scholarly journals Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

2020 ◽  
Vol 38 (5) ◽  
pp. 1472-1482 ◽  
Author(s):  
Frank Kroschinsky ◽  
Jan Moritz Middeke ◽  
Martin Janz ◽  
Georg Lenz ◽  
Mathias Witzens-Harig ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Transmembrane Protein ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma

Summary BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

scholarly journals Safety and pharmacokinetics of polatuzumab vedotin in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma: a phase 1 dose-escalation study

2020 ◽  
Vol 51 (1) ◽  
pp. 70-77
Author(s):  
Tomohiro Kinoshita ◽  
Kiyohiko Hatake ◽  
Kazuhito Yamamoto ◽  
Yusuke Higuchi ◽  
Satsuki Murakami ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Japanese Patients ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma

Abstract Objective A phase 1 dose-escalation study of polatuzumab vedotin (pola) was conducted to assess safety, pharmacokinetics and preliminary antitumor activity of pola in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Methods Patients received pola (1.0 or 1.8 mg/kg) intravenously every 21 days until disease progression or intolerance. Intra-patient dose escalation was prohibited. Tolerability was determined by the standard 3 + 3 rule. Blood sampling was performed to characterize pharmacokinetics. Antitumor activity was evaluated through computed tomography and bone marrow sampling. Results Four patients received pola 1.0 mg/kg; three received 1.8 mg/kg. Patients had follicular lymphoma (n = 4) or diffuse large B-cell lymphoma (n = 3), median age of 62 years, received a median of 3 prior therapies; six were female. Pola was well tolerated in both cohorts, with no dose-limiting toxicities observed. The most common adverse event was peripheral sensory neuropathy (n = 4). Grade 3 adverse events were cholecystitis and neutrophil count decreased (one each; both 1.0 mg/kg), and syncope and cataract (one each; both 1.8 mg/kg). The plasma half-life of antibody-conjugate monomethyl auristatin E was 4.43–7.98 days, and systemic exposure of unconjugated monomethyl auristatin E was limited in both cohorts. Four patients achieved objective responses (three complete, one partial) without disease progression during the study. Conclusions This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Pola 1.8 mg/kg, the recommended phase 2 dose, was tolerable in Japanese patients.

Anti-CD79B Antibody-Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study

2022 ◽  
pp. clincanres.3261.2021
Author(s):  
Alex F. Herrera ◽  
Manish R. Patel ◽  
John M. Burke ◽  
Ranjana Advani ◽  
Bruce D. Cheson ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Drug Conjugate ◽  
Non Hodgkin Lymphoma ◽  
Antibody Drug

scholarly journals Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

2017 ◽  
Vol 35 (8) ◽  
pp. 826-833 ◽  
Author(s):  
Matthew S. Davids ◽  
Andrew W. Roberts ◽  
John F. Seymour ◽  
John M. Pagel ◽  
Brad S. Kahl ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
B Cell Lymphoma ◽  
Tumor Lysis ◽  
Non Hodgkin Lymphoma

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

scholarly journals Final Results of a Phase 1 Study of Loncastuximab Tesirine in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Author(s):  
Mehdi Hamadani ◽  
John Radford ◽  
Carmelo Carlo-Stella ◽  
Paolo F Caimi ◽  
Erin G Reid ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Non Hodgkin Lymphoma

The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a Phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL. Objectives were to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion and to evaluate safety, clinical activity, pharmacokinetics, and immunogenicity of loncastuximab tesirine. Overall, 183 patients received loncastuximab tesirine, with 3+3 dose escalation at 15-200 µg/kg and dose expansion at 120 and 150 µg/kg. Dose-limiting toxicities (all hematologic) were reported in 4 patients. The MTD was not reached, although cumulative toxicity was higher at 200 µg/kg. Hematologic treatment-emergent adverse events were most common, followed by fatigue, nausea, edema, and liver enzyme abnormalities. Overall response rate (ORR) in evaluable patients was 45.6%, including 26.7% complete responses (CR). ORRs in patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and follicular lymphoma were 42.3%, 46.7%, and 78.6%, respectively. Median duration of response in all patients was 5.4 months and not reached in patients with DLBCL (doses ≥120 µg/kg) who achieved CR. Loncastuximab tesirine had good stability in serum, notable anti-tumor activity, and an acceptable safety profile, warranting continued study in B-NHL. The recommended dose for Phase 2 was determined as 150 µg/kg every 3 weeks (Q3W) for 2 doses followed by 75 µg/kg Q3W. Study: NCT02669017.

Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study

2020 ◽  
Vol 7 (9) ◽  
pp. e649-e659 ◽  
Author(s):  
Jean-Marie Michot ◽  
Reda Bouabdallah ◽  
Umberto Vitolo ◽  
Jeanette K Doorduijn ◽  
Gilles Salles ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Expansion Phase ◽  
Non Hodgkin Lymphoma
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