Glofitamab step-up dosing (SUD): Complete response rates in updated efficacy data in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) patients (pts).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7519-7519
Author(s):  
Carmelo Carlo-Stella ◽  
Martin Hutchings ◽  
Fritz C. Offner ◽  
Franck Morschhauser ◽  
Emmanuel Bachy ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Metabolic Response ◽  
Response Rates ◽  
Complete Response ◽  
Low Grade ◽  
Target Dose ◽  
Efficacy Data ◽  
Efficacy Analysis ◽  
Non Hodgkin Lymphoma ◽  
Heavily Pretreated

7519 Background: Glofitamab (RG6026), a T-cell-engaging, bispecific, full-length antibody, allows bivalent binding to CD20 (B-cells), and monovalent binding to CD3 (T-cells). In NP30179 (NCT03075696), an ongoing multicenter, Phase I dose-escalation and expansion study, 0.6–25mg glofitamab fixed-dosing with obinutuzumab pretreatment (Gpt), showed high, durable complete responses and manageable safety in heavily pretreated R/R NHL (Dickinson, et al. EHA 2020). Glofitamab SUD, in addition to Gpt, allowed dose escalation up to 30mg to maximize efficacy, while mitigating cytokine release syndrome (CRS) (Hutchings, et al. JCO 2021). We present updated efficacy data from glofitamab monotherapy SUD cohorts. Methods: Gpt (1000mg) was given to pts 7 days pre-glofitamab initial dose. Intravenous SUD of glofitamab was given on Day (D) 1 and 8 of Cycle (C) 1 and then at the target dose from C2D1 (2.5/10/16mg or 2.5/10/30mg); treatment continued for up to 12 cycles, every 21 days. Response rates were based on the Lugano criteria (Cheson, et al. JCO 2014). Results: Fifty-two pts received glofitamab SUD; 17 and 35 pts received 2.5/10/16mg and 2.5/10/30mg, respectively. Twenty-eight pts (53.8%) had aggressive NHL (aNHL) and 24 pts had indolent NHL (iNHL). Pts had a median age of 68 (44–85) years and received a median of 3 (1–12) prior lines of therapy. Forty (76.9%) and 38 (73.1%) pts were refractory to their most recent and any prior CD20 therapy, respectively. After a median follow-up of 6.3 months, an updated efficacy analysis was conducted on December 1, 2020. For pts with aNHL (N = 28), the best overall response (OR) and complete metabolic response (CMR) rates were 64.3% and 57.1%, respectively; a trend of improved response was observed with increased target dose, with a CMR rate of 71.4% at 2.5/10/30mg (N = 14). Notably, 4/5 pts (80%) with mantle cell lymphoma (2.5/10/16mg, n = 2; 2.5/10/30mg, n = 2) had CMR. For aNHL, 13/16 CMRs are ongoing, with 8 CMRs lasting > 3 months. For pts with iNHL (N = 24), OR and CMR rates were 79.2% and 70.8%, respectively; 14/17 CMRs are ongoing, with 10 CMRs lasting > 3 months. As of August 3, 2020, common adverse events (52 pts) were CRS (63.5%), neutropenia (38.5%), and pyrexia (32.7%). CRS was mostly confined to C1: 24/50 pts had CRS after 2.5mg; 20/49 pts after 10mg; 2/16 and 8/32 pts had CRS after 16 and 30mg (C2D1), respectively. Grade [Gr] 1 and 2 CRS was reported in 18 (34.6%) and 12 (23%) pts, respectively; 3 pts had Gr 3 CRS; none had Gr 4/5 events (ASTCT 2019). Updated data, including biomarker data on baseline CD20 expression and CD8 levels in the tumor, will be presented. Conclusions: Updated data for glofitamab monotherapy SUD show higher preliminary response rates than previously reported in pts with R/R NHL who have failed multiple lines of therapy. CRS was mostly manageable, of low grade, and confined to the first cycle of treatment. Clinical trial information: NCT03075696.

scholarly journals Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study

2021 ◽  
Author(s):  
Lihua E. Budde ◽  
Sarit Assouline ◽  
Laurie H. Sehn ◽  
Stephen J. Schuster ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Single Agent ◽  
Response Rates ◽  
Complete Response ◽  
Low Grade ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Dose Escalation Study ◽  
Group B

PURPOSE Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs). METHODS This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407 ) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response. RESULTS Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively. CONCLUSION Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study.

Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 45-52 ◽  
Author(s):  
Michael F. Leahy ◽  
J. Harvey Turner
Keyword(s):  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cost Effective ◽  
Response Rates ◽  
Complete Response ◽  
Routine Practice ◽  
Low Grade ◽  
Non Hodgkin Lymphoma

Abstract Radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) has achieved objective response rates in clinical trials comparable with standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, but is relatively underused in routine practice. In this article, we report our clinical experience in 142 consecutive patients who received iodine-131 rituximab radioimmunotherapy for low-grade, predominantly follicular, relapsed NHL. Objective response rates of 67%, with complete response (CR) in 50% and median overall survival of 32 months, matched the response rates in a phase 2 clinical trial of 131I-rituximab radioimmunotherapy and compares favorably with those reported for 131I-tositumomab or 90Y-ibritumomab tiuxetan. Progression-free survival was 18 months overall and 32 months in CR or CR-unconfirmed patients. Our patients comprised 107 (75%) follicular lymphoma, 21 (15%) small lymphocytic lymphoma, 6 (4%) mucosa-associated lymphoid tissue/marginal zone lymphoma, and 8 (6%) mantle-cell lymphoma, with median follow-up of 32 months and 8-year overall survival of 48%. Toxicity was limited to hematologic grade 4 neutropenia, occurring in 10% and thrombocytopenia in 6%. There were no episodes of bleeding or infection requiring hospital admission. Radioimmunotherapy with 131I-rituximab in routine clinical outpatient practice provides cost-effective, safe treatment of relapsed/refractory indolent NHL, with half of patients achieving durable, complete remission with potential for repeat radioimmunotherapy on relapse.

405 CDX1140–01, a phase 1 dose-escalation/expansion study of CDX-1140 alone (Part 1) and in combination with CDX-301 (Part 2) or pembrolizumab (Part 3)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A430-A430
Author(s):  
Rachel Sanborn ◽  
Ralph Hauke ◽  
Nashat Gabrail ◽  
Mark O’Hara ◽  
Nina Bhardwaj ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Metabolic Response ◽  
Phase 1 ◽  
Safety Data ◽  
Systemic Exposure ◽  
University Of Pennsylvania ◽  
Cancer Center ◽  
Low Grade ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Expansion Cohort

BackgroundCDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb.MethodsPatients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing.Results92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response.ConclusionsThe CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma.Trial RegistrationNCT03329950Ethics ApprovalThe study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

scholarly journals Final Results of a CTEP Sponsored Phase I Study of Alistertib in Combination with Bortezomib and Rituximab in Relapsed and Refractory Mantle Cell and Low Grade Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4166-4166
Author(s):  
Stefan Klaus Barta ◽  
Noah Kornblum ◽  
Bruce G. Raphael ◽  
Kenneth B. Hymes ◽  
Michael L. Grossbard ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dose Escalation ◽  
Research Funding ◽  
Low Grade ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Non Hodgkin Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Background: Over-expression of Aurora A has been shown in many subtypes of non-Hodgkin lymphoma (NHL) and is a negative prognostic factor in mantle cell lymphoma (MCL), where expression correlates with tumor proliferative signature (Ki67), and may contribute to cell cycle dysregulation. Aurora A regulates chromosomal stability through effects on mitosis and cell cycle regulation. Bortezomib increases both pro-apoptotic proteins and cell cycle dependent kinase inhibitors. Thus, there is a strong scientific rationale to combine Aurora A kinase and proteasome inhibition. We evaluated the combination of alistertib, an oral Aurora A kinase inhibitor, with bortezomib and rituximab in a CTEP sponsored phase 1 study of patients with relapsed /refractory (RR) low grade NHL or MCL. Methods: