high as 50 mg for 21 days (d) of a 28 d cycle (Blum et al, JCO, 2010.). Based upon this activity profile we developed a phase I study to evaluate the safety and tolerability of Len in combination with AraC in patients with r/r AML. Methods: Eligible patients were older than 18 years(y), had r/r AML with an Eastern Cooperative Oncology Group performance status better than 2 and adequate renal and hepatic function. Patients were excluded for active CNS disease, uncontrolled infections, congestive heart failure, adrenal insufficiency, anti-cancer therapy within 14 d of enrollment, or prior exposure to Len. All enrolled patients had to practice appropriate contraception. Patients received AraC 1.5 g/m2/d over 3 hours on d 1-5 of a 28 day cycle, with a plan for standard 3+3 Len dose escalation. Initial patients received Len 25 mg on d 6-10 (n= 3), subsequent patients received doses between 25 and 10 mg (dose de-escalation) on d 6-26 with 2 d of rest prior to the next cycle. Following induction, patients who had residual AML (>5%) could receive a second identical course of therapy, provided they demonstrated an improvement in blast percentage relative to baseline. Patients who achieved CR received maintenance with Len 10 mg/d continuously. A 12 patient expanded cohort was enrolled at the maximum tolerated dose (MTD) to assess efficacy. Responses were assessed by International Working Group Criteria for AML (Cheson B et al. JCO, 2003.). Patient Characteristics: Fifty-one patients were consented and 45 were treated on study, 32 of these were evaluable for response, all patients were evaluated for toxicity. Approximately half the patients were female (20/45). The median age was 66 y (range 33-82) and median WBC 2.42x109/L (range 0.18-63.15). Four patients (8%) had an antecedent hematological disorder. By European LeukemiaNet criteria 2 patients (4%) had favorable risk disease, 8 (18%) were Int-1, 12(27%) were Int-2 and 11 (24%) were adverse risk; 12(27%) patients were not evaluable by ELN due to lack of karyotype or molecular data from diagnosis. Twelve patients had primary refractory AML. Results: The MTD for Len given on d 6-26 in combination with AraC at 1.5 g/m2/d x 5 d was 10 mg. Dose de-escalation from the starting dose of 25 mg on this schedule was required due to excess toxicity. The most commonly observed non-hematologic drug related adverse events seen on the study (all < grade 2 unless indicated) were nausea, increased liver function tests (>grade 3), rash (grade >3), hypokalemia (> grade 3) and fatigue. At the 25 mg dose level the dose limiting toxicity was rash, while patients enrolled at the 15 mg dose level experienced dose limiting elevation in LFTs, fatigue and bleeding. Five patients achieved a CR (16%), 5 demonstrated CRi (16%) and there were 3 hematological improvements (HI) for an overall response rate (CR+Cri+HI) of 41% (13/32). The median overall survival (OS) (95% confidence interval) for patients treated on study was 5.8 (2.5, 10.6) months and disease free survival was 3.4 (2.3, 6.2) months. Conclusions: Although prior interesting data support the activity of single agent high dose Len in r/r AML, our single institute phase I study of intermediate dose AraC followed by Len was associated with marked skin and other toxicities at the Len 25 mg dose level, precluding dose escalation to the historically more active 50 mg dose. The CR rate in this study was not dissimilar to previously reported responses with single agent or combination AraC based regimens. Issues of dose and schedule for this combination may have had a significant impact on the potential benefit for these two drugs in combination. Nevertheless, the overall low CR rate from this study does not suggest any superiority for this combination in comparison with the historical single agent response rate for intermediate dose AraC in r/r AML. Disclosures Griffiths: Celgene, Incyte and Alexion: Honoraria; Astex Pharmaceuticals: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Other. Wetzler:MedPace: Consultancy; Bristol Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Plexus: Consultancy; Celgene: Research Funding.

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.

A Phase I Trial of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Combination with Rituximab (R) and Bendamustine in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1643-1643 ◽  
Author(s):  
Kristie A. Blum ◽  
Beth Christian ◽  
Joseph M. Flynn ◽  
Samantha M. Jaglowski ◽  
Jeffrey Alan Jones ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Irreversible Inhibitor ◽  
Grade 3 ◽  
Dose Reductions

