Phase I Study of Novel Prodrug Dual PI3K/mTOR Inhibitor SF1126 In B-Cell Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1783-1783 ◽  
Author(s):  
Joseph R Garlich ◽  
Michael D Becker ◽  
Candace F Shelton ◽  
Wenqing Qi ◽  
Xiaobing Liu ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Mtor Inhibitor ◽  
International Workshop ◽  
Mtor Inhibitors ◽  
B Cell Malignancies ◽  
Mtor Inhibition ◽  
Over Time

Abstract Abstract 1783 Background: The PI3K/Akt/mTOR signaling pathway is an attractive target to inhibit for cancer therapy because it is altered in many cancers and is vital to essential biological processes. While inhibition of specific PI3K isoforms, such as δ, has demonstrated efficacy in B-cell malignancies, recent studies suggest that inhibition of all Class IA isoforms (α, β, and δ) is essential to produce maximal inhibition of cell proliferation and to induce apoptosis. For example, the pan PI3K inhibitor LY294002 has been shown to inhibit both the viability and chemotaxis of chronic lymphocytic leukemia (CLL) B-cells, whereas a PI3K δ inhibitor did not. Dual PI3K and mTOR inhibition is also expected to offer a therapeutic advantage, as several mTOR inhibitors have demonstrated promising activity in B-cell malignancies, including the mobilization of CLL cells from tissue sites into the circulation that could enhance the cytotoxicity of other agents. Objectives: The role of PI3K in a wide range of normal biologic processes raises potential safety concerns about dual inhibition of mTOR and all PI3K Class I isoforms. The objective of this Phase I study is to demonstrate that SF1126 can overcome these concerns by accumulating preferentially in tumor tissue to both maximize efficacy and minimize toxicity. SF1126 is a peptidic prodrug that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors. LY294002 is conjugated to an Arg-Gly-Asp (RGD) peptide via a cleavable linker to form SF1126, which has improved properties for clinical use. As a prodrug with improved solubility and site selectivity due to targeting of RGD-recognizing integrin receptors, SF1126 opened up a new avenue for the clinical development of LY294002. Furthermore, the fact that proliferation of CLL cells requires stromal support mediated through cytokines and adhesion molecules (eg, integrins) provides additional biological rationale for testing a RGD-targeted agent as a treatment for CLL. Methods: Based on translational studies demonstrating that LY294002 induces apoptosis in CLL cells and sensitize CLL cells to cytotoxic drugs, patients with CLL and other B-cell malignancies will be enrolled on this expanded Phase I trial at the maximum administered dose of SF1126 (1110 mg/m2) as determined by 47 patients treated to date in dose-escalation studies. SF1126 will be administered intravenously over 90-minutes on days 1 and 4 weekly in cycles of 4 weeks. Patients with CLL will be assessed using the International Workshop on CLL (IWCLL) criteria and patients with indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL) will be assessed using the International Workshop Group (IWG) criteria. Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of PI3K in tumor cells from patients enrolled in this trial. Results: At the maximum administered dose of 1110 mg/m2, SF1126 appears to be well tolerated and demonstrates activity in relapsed and refractory CLL patients treated to date in this ongoing Phase I study. Similar to the tumor flare reaction (TFR) demonstrated in CLL patients treated with immune-modulating agents, such as lenalidomide, two patients treated with SF1126 experienced TFR during the cycle one, day 1–4 time period. TFR has been postulated to be associated with a drug-induced, immune-mediated anti-tumor response and is manifested as an acute onset of swelling of involved lymph nodes that is not associated with disease progression. Time course analysis by flow cytometry of isolated lymphocytes from the first two CLL patients treated demonstrate consistent increases in late apoptosis over time relative to baseline following the first dose of SF1126. Western blot analyses of isolated lymphocytes from the first CLL patient treated demonstrate decreased pAKT (473) signaling and increased PARP cleavage over time relative to baseline. One CLL patient with a 17p deletion genotype demonstrated clinical activity as indicated by stable disease and significant lymph node decreases accompanied by an increases in absolute lymphocyte count (ALC) as seen with the mTOR inhibitor everolimus. The trial continues to enroll patients and updated results from this study will be presented. In view of SF1126's ability to mobilize CLL cells into the circulation, combination studies with synergistic agents that are effective against circulating CLL cells are also being planned. Disclosures: Garlich: Semafore Pharmaceuticals: Employment, Patents & Royalties. Becker:Semafore Pharmaceuticals: Consultancy, Patents & Royalties. Shelton:Semafore Pharmaceuticals: Consultancy. Qi:Seamfore Pharmaceuticals: Research Funding. Liu:Semafore Pharmaceuticals: Research Funding. Cooke:Semafore Pharmaceuticals: Research Funding. Mahadevan:semafore pharmaceuticals: Research Funding.

