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.

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.

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

A Phase 2 Clinical Trial of SGN-40 Monotherapy in Relapsed Diffuse Large B-Cell Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1000-1000 ◽  
Author(s):  
Ranjana Advani ◽  
Sven De Vos ◽  
Stephen M. Ansell ◽  
Brad Kahl ◽  
Bruce D. Cheson ◽  
...  
Keyword(s):  
B Cell ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract BACKGROUND: SGN-40 is a humanized monoclonal antibody that targets CD40. Upon binding to CD40, SGN-40 triggers pro-apoptotic signal transduction pathways and mediates effector cell functions (ADCC and ADCP). SGN-40 demonstrated preliminary anti-tumor activity in a phase 1 study of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL) patients (ASH 2006, Abstract 695). METHODS: We conducted a multicenter, phase 2, open-label study to determine the overall response rate and toxicity profile of SGN-40 in patients with relapsed DLBCL. Tumor samples were assessed by a central lab for pathology confirmation and CD40 expression. Eligible patients had de novo or transformed DLBCL at diagnosis and were excluded if previously treated for indolent lymphoma. Required prior therapy consisted of combination chemotherapy with rituximab and, if eligible, autologous stem cell transplantation. Patients received 6 intravenous infusions of SGN-40 over 5 weeks (Cycle 1) with intra-patient dose loading (1 mg/kg on Day 1; 2 mg/kg on Day 4; 4 mg/kg on Day 8) and 8 mg/kg/wk thereafter. Responding patients and those with stable disease were eligible to continue therapy until disease progression or a maximum of 12 cycles. RESULTS: Forty-six patients (28 M, 18 F), with a median age of 72 years (range 17–85), were enrolled at 10 centers in the US. Patients were heavily pre-treated, with a median of 4 prior systemic chemotherapy regimens (range 1–10). Immunohistochemistry analysis of patient tumor samples demonstrated high expression of CD40 in all patients with the exception of 1 patient who was negative. Thirty-eight of the 46 patients met predefined criteria for evaluation (completed dose loading and had no major protocol violations). Best responses seen were CR (n=2, 5%) and PR (n=2, 5%), yielding an ORR of 10%. Furthermore, 9 (24%) patients had SD as best response. Reductions in tumor size were seen in approximately one-third of patients. Twenty (53%) patients had PD and 5 (13%) patients have yet to be assessed. Treatment with SGN-40 was generally well tolerated. Grade 3/4 events that occurred in more than 1 patient in the intent-to-treat population (N=46), regardless of drug attribution were thrombocytopenia (n=5); neutropenia (n=4); and anemia, fatigue, pneumonia, hyponatremia, DVT, and disease progression (n=2 pts each). Of these events, only fatigue (n=2) and neutropenia (n=2) were considered drug related by the investigator. CONCLUSION: Monotherapy with SGN-40 in DLBCL patients is well tolerated and resulted in objective responses consistent with the previous phase 1 experience. These data support further evaluation of SGN-40 in combination with chemotherapy in non-Hodgkin lymphoma; 3 combination clinical trials are ongoing. Retrospective correlation of clinical outcome and a gene signature that includes baseline CD40 activation status are planned.

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

Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: Preliminary results from a phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8070-8070
Author(s):  
Ranjana Advani ◽  
Yasuhiro Oki ◽  
Andrei R. Shustov ◽  
Laurie E. Grove ◽  
Nancy Bartlett
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Objective Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
Non Hodgkin Lymphoma

8070 Background: Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL) after failure of other therapies. Based on the high objective response rate observed in patients with systemic ALCL, a type of non-Hodgkin lymphoma that is characterized by homogeneous CD30 expression, a study was initiated in other non-Hodgkin lymphomas that express the CD30 target. Methods: A phase 2 open-label single-arm study is underway in patients with relapsed or refractory CD30-positive non-Hodgkin lymphoma, excluding ALCL (NCT01421667). Brentuximab vedotin is administered IV at 1.8 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint is objective response rate assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Tumor specimens are assessed by central lab in order to characterize the relationship of CD30 expression with antitumor activity. Results: Ten patients (age range 28–83; 5 M, 5 F) have enrolled to date. Diagnoses include diffuse large B-cell lymphoma (DLBCL, n=2), EBV-positive DLBCL of the elderly (n=3), primary mediastinal B-cell lymphoma (n=2), peripheral T-cell lymphoma NOS (n=2), and angioimmunoblastic T-cell lymphoma (AITL). Patients had received 1–6 prior chemotherapy regimens; 3 patients had prior stem cell transplants. Of 6 patients who have completed the cycle 2 response assessment, 2 attained complete remission, 1 with DLBCL (90% CD30+) and 1 with AITL (8% CD30+), 1 had stable disease, and 3 had progressive disease. Treatment-related serious adverse events observed to date were rash, febrile neutropenia, and mastoiditis. Conclusions: Preliminary results suggest that brentuximab vedotin may have antitumor activity in patients with relapsed or refractory CD30-expressing non-Hodgkin lymphomas, in addition to the efficacy previously observed in systemic ALCL. Updated study results will be presented.

A phase 1 multicenter open-label dose-escalation study of BMS-936561 (MDX-1203) in clear cell renal cell carcinoma (ccRCC) and B-cell non Hodgkin lymphoma (B-NHL).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 2558-2558 ◽  
Author(s):  
Taofeek Kunle Owonikoko ◽  
Arif Hussain ◽  
Walter Michael Stadler ◽  
David C. Smith ◽  
Mario Sznol ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
B Cell ◽  
Dose Escalation ◽  
Clear Cell ◽  
Phase 1 ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Label Dose
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