Abstract Abstract 1643 Introduction: Ibrutinib is an orally available, irreversible inhibitor of BTK, a downstream protein in the B-cell receptor signaling pathway critical for normal B-cell development. In a phase I study in patients with relapsed B-cell malignancies (Fowler ASH 2010), the overall response rate (ORR) was 43%, with responses observed in patients with relapsed mantle cell (MCL), diffuse large B-cell (DLBCL), follicular (FL), and marginal zone lymphoma (MZL). In a phase II single agent study in MCL (Wang ASH 2011), ORR was 67% with several responding patients remaining on ibrutinib over 1 year. Rituximab (R) and bendamustine is a highly active regimen with ORR ranging from 52–92% in patients with relapsed/refractory NHL. This phase I study was designed to determine the maximum tolerated dose, dose limiting toxicity (DLT), toxicities, and preliminary efficacy of R-bendamustine in combination with ibrutinib in patients with relapsed/refractory NHL. Methods: Eligibility included patients with relapsed/refractory FL, MZL, MCL, transformed NHL, and DLBCL, and patients with previously untreated MCL not candidates for autologous stem cell transplantation (ASCT). ANC ≥1000/mm3, platelets ≥50,000/mm3, and creatinine ≤ 2.0 mg/dL were required at study entry. Prior ASCT, rituximab, bendamustine, and ibrutinib were permitted. Treatment consisted of R 375 mg/m2 day 1, bendamustine 90 mg/m2days 1 and 2, and escalating doses of ibrutinib (280 mg or 560 mg) days 1–28 every 28 days for 6 cycles. Six patients were enrolled at each dose level. Responding patients could continue ibrutinib alone after cycle 6 until disease progression or unacceptable toxicity. Pegfilgrastim was permitted for patients with grade 4 neutropenia during cycles 1–6. Response was assessed after cycles 3 and 6 by International Harmonization Criteria (Cheson, JCO 2007). Results: Eleven patients (9 males) with a median age of 72 (range 45–84) previously treated with a median of 3 prior therapies (range 0–10) were enrolled. Six patients were refractory to their most recent therapy, 4 patients had prior ASCT, 2 patients had received prior bendamustine, and no patients had prior ibrutinib. Other characteristics included stage III-IV disease in 82%, extranodal involvement in 64%, elevated IPI ≥3 in 55%, bulky adenopathy ≥5 cm in 45%, B-symptoms in 45%, and elevated LDH in 36%. Histologies included MCL (n=3), DLBCL (n=3, all germinal center origin by Hans immunohistochemical criteria), transformed NHL (n=2), FL (n=2), MZL (n=1). Nine patients completed two or more cycles of therapy (median 3, range 1–6) with 280 mg of ibrutinib (n=6) and 560 mg of ibrutinib (n=3). Two patients who discontinued therapy prior to completing cycle 1 for progressive disease (PD) at 280 mg and 560 mg of ibrutinib, respectively, were replaced. Six patients continue to receive protocol treatment. The 5 patients off study included the 2 patients with DLBCL and transformed NHL who were replaced for PD prior to completing cycle 1, 2 patients with DLBCL and PD after cycles 3 and 4, and 1 patient with MCL receiving 280 mg ibrutinib with R-bendamustine who discontinued due to grade 3 neutropenia lasting > 14 days after cycle 4. No DLTs have been observed. Grade 3–4 events included lymphopenia (64%), neutropenia (27%), thrombocytopenia (18%), pancreatitis (9%), vomiting (9%), shingles (9%), and rash (9%). Dose reductions from 280 mg ibrutinib to 140 mg were required in 3 patients for grade 3 thrombocytopenia, pancreatitis, and rash. Bendamustine dose reductions to 60 mg/m2were required in 1 patient for grade 3 thrombocytopenia. ORR was 38% in 8 evaluable patients, with 3 patients currently receiving protocol treatment who have not yet undergone restaging scans. Responses included 2 complete responses and 1 partial response in the 3 patients with MCL. Conclusions: Combined ibrutinib with R-bendamustine appears well tolerated without unexpected toxicity and with preliminary activity in patients with previously untreated and relapsed MCL. Three additional patients will be accrued to the 560 mg dose level and expansion cohorts examining this combination specifically in patients with FL, DLBCL, and MCL are planned. Disclosures: Blum: Pharmacyclics: Research Funding. Off Label Use: Ibrutinib is not approved for the treatment of NHL. Jaglowski:Pharmacyclics: Research Funding. Maddocks:Pharmacyclics: Research Funding. Byrd:Pharmacyclics: Research Funding.

A Phase I Study of the Safety and Pharmacokinetics of Escalating Doses of MFGR1877S, a Fibroblast Growth Factor Receptor 3 (FGFR3) Antibody, in Patients with Relapsed or Refractory t(4;14)-Positive Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4029-4029 ◽  
Author(s):  
Suzanne Trudel ◽  
P. Leif Bergsagel ◽  
Seema Singhal ◽  
Ruben Niesvizky ◽  
Raymond L. Comenzo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Human Monoclonal Antibody ◽  
Volume Of Distribution ◽  
Central Volume ◽  
Grade 3

Abstract Abstract 4029 Introduction: Chromosomal translocation of the FGFR3 oncogene in t(4;14)-positive multiple myeloma (MM) causes FGFR3 overexpression in plasma cells, chemoresistance, and poor prognosis leading to shorter overall survival in MM patients (pts). MFGR1877S is a human monoclonal antibody that targets FGFR3 to prevent ligand binding, receptor-receptor association, and FGFR3 signaling. In preclinical studies, anti-FGFR3 antibody suppresses FGFR3-mediated cell proliferation, and exerts strong anti-tumor activity in mouse xenograft models of both t(4;14)-positive MM and bladder carcinoma. Methods: This Phase I study assessed the safety, tolerability, and biologic activity of MFGR1877S given intravenously, weekly for 3 weeks, followed by every 28-day dosing, to eligible patients with t(4;14)-positive MM. Dose escalation started with single-pt cohorts at 1 and 2 mg/kg, followed by a standard 3+3 dose-escalation scheme at doses ranging from 4–15 mg/kg. Dose escalation decisions were made based on monitoring pts for dose-limiting toxicities (DLT) during the first 22 days on study. FGFR3 expression, safety, pharmacokinetics (PK), and response (EBMT/IMWG criteria) were assessed. Main efficacy outcome measures include serum/urine M protein and free light chain (FLC) quantities. Results: A total of 14 pts (median age 66, range 45–78; 43% female) with a baseline ECOG status of 0–2, and a median number of 5 prior therapies (range 1–10), received a median of 3.5 doses (range 1–7) of MFGR1877S. Adverse events (AEs) deemed related to MFGR1877S were diarrhea, fatigue, and nausea (14% each), and anemia, increased creatinine, bone pain, confusion, decreased appetite, myalgia, and fever (7% each). The only Grade ≥ 3 related AE was fatigue (7%). Six pts experienced 9 serious AEs (SAE), one of which was Grade 2 pyrexia attributed to MFGR1877S that occurred within 24 hours of infusion and required hospitalization. This pt later discontinued due to a second SAE of Grade 2 pyrexia requiring hospitalization not attributed to MFGR1877S. One pt died of intracranial hemorrhage not attributed to MFGR1877S. No Grade 4 SAEs were reported. Other reported SAEs included Grade 3 hypercalcemia, neutropenia, pain in extremity, and musculoskeletal chest pain (1 pt each), Grade 2 ankle fracture, pneumonia, and pyrexia × 2 (1 pt each). No maximum tolerated dose was identified, as no DLTs were observed through the highest dose tested (15 mg/kg). Preliminary PK analysis for limited number of multiple myeloma patients (n=14) by non-linear mixed effect modeling demonstrated a trend of dose proportional increase of exposure (area under the concentration-time curve and maximal concentration) from 2 to 15 mg/kg. Population clearance of MFGR1877S was estimated to be ∼0.62 L/day, suggesting that MFGR1877S appeared to have a slightly faster clearance in MM patients, compared to the typical IgG1 monoclonal antibody clearance in human. The central volume of distribution of MFGR1877S was ∼3.4 L, which approximated human serum volume and appeared similar to the central volume of distribution of other typical IgG1 monoclonal antibodies. While some degree of FGFR3 expression was detected by immunohistochemistry in 10/14 patient bone marrow samples taken at screening, FACS analysis of FGFR3 surface expression on myeloma cells, although largely consistent with IHC measurements, also revealed heterogeneity in the levels of detectable surface FGFR3 expression. Six pts had stable disease as their best response: 2 pts up to 4 cycles, 1 pt up to 3 cycles, and 3 pts up to 1 cycle. Conclusions: MFGR1877S was well-tolerated overall in these patients with multiple relapsed or refractory MM. Although no objective responses were observed, stable disease was observed in 3 pts for 3–4 cycles. Disclosures: Off Label Use: MFGR1877S is a human monoclonal antibody that targets FGFR3 to prevent ligand binding, receptor-receptor association, and FGFR3 signaling. Singhal:Millennium and Celgene: Speakers Bureau. Niesvizky:Onyx, Millemium, Celgene. Speakers bureau: Millenium and Celgene: Consultancy, Research Funding. Comenzo:Millenium, Neotope; Onyx, Osiris, Millenium: Consultancy, Research Funding. Lebovic:Genentech: Speakers Bureau. Choi:Genentech: Employment. Lu:Genentech: Employment. French:Genentech: Employment. Penuel:Genentech: Employment. Ho:Genentech: Employment.

Phase I Study of the Novel Surivin and cdc2/CDK1 Inhibitor Terameprocol in Patients with Advanced Leukemias.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1039-1039 ◽  
Author(s):  
Raoul Tibes ◽  
Kevin T. McDonagh ◽  
Lazaros Lekakis ◽  
Neal Frazer ◽  
Scott Mohrland ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
Drug Exposure ◽  
Hematological Malignancies ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
The Novel ◽  
Regulatory Pathways ◽  
Apoptosis Protein ◽  
Grade 3

Abstract Abstract 1039 Poster Board I-61 Background: The inhibitor of apoptosis protein (IAP) survivin is central in integrating proliferative and cell cycle regulatory networks. In leukemic cells, survivin mediates survival as well as resistance to chemotherapeutics and Flt-3 inhibitors. Experimentally targeting survivin has shown anti-leukemic activity and is a postulated therapeutic approach. Herein we report a clinical trial with the novel survivin and cdc2 (CDK1) inhibitor Terameprocol (EM-1421) in patients (pts) with advanced hematological malignancies. As little is known about in-vivo up- and downstream regulatory pathways of survivin and it's inhibition, specimens from pts were collected for correlative pharmacodynamic (PD) marker analysis. Methods: Open-label, single agent, phase I dose escalation study of Terameprocol (T) in pts with advanced, relapsed or refractory hematological malignancies (AML, ALL, MDS, advanced CLL or CML). Pts age > 18 years with adequate organ function and performance status (ECOG) ≤ 1were treated with 1000, 1500 and 2200 mg of intravenous Terameprocol 3x/week (wk) for 2 of 3 wks in cohorts of 3 pts to establish the safety, maximum tolerated dose (MTD) and to assess pharmacokinetics at the studied dose schedule (primary objectives). Secondary objectives were to select the recommended phase 2 dose (RP2D) and to assess anti-leukemic activity and PD marker regulation (baseline, cycle 1 day 5 and 12, end of study). Results: Between 8/2007 and 3/2009, sixteen pts (4 female, 12 male) with a median age of 68.5 years (range 42-78) and median of 2 prior regimens (range 0-5) were enrolled. Most pts had AML (n=13), 7 pts primary and 6 pts secondary or treatment related AML; one pt each had CML-BP, T-ALL and MDS. Ten pts had unfavorable or complex cytogenetics including 6 pts with 5q/7q and 2 pts with 11q23 aberrations. Four, 5 and 6 pts were treated at the 1000, 1500 and 2200 mg dose cohorts respectively. One pt did not start treatment on study. 15 pts received ≥ 1 dose/cycle, 6 of whom (38%) received ≥ 2 cycles of T (range 1-5). Common possible or probable treatment related adverse events (AE) were grade 1 or 2 headache (n=3, 20%), transaminitis (grade 2 n=2, grade 3 n=2) and pruritus (n=2). Treatment related serious AE's (SAE) was a grade 4 pneumonia in 1 pt. Non-drug related SAE's ≥ grade 3 or 4 included sepsis/febrile neutropenia (n=3), pneumonia (n=2), dyspnea (n=2), cerebral hemorrhage (n=1), confusion/mental status change (n=1), cardiac arrest (n=1) and AML progression (n=3) leading to death in 2 pts. No AE/SAE was felt to constitute a dose limiting toxicity (DLT) per protocol definition. However, due to grade 3 transaminitis observed in 2 pts together with concerns of compromised respiratory status of pts treated at the 2200 mg cohort, the investigators determined the maximum tolerated dose (MTD) to be 1500 mg 3x/week for 2 of 3 weeks, which is also the recommended RP2D. One heavily pretreated pt (3 prior regimens) with CML-BP myeloid, achieved a partial remission (1500 mg) and transfusion independence for 5 cycles prior to disease progression. Hematological improvement (HI-E, HI-P) was seen in 1 pt (1000 mg), and 5 pts had stable disease. Surprisingly, Cmax of T at 1500 mg was higher than at 2200 or 1000 mg. Overall concentrations of T were in the same range as measured in previous studies of T in solid tumors (daily x5), indicating adequate drug exposure at the schedule studied. PD samples at indicated time points were collected and are currently being analyzed to assess the effects of T on survivin, cdc2/CDK1 and survivin associated regulatory genes. Conclusion: The novel small molecule surivin inhibitor Terameprocol can be safely administered to pts with advanced leukemias. Sufficient drug exposure was seen in pts and the MTD and RP2D were established for future studies. Clinical activity was observed in a pt with myeloid CML-BP and potentially in pts with AML. Interestingly, previous work showed an association between progression to advanced stages of CML and survivin expression. Data on correlative PD marker experiments will be presented. Disclosures: Tibes: Erimos Pharmaceuticals : Research Funding. McDonagh:Erimos: Research Funding. Frazer:Erimos Pharmaceuticals: Employment. Mohrland:Erimos Pharmaceuticals: Employment. Von Hoff:Erimos Pharmaceuticals: Consultancy.

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.

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