scholarly journals Safety and Antitumor Activity of Acalabrutinib for Relapsed/Refractory B‐cell Malignancies: A Japanese Phase I Study

2021 ◽  
Author(s):  
Koji Izutsu ◽  
Kiyoshi Ando ◽  
Daisuke Ennishi ◽  
Hirohiko Shibayama ◽  
Junji Suzumiya ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
B Cell Malignancies

scholarly journals Efficacy and safety of the dual SYK/JAK inhibitor cerdulatinib in patients with relapsed or refractory B‐cell malignancies: Results of a phase I study

2019 ◽  
Vol 94 (4) ◽  
Author(s):  
Paul A. Hamlin ◽  
Ian W. Flinn ◽  
Nina Wagner‐Johnston ◽  
Jan A. Burger ◽  
Greg P. Coffey ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Jak Inhibitor ◽  
Efficacy And Safety ◽  
B Cell Malignancies

Phase I Study of On 01910.Na (rigosertib), a Multikinase PI3K Inhibitor in Relapsed/Refractory B-Cell Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1803-1803 ◽  
Author(s):  
Mark Roschewski ◽  
Mohammed Farooqui ◽  
Georg Aue ◽  
Clifton C. Mo ◽  
Janet Valdez ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Phase I Study ◽  
Clinical Testing ◽  
B Cell Malignancies ◽  
Biologic Activity ◽  
Flat Dose ◽  
Clinical Responses ◽  
Secondary Endpoints

Abstract Abstract 1803 Background: Chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and related B-cell malignancies are incurable diseases that universally relapse after initial therapy. Resultant cytopenias in refractory patients are a common barrier to salvage therapy. Innovative targeted agents with favorable tolerability profiles that can overcome acquired mechanisms of resistance are urgently needed. ON 01910.Na (rigosertib) is a selective non-ATP competitive multikinase inhibitor that potently inhibits PI3 kinase and induces reactive oxygen species and NOXA-dependent apoptosis in vitro. Pre-clinical testing of rigosertib demonstrated selective cytotoxicity against CLL and MCL cells with minimal effects on normal B and T cells (Chapman et al 2012). Extensive clinical testing of rigosertib in patients with solid tumors or myelodysplastic syndromes (MDS) has indicated lack of myelosuppression and overall good tolerability (Raza et al ASH 2011 #3822). Here, we present the results from the phase I study assessing the safety and maximum tolerated dose (MTD) of intravenous rigosertib in patients with relapsed CLL, MCL, and related B-cell malignancies. Materials and Methods: phase I dose-escalation clinical trial was conducted to evaluate the safety and efficacy of rigosertib in patients with CLL, MCL, MM, and HCL who were refractory or relapsed after ≥1 lines of therapy. Baseline cytopenias were permitted unless ANC < 500 or platelets were < 10K and unable to be supported with transfusion. Pts with GFR < 40ml/min, serum sodium < 134meq/L, and active ascites were excluded. Dose escalation followed a traditional 3+3 design and dosing cohorts were 1200mg/m2, 1500mg/m2 and 1800mg/m2 over 48 hours and 1800mg (flat dose), and 2100mg (flat dose) over 72 hours. Infusions were delivered via an ambulatory infusion pump and repeated in 14 day cycles for up to 4 cycles. Response was determined in patients who completed 4 cycles. Pts who demonstrated a biologic response without DLT were allowed to continue infusions until disease progression. Primary endpoint was toxicity after 2 cycles. Secondary endpoints included the toxicity with extended dosing and measures of biologic activity after 4 cycles. Results: Increasing doses of rigosertib were evaluated in 16 pts with relapsed CLL (10), MCL (2), MM (2), and HCL (2). All patients were evaluated for toxicity, while 10 patients completed 4 cycles of therapy and were evaluable for secondary endpoints. Median age was 61 yrs [range 52–65]. Drug-related adverse events (AEs) were reported in 15 pts (94%) and were almost exclusively grade ≤2. Most frequent drug-related AEs were fatigue 31%, musculoskeletal pain 31%, nausea 19%, constipation 19%, and diarrhea 12%. Grade 3/4 drug-related AEs included 2 cases of G4 neutropenia (both patients had neutropenia at baseline) and 1 case of syncope; there was 1 cardiac death in a patient with pre-existing heart disease that was classified as unrelated. No dose-limiting toxicities (DLTs) were observed. Analysis of blood samples collected for pharmacokinetics is planned. Response data in the 13 patients evaluable for response indicated that 7 had stable disease and 6 had disease progression. No clinical responses or evidence of biologic activity was observed. Conclusions: Escalating doses of rigosertib were well tolerated in patients with relapsed/refractory B-cell malignancies with rare G3/G4 toxicities. Of note, most patients with baseline cytopenias tolerated the therapy well. The highest dose level studied in this study is one step up from the dose level of the ongoing pivotal trial of rigosertib in MDS. However, as a single agent no clinical responses were observed with rigosertib in B-cell malignancies. Further development of rigosertib in lymphoid malignancies will require either combination therapy or alternative dosing schedules. Disclosures: Wilhelm: Onconova: Employment, Equity Ownership.

Idelalisib Treatment Is Associated with Improved Cytopenias in Patients with Relapsed/Refractory iNHL and CLL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1747-1747
Author(s):  
Susan O'Brien ◽  
Andrew John Davies ◽  
Ian W. Flinn ◽  
Ajay K Gopal ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Advisory Committees ◽  
Time To Peak ◽  
Non Hodgkin Lymphoma ◽  
Pharmaceutical Industries ◽  
Grade 3 ◽  
Over Time

Abstract BACKGROUND Chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) are B-cell malignancies associated with neutropenia, anemia and thrombocytopenia.The etiology of impaired hematopoiesis is not well understood, however the bone marrow leukemia/lymphoma cell infiltrates that often occur with these diseases is thought to contribute. In studies evaluating the selective PI3Kd inhibitor idelalisib (IDL) in B-cell malignancies, hematologic responses across all 3 lineages were observed in a majority of patients (pts) with baseline (BL) cytopenias. This post hoc analysis reports hemogram changes in pts with relapsed or refractory (R/R) CLL/iNHL treated with IDL in two pivotal studies and describes trends in hematologic parameters over time during IDL treatment in pts with or without BL cytopenias. METHODS In phase 3 study 312-0116 (NCT01539512), frail pts with R/R CLL were randomized to receive a combination of 8 doses of rituximab (R) with IDL 150 mg BID or placebo (P). In phase 2 study 101-09 (NCT01282424), pts with refractory iNHL received IDL 150 mg BID. In both studies, IDL was continued until disease progression (PD) or unacceptable toxicity. Trial inclusion criteria allowed enrollment of pts with BL cytopenias of any grade (CLL) or grade ˂3 (iNHL). Hematologic profiles for pts in each study were categorized as normal or abnormal (any grade of cytopenia) at BL. In the iNHL study, pts with PD at the first assessment were excluded from this analysis to avoid confounding by underlying uncontrolled disease. RESULTS A total of 345 pts participated in the 2 trials. The overall response rates of IDL-treated patients in the CLL and iNHL studies were 81% and 57%, respectively. For pts with CLL on IDL+R (n=110), BL cytopenias (grade ≥1) included anemia (76%), thrombocytopenia (62%), and neutropenia (34%). For pts with iNHL on IDL-mono (n=115), BL cytopenias included anemia (50.4%), thrombocytopenia (64.3%), and neutropenia (75.7%). We present changes in hemoglobin (Hgb), platelet (PLT), or neutrophil (ANC) counts over time (BL, peak, and time to peak) in pts with an abnormal BL hemogram in Table 1. Median hematologic lab values over time were unchanged in pts with normal hemograms at BL. Among patients with BL cytopenia, anemia and thrombocytopenia improved over time in pts with CLL and iNHL while on treatment with IDL. For pts with CLL, the magnitude of improvement was larger for pts in the IDL+R arm compared to those in the P+R arm. For pts in the IDL+R arm, median peak values of Hgb and PLT were observed within 6 months of IDL initiation. For pts with iNHL, median peak values for Hgb and PLT were observed within 3 months. ANC remained stable over time in CLL, and increased in iNHL. CONCLUSIONS Idelalisib treatment was associated with improvement in Hgb and PLT counts in this population of pts with R/R CLL or iNHL. In those pts with BL anemia or thrombocytopenia, peak improvement in Hgb or PLT values occurred early in treatment (≤3 months for iNHL and ≤6 months for CLL). Disclosures O'Brien: Gilead: Research Funding. Davies:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Gopal:Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche: Speakers Bureau. Newcomb:Gilead: Employment. Waldapfel:Gilead: Employment. Zhang:Gilead: Employment. Stilgenbauer:Gilead: Honoraria, Research Funding.

scholarly journals Phase I study of ON 01910.Na (Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies

Leukemia ◽  
2013 ◽  
Vol 27 (9) ◽  
pp. 1920-1923 ◽  
Author(s):  
M Roschewski ◽  
M Farooqui ◽  
G Aue ◽  
F Wilhelm ◽  
A Wiestner
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Pi3k Inhibitor ◽  
B Cell Malignancies

scholarly journals Preliminary Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4185-4185 ◽  
Author(s):  
Kami J. Maddocks ◽  
Farrukh T. Awan ◽  
Ying Huang ◽  
Sabarish Ayyappan ◽  
Robert A Baiocchi ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Tumor Lysis ◽  
Genetics Research ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Introduction: Combined obinutuzumab (O) and lenalidomide (L) has demonstrated safety and preliminary efficacy in follicular lymphoma1. Venetoclax (V), a BCL2 inhibitor, as a single agent2 and in combination with rituximab3 is under development in several subtypes of B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of O, V, and L to determine the maximum tolerated dose, dose-limiting toxicities (DLT), and preliminary efficacy. Methods: Pts with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell, Burkitt, marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant were permitted. Prior L or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of L days 1-21 and V days 1-28 of a 28 day cycle (Table 1). O 1000 mg was administered on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6. A 3+3 dose escalation schema was followed. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection or grade 3 that fails to resolve within 7 days; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, tumor flare reaction controllable with steroids, tumor lysis syndrome that does not require dialysis, diarrhea, nausea, or vomiting responsive to medical treatment, transient electrolyte abnormalities or elevations of ALT / AST that resolve ≤ grade 1 within 48 hours, grade 3 infusion reactions responsive to medical therapy. Pts without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: 14 pts have been treated. Median age is 61 years (range 35-78 years) with 10 males. Median prior therapies is 2 (range 1-10). 5 pts had bulky disease (≥ 7.5 cm) and median baseline lactate dehydrogenase was 274 U/L (range 151-894, 12/14 above ULN 190 U/L). 10 pts were refractory to their last therapy. Histologies include DLBCL/transformed lymphoma (n=11) and FL (n=3). 3 pts were treated at dose level (DL) 1 (V 400 mg / L 15 mg). One pt experienced DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. One pt with DLBCL was replaced for disease progression. 4 pts were then treated at DL 2 (V 600 mg / L 15 mg), and no DLTs were encountered. One pt was replaced due to missed doses of the oral agents. A total of 3 pts have been treated at DL 3 (V 800 mg / L 15 mg) and no DLTs have occurred at the time of data cutoff. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n= 11, 78.6%), anemia (n=1, 7%), and thrombocytopenia (n=2, 14.3%). Grade 3-4 infections included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. No clinically significant tumor lysis has occurred. Pts have received a median of 3 cycles (range 1-12) and 4 remain on therapy. Five pts have achieved a response. At DL 1, a pt with DLBCL, GC type, achieved a complete response (CR) and 2 pts with transformed FL achieved a partial response (PR). At DL 2, 1 pt with FL achieved a CR. At DL 3, 1 pt with transformed FL/double hit achieved a PR. Ten pts have discontinued, 6 with progression and 1 for DLT, alternative treatment, physician preference, and diagnosis of MDS in a patient with 3 prior lines of chemotherapy, respectively. Conclusions: Combined treatment with O, V, and L administered up to 12 cycles has been feasible with hematologic toxicity being the most common adverse event. Enrollment is ongoing and will include expansion cohorts in FL and DLBCL.Fowler et al. Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study. JCO 2015; 35: 7531.Gerecitano et al. A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. Blood 2015; 126: 254.Zinzani et al. Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data. Blood 2016; 128:617. Disclosures Maddocks: Merck: Research Funding; Pharmacyclics/Janssen: Honoraria; BMS: Research Funding; Pharmacyclics: Research Funding; Teva: Honoraria; Novartis: Research Funding; AstraZeneca: Honoraria. Jaglowski:Juno: Consultancy; Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Seattle Genetics: Research Funding. Christian:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding.

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.

Ibrutinib in Japanese patients with relapsed/refractory B-cell malignancies: final analysis of phase I study

2019 ◽  
Vol 109 (3) ◽  
pp. 366-368 ◽  
Author(s):  
Kensei Tobinai ◽  
Toshiki Uchida ◽  
Noriko Fukuhara ◽  
Tomoaki Nishikawa
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Final Analysis ◽  
Japanese Patients ◽  
B Cell Malignancies

scholarly journals Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3983-3983 ◽  
Author(s):  
Beth A Christian ◽  
John G. Kuruvilla ◽  
Sonali M. Smith ◽  
Pierluigi Porcu ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Off Label ◽  
Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton's tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500/mm3 or platelets <25, 000/mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin's lymphoma is off-label. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu:Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks:Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd:Pharmacyclics: Research Funding. Blum:Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

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