A Phase I Study Of The Oral Btk Inhibitor ONO-4059 In Patients With Relapsed/Refractory B-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4397-4397 ◽  
Author(s):  
Simon Rule ◽  
Nimish Shah ◽  
Gilles Andre Salles ◽  
Lionel Karlin ◽  
Franck Morschhauser ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoid Cells ◽  
Flat Dose ◽  
Btk Inhibitor

Abstract Introduction The B-cell receptor (BCR) pathway plays a central role in signal transduction pathways that regulate survival, activation, proliferation and differentiation of B-lineage lymphoid cells. Bruton’s tyrosine kinase (Btk) is a critical kinase in BCR signal transduction and recent studies support that targeting Btk is effective in the treatment of B-cell malignancies. ONO-4059 is a highly potent and selective oral Btk inhibitor with an IC50 in the sub-nmol/L range that has demonstrated anti-tumour activity in several pre-clinical models (Yasuhiro T et al, AACR 2013). Methods This Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), pharmacokinetics and pharmacodynamics of ONO-4059 given as monotherapy to patients with relapsed/refractory NHL for whom no therapy of higher priority was available. In this safety-driven, dose-escalating 3+3 design, ONO-4059 was administered as an oral, daily dose (flat dose) given continuously initially for up to 6 months, with the option of additional dosing up to 2 years. We present the safety and efficacy data on 14 evaluable patients (mantle cell lymphoma n=7, follicular lymphoma n=3, plasmablastic DLBCL n=1, ABC-DLBCL n=1, small lymphocytic lymphoma n=1 and Waldenstrom’s macroglobulinaemia n=1), with a median age 64 yrs (range 48-88), median baseline tumour burden 5,668 mm2 [1,582-19,509]. Patients received a median of 3 prior therapies [range 2-8], with all patients having prior exposure to a rituximab-containing regimen 93% (13/14) and 29% of patients (4/14) had prior ASCT. Patients received ONO-4059 at doses ranging from 20mg-160mg (cohorts 1-4) and the study is currently ongoing with additional dose escalation cohorts to be completed. Results ONO-4059 was found to be well tolerated, with no dose limiting toxicities (DLTs). A total of 18 ONO-4059-related adverse events were reported in 6 out of 14 patients; CTCAE-V4.0 G1 (n=10 [n=6 in 1 patient]) and G2 (n=5). Three ONO-4059-related G3 haematological toxicities were reported in 2 patients; thrombocytopenia (x2) and anemia. No ONO-4059-related G4 events, or related SAEs or infections were reported. The pharmacokinetics of ONO-4059 reflects rapid absorption and elimination, a half-life of ∼6 hours, a dose dependent increase in exposure with no accumulation of ONO-4059 exposure and low inter- or intra-patient variability; with Btk occupancy in peripheral blood (as measured by phosphorylated Btk) being maintained for at least 24 hours across all dose levels. Responses have occurred at doses of 40, 80 and 160mg, with a best overall response rate of 42% [based on CT-scan and physical examination for 5/12 evaluable patients]; with 5 PR, 4 SD, 2 PD (both MCL) and one ABC-DLBCL patient was withdrawn due to non-related SAE during Cycle 1. Of the 6 evaluable MCL patients, 3 have achieved PR resulting in a best ORR of 50% (median reduction of lymph nodes was 73% [45%-84%]). Almost all patients experienced clinically meaningful rapid reductions in lymphadenopathy observed within the first cycle. Ten of the fourteen patients are currently still on study with a median progression-free survival of 93.5 days [Range 8-268]. In conclusion, ONO-4059 is a highly potent and selective oral Btk inhibitor that shows a favourable safety profile along with promising efficacy in this difficult-to-treat patient population. Disclosures: Salles: Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Karlin:Janssen: Honoraria; Celgene: Honoraria. Morschhauser:ONO Pharma: Honoraria; Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Dyer:Ono Pharma: Honoraria, Research Funding. Hutchinson:Ono Pharma: Research Funding. Fegan:ONO Pharma: Honoraria. Cartron:ONO Pharma: Honoraria. Knurowski:ONO Pharma: Consultancy. Wright:ONO Pharma: Consultancy. Saunders:ONO Pharma: Consultancy; Pharmacyclics: Consultancy. Honda:ONO Pharma: Employment. Mazur:ONO Pharma: Consultancy. Yoshizawa:Ono Pharma: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment. Birkett:Ono Pharma UK: Employment.

A Multicenter Phase I Study of the Humanized Anti-CD19 Monoclonal Antibody, MEDI-551, in Patients with Relapsed or Refractory B-Cell Lymphoma and Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1756-1756 ◽  
Author(s):  
Michinori Ogura ◽  
Kiyoshi Ando ◽  
Naokuni Uike ◽  
Yoshiaki Ogawa ◽  
Toshiki Uchida ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Stock Ownership ◽  
Multicenter Phase ◽  
Related Reaction

Abstract Background: MEDI-551 is an affinity-optimized and afucosylated humanized IgG kappa anti-CD19 monoclonal antibody enhanced for antibody-dependent cellular cytotoxicity. In a previous multicenter, phase 1/2 trial conducted in the United States and Europe, an overall disease control (objective response + stable disease) rate of 73.5% was achieved with MEDI-551 in patients (N=83) with relapsed or refractory B-cell malignancies, and median progression-free survival was 9.4 months (95% CI, 3.9–18.6 months) (Forero-Torres A, et al. 2013, ASH meeting). Objective: We conducted an open-label, multicenter, phase 1 dose escalation study of MEDI-551 in Japan in patients with relapsed or refractory B-cell lymphoma and myeloma to determine the safety profile, maximum tolerated dose (MTD) or optimal biologic dose (OBD), and the preliminary antitumor activity of MEDI-551. Methods: Patients aged 20 years or older with relapsed or refractory chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or multiple myeloma (MM) were enrolled at 3 institutes in Japan. All patients received MEDI-551 (at 2, 4, or 8 mg/kg) intravenously on days 1 and 8 of the first 28-day cycle, then once every 28 days, with an additional dose cohort of 12 mg/kg added. Dose escalation continued to the maximum dose of 12 mg/kg or until MTD was reached. Therapy continued for 2 cycles after the achievement of complete response (CR) or until unacceptable toxicity or disease progression. Dose-limiting toxicity (DLT) was defined as a MEDI-551–related adverse event (AE) that inhibited completion of a full first cycle of MEDI-551, or as a grade ≥3 toxicity that could not be attributed to another cause. Results: From April 2011 through June 30, 2014, a total of 20 patients, including 6 with DLBCL, 11 with FL, 2 with CLL, and 1 with MM, received study treatment across 4 dose levels (2-mg/kg cohort; n=3; 4-mg/kg cohort, n=7; 8-mg/kg cohort, n=4; 12-mg/kg cohort, n=6). Two DLTs, including one infusion-related reaction and one case of neutropenia/leukopenia, were observed at the 12-mg/kg dose; thus, the MTD was determined to be 8 mg/kg. The AEs most commonly reported (in ≥15% of patients) were infusion-related reaction, hypertriglyceridemia, leukopenia, nasopharyngitis, decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and rash. A serious AE of epiglottitis (not treatment-related) was observed on day 64 after 4 cycles of MEDI-551 12-mg/kg. No treatment-related deaths were reported. Two patients with 12-mg/kg were discontinued due to treatment-related AEs (infusion-related reaction, decreased neutrophil count). Among 20 patients evaluable for response, 2 and 10 patients achieved CR and partial response, respectively, with an overall response rate of 60%. Six patients (30%) had stable disease. Response was obtained in 3/6 patients with DLBCL, 0/2 with CLL, 9/11 with FL, and 0/1 with MM, and in 2/3 at the MEDI-551 2-mg/kg dose, 3/7 at 4 mg/kg, 3/4 at 8 mg/kg, and 4/6 at 12 mg/kg. Data from this phase I study are being finalized. Conclusions: This phase I study demonstrated acceptable toxicity and preliminary but promising antitumor activity of MEDI-551, with an MTD of 8 mg/kg, in Japanese patients with relapsed or refractory DLBCL or FL. Disclosures Ogura: AstraZeneca: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Eizai: Research Funding; Symbio: Research Funding; Kyowahakko-Kirin: Research Funding; Chugai: Research Funding; Zenyaku: Research Funding; Otsuka: Research Funding; Dainippon Sumitomo: Research Funding; Jansen: Research Funding; Soraisia: Research Funding; Mundi: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Ando:Kyowahakko-Kirin: Research Funding. Yagawa:AstraZeneca: Employment; AstraZeneca: Stock ownership, Stock ownership Other. Yokoi:AstraZeneca: Employment; AstraZeneca: Stock ownership, Stock ownership Other.

scholarly journals PF515 A PHASE I STUDY OF THE BTK INHIBITOR ABIVERTINIB (AC0010) IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL LYMPHOMA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 210
Author(s):  
M. Yang ◽  
J. Qian ◽  
J. Huang ◽  
Y. Jiao ◽  
W. Tang ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Btk Inhibitor

scholarly journals A PHASE I STUDY OF THE BTK INHIBITOR ABIVERTINIB (AC0010) IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL LYMPHOMA

HemaSphere ◽  
2019 ◽  
Vol 3 ◽  
pp. 210
Author(s):  
M. Yang ◽  
J. Qian ◽  
J. Huang ◽  
Y. Jiao ◽  
W. Tang ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Btk Inhibitor

scholarly journals A Phase I Study of Nivolumab and Lenalidomide in Relapsed/ Refractory B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4091-4091 ◽  
Author(s):  
David A. Bond ◽  
Vedat Yildiz ◽  
Lai Wei ◽  
Lapo Alinari ◽  
Basem M. William ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Board Of Directors ◽  
Immune Checkpoint ◽  
Research Funding ◽  
Phase I Study ◽  
Progressive Disease ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees

Introduction: Both lenalidomide and monoclonal antibodies targeting the immune checkpoint PD-1, including nivolumab, have single agent activity in subsets of patients with Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL). Lenalidomide mediates increased T cell IL-2 production and may enhance T and NK cell response to immune checkpoint blockade resulting in synergistic activity, but with potential for overlapping immune related toxicities. We conducted a phase I study to determine the safety, tolerability, and maximum tolerated dose (MTD) of nivolumab and lenalidomide in patients with relapsed/ refractory (R/R) HL and NHL. Methods: Patients (age ≥18 years) with R/R B-cell NHL who were transplant ineligible or patients with R/R HL with ≥ 2 prior lines of treatment were eligible (NCT03015896). Inclusion criteria included ECOG performance status ≤ 2, creatinine clearance ≥ 40 mL/min, platelets ≥ 100,000/mm3, absolute neutrophil count (ANC) ≥ 1,500/mm3, and bilirubin ≤ 1.5 times the upper limit of normal. The primary objective was to determine the MTD of lenalidomide when combined with nivolumab given at standard fixed dosing. Nivolumab was administered as 240 mg IV every 2 weeks; lenalidomide was administered orally on days 1-21 of 28-day cycles. Aspirin 81 mg daily was required for thromboprophylaxis in patients not already receiving therapeutic anticoagulation. Dose escalation of lenalidomide was performed using a 3+3 design, with dose levels (DL): 10 mg (DL -1), 15 mg (DL 1), and 20 mg (DL 2). Dose limiting toxicity (DLT) was defined within cycle 1 as grade Gr 3 or 4 non-hematologic toxicity, Gr 3/4 febrile neutropenia, any Gr 5 toxicity, or either ANC ≤ 500/mm3 or platelets < 25,000/mm3 persisting > seven days. Adverse events (AEs) were reported using CTCAE Version 4.0. Responses were investigator assessed according to the 2014 Lugano criteria. Results: Ten patients were enrolled. The median age was 68.5 (range 23-80), 5 were male, and the histologic diagnoses included diffuse large B cell lymphoma (DLBCL) in 5 patients (1 GCB, 4 non-GCB including 2 double expressor), high grade B cell lymphoma (HGBCL) in 1 patient, HL in 3 patients, and lymphoplasmacytic lymphoma in 1 patient. Two DLTs occurred at DL 1: Gr 3 rash requiring dose interruption and subsequent dose reduction in one patient and Gr 3 generalized weakness in a patient with rapidly progressive disease, considered possibly related to therapy. Six patients were treated at DL -1 with no DLTs. Gr ≥ 3 AEs occurred in 9/10 patients (Table 1). Neutropenia occurred in 7/10 patients: Gr 4 in two patients (both DL1), Gr 3 in four patients, and Gr 2 in one patient. Gr 3 rash occurred in two patients, and Gr 3 lung infection (pneumonia), Gr 3 fatigue, and Gr 3 duodenal hemorrhage (at site of DLBCL involvement) all occurred once respectively. Thromboembolic events occurred in two patients, one Gr 3 and one Gr 2. One Gr 4 non-hematologic AE occurred, Gr 4 respiratory disorder (COPD exacerbation) considered unrelated to treatment. One patient with rapidly progressive HGBCL prior to study entry died on study due to disease progression. Immune related AEs included Gr 1 hypothyroidism and Gr 1 fever in one patient. Common non-hematologic AEs of any grade are summarized in Table 2. Therapy related AEs lead to treatment discontinuation in one patient (Gr 3 rash and Gr 3 neutropenia); three additional patients required dose reductions of lenalidomide due to therapy related AEs. As of July 1, 2019, one patient remains on treatment. Therapy was discontinued for disease progression in five patients, including one patient who died on study from progressive disease. Three patients discontinued treatment without progression in order to pursue definitive therapy (axicabtagene ciloleucel, autologous transplant, and allogeneic transplant respectively). Three patients achieved an objective response, one complete response and two partial responses, with an additional three patients with best response of stable disease, two of whom discontinued for alternative therapies without progression of disease. Conclusions: We determined the MTD in R/R HL and NHL to be 10 mg lenalidomide in combination with 240 mg nivolumab. Treatment discontinuation due to toxicity was uncommon as were immune related AEs. A pre-planned phase 2 study in DLBCL and dose expansion study in HL is underway to evaluate preliminary efficacy of this combination at the MTD. Disclosures William: Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Christian:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Merck: Research Funding; Janssen: Research Funding; Cephalon: Research Funding; Bristol-Myers Squibb: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Millennium Pharmaceuticals Inc: Research Funding. Maddocks:Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma

2018 ◽  
Vol 24 (24) ◽  
pp. 6150-6159 ◽  
Author(s):  
Kevin R. Kelly ◽  
Jonathan W. Friedberg ◽  
Steven I. Park ◽  
Kevin McDonagh ◽  
John Hayslip ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Aggressive B Cell Lymphoma

A Phase I Study of Myeloablative I-131-Anti CD-20 (Tositumomab) Radioimmunotherapy with Escalating Doses of Fludarabine Followed by Autologous Hematopoietic Stem Cell Transplantation (ASCT) for Adults ≥ 60 Years of Age with High-Risk or Relapsed/Refractory B-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 663-663
Author(s):  
Ajay K. Gopal ◽  
Ted Gooley ◽  
Joseph Rajendran ◽  
John M. Pagel ◽  
Darrell R. Fisher ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
B Cell ◽  
Radiation Exposure ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Nucleoside Analogs ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Abstract 663 Background: The majority of patients with relapsed or refractory B-cell, non-Hodgkin's lymphoma (NHL) are over 60 years of age, yet many are denied potentially curative high-dose regimens due to concerns of excessive toxicity. We have shown that myeloablative anti-CD20 radioimmunotherapy (RIT) can safely deliver effective radiation doses to tumor sites while limiting exposure to normal organs in older adults requiring high-dose therapy, however, not all patients in this series remained progression-free (Gopal, JCO 2007). Preclinical data suggest that improved anti-tumor activity may be attained by the concurrent administration of nucleoside analogs (fludarabine, cytarabine) which synergize with RIT (Johnson, Int J Cancer; Gopal, BBMT, 2006). We hypothesized that a prolonged regimen of fludarabine could be administered concurrently with myeloablative RIT and ASCT to safely augment the efficacy of this approach. We present the phase I data evaluating this strategy. Methods: Patients were eligible if they were 60 years of age or older, had mantle cell lymphoma (MCL) in first remission or relapsed/refractory B-NHL, an ECOG PS of 0–1, acceptable organ function, >2×106 autologous CD34+ peripheral blood stem cells/kg collected, <20 Gy prior radiation to critical organs, and no human-anti-mouse-antibodies (HAMA). All patients underwent outpatient biodistribution studies for dosimetry using tositumomab (1.7 mg/kg, n=3 or 485mg flat dose, n=33) labeled with ∼10mCi I-131 followed by serial quantitative gamma camera imaging to calculate individualized organ-specific absorbed dose estimates. Patients then received therapeutic infusions of I-131-tositumomab to deliver 27Gy to the critical normal organ receiving the highest radiation exposure. Forty-eight hours later fludarabine was administered in escalating doses to patients (Table) to define a regimen associated with a dose limiting toxicity (DLT = grade III/IV Bearman toxicity) rate of <25%. ASCT occurred when radiation exposure was estimated to be <2mR/hr at 1meter. Filgrastim at 5μg/kg/day or pegfilgrastim at 6mg × 1 was started on day 1. Response was scored using standard criteria. Results: Between July 2005 and May 2011 36 patients were treated. Baseline characteristics included: median age 65 yrs (range 60–76), stage III/IV = 34 (94%), median number of prior regimens = 2 (range 1–9), chemoresistant disease (defined as < a partial response [PR] to the most recent regimen) = 12 (33%), >1 extranodal site = 14 (39%), elevated LDH at treatment = 13 (36%), IPI score at transplant 3–5 = 53%. Histology: MCL = 23, diffuse large B-cell = 8 (with 5 transformed from follicular lymphoma [FL]), FL=3, and marginal zone = 1, Waldenstrom's = 1. Dose limiting organs receiving up to 27Gy included lung (30), kidney (4), and liver (2) with a median administered I-131 activity of 471 mCi (range 260–1620). Fludarabine was escalated from 10 mg/m2/day × 5 days to 30 mg/m2 × 7 days without observation of a DLT (Table). The median CD34 dose was 5.42 ×106/kg with neutrophil (ANC>500μl) and platelet (>20 K/μl) engraftment occurring a median on 10 and 12 days after ASCT, respectively. Only 2 patients developed grade 4 NCI-CTC grade 4 non-hematologic toxicities (hypokalemia/hypophosphatemia, depression), 25 (69%) remained outpatients after discharge from radiation isolation, and there were no non-relapse deaths in the first 100 days after transplant. Responses to therapy were as follows: CR/CRu = 26 (79%), PR = 2 (6%), SD = 4 (11%), and PD = 4 (11%). Currently, 23 (64%) patients are alive with 22 (61%) progression free. The estimated 3 yr overall survival, progression-free survival, relapse, and non-relapse mortality are 54%, 53%, 41%, and 7%, respectively (median follow up of 2.5yrs after ASCT, Figure). Improved survival was associated with <2 prior regimens (HR=.08, p=.02) and chemosensitive disease (HR=.35, p=.07). Conclusions: High-dose (27 Gy) I-131 tositumomab can safely be administered concurrently with up to 210 mg/m2 fludarabine in an older, high-risk patient population. This strategy warrants further investigation as a method to safely augment the antitumor activity of myeloablative RIT. Disclosures: Gopal: GSK: Research Funding; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Piramal: Research Funding; Cephalon: Research Funding; Millenium: Speakers Bureau; Abbott: Research Funding; Pfizer: Research Funding; SBio: Research Funding; Bio Marin: Research Funding; Biogen-Idec: Research Funding. Off Label Use: High-dose use of I-131-tositumomab. Maloney:GSK: Consultancy, Honoraria.

A Phase I Study of DCDT2980S, an Antibody-Drug Conjugate (ADC) Targeting CD22, in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 59-59 ◽  
Author(s):  
Ranjana Advani ◽  
Daniel Lebovic ◽  
Mark Brunvand ◽  
Andy I. Chen ◽  
Andre Goy ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Antibody Drug Conjugate ◽  
Safety And Efficacy ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

Abstract Abstract 59 Introduction: CD22 is a lineage marker expressed in most B-cell lymphomas. DCDT2980S is an ADC consisting of an anti-CD22 monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a potent microtubule disrupting agent linked to the antibody via a protease-cleavable peptide linker. DCDT2980S exhibits potent anti-tumor activity in murine xenograft models of B-cell lymphoma and is being evaluated in a Phase I study to assess the safety, tolerability, pharmacokinetics (PK), and biologic activity in patients (pts) with relapsed/refractory B-cell NHL. Methods: Pts receive DCDT2980S intravenously every 21 days at dose levels 0.1 to 3.2 mg/kg until disease progression or unacceptable toxicity. Intrapatient dose escalation based on tolerability at higher doses is permitted. Following determination of the recommended Phase II dose (RP2D) based on protocol-defined dose-limiting toxicities (DLTs) occurring within 21 days of dosing, additional pts with indolent and aggressive B-cell NHL are being enrolled to further evaluate safety and efficacy based on Cheson response criteria. Here we report the RP2D and preliminary safety and efficacy results. Results: To date, 35 pts (57% male), median age 66 years (range 30–85) have been enrolled: diffuse large B-cell lymphoma (DLBCL, n=18), follicular lymphoma (FL, n=11), transformed FL (n=4), and small lymphocytic lymphoma (n=2). Enrolled patients were heavily pre-treated: 26 pts had received ≥ 3 prior regimens, all pts had received prior rituximab, and 7 pts received prior high-dose therapy followed autologous or allogenic stem cell transplantation. Overall, pts received a median of 4 doses (range 1–25) of DCDT2980S in 7 dose-escalation cohorts, and 2 expansion cohorts at the RP2D. All 3 pts treated with DCDT2980S at 3.2 mg/kg developed Grade 4 neutropenia following the first dose, one of which constituted a DLT. No DLTs were reported in the 6 pts treated at 2.4 mg/kg, which is the RP2D. Across all dose levels, the most common treatment-emergent adverse events (AE) in ≥ 20% of pts were diarrhea (34%), fatigue (34%), nausea (31%), neutropenia (26%), decreased appetite (23%), vomiting (23%), and peripheral edema (20%). Treatment-emergent Grade ≥ 3 AEs were reported in 9 (27%) pts including 5 out of 9 pts who were treated at the RP2D of 2.4 mg/kg. Overall, neutropenia (24%) was the only Grade ≥ 3 AE in ≥ 10% of pts (24%) and was the only Grade ≥ 3 AE reported in > 1 pt (n=2) treated at the RP2D. Eight (26%) pts across all dose levels experienced a serious AE (SAE) of which one Grade 3 dehydration in a pt treated at 3.2 mg/kg was attributed to DCDT2980S. Treatment discontinuation due to AEs occurred in 3 pts: Grade 3 neutropenia (n=1) and Grade 3 peripheral sensory neuropathy (n=2). No deaths were reported within 30 days of the last dose of DCDT2980S. Assessment of Cycle 1 PK after the first dose of DCDT2980S indicated that the exposure of antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE increased with dose. The clearance estimates of both acMMAE and total antibody were similar across doses from 1.0–3.2 mg/kg. The volume of distribution estimates for acMMAE and total antibody approximated plasma volume and did not change with dose and suggest dose-proportional increase of acMMAE and total antibody exposures for doses of 1.0–3.2 mg/kg. Early evidence of anti-tumor activity was observed. At the RP2D of 2.4 mg/kg, 2 of 3 pts with DLBCL had > 75% reduction in tumor sum of perpendicular dimensions (SPD) and negative PET scans; 1 partial response was noted in a pt with FL treated at 1.8 mg/kg. These 3 pts continue on study, each having received at least 8 cycles of study treatment. Two additional pts with DLBCL receiving 0.5 mg/kg and 3.2–2.4 mg/kg had > 50% reduction in tumor SPD and discontinued study treatment after 8 and 6 cycles, respectively, to undergo stem cell transplant. Conclusions: In this early experience, DCDT2980S is well tolerated, has a favorable safety profile and has evidence of anti-tumor activity in in a heavily pretreated pts with relapsed/refractory B-cell NHL. Updated clinical data will be presented. These results support additional clinical evaluation of DCDT2980S in B-cell malignancies. Disclosures: Advani: Genentech: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A. Lebovic:Genentech: Speakers Bureau. Brunvand:Genentech: Speakers Bureau. Chen:Genentech: Research Funding. Chang:Genentech: Research Funding. Ho:Genentech: Employment. Kahn:Genentech: Employment. Lu:Genentech: Employment. Su:Genentech: Employment. Chu:Genentech: Employment.

A phase I study of IV aflibercept (Afl) in combination with R-CHOP in untreated patients (pts) with B-cell lymphoma.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 8010-8010 ◽  
Author(s):  
F. Kuhnowski ◽  
C. Thieblemont ◽  
F. Jardin ◽  
F. Broussais-Guillemot ◽  
M. Meignan ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma

Safety, Pharmacokinetics, and Preliminary Clinical Activity of Inotuzumab Ozogamicin, a Novel Immunoconjugate for the Treatment of B-Cell Non-Hodgkin's Lymphoma: Results of a Phase I Study

2010 ◽  
Vol 28 (12) ◽  
pp. 2085-2093 ◽  
Author(s):  
Anjali Advani ◽  
Bertrand Coiffier ◽  
Myron S. Czuczman ◽  
Martin Dreyling ◽  
James Foran ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Inotuzumab Ozogamicin ◽  
Large B Cell Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Large B Cell

Purpose Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22+ B-cell non-Hodgkin's lymphoma (NHL). Patients and Methods Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m2. Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m2. Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. Conclusion Inotuzumab ozogamicin has demonstrated efficacy against CD22+ B-cell NHL, with reversible thrombocytopenia as the main toxicity.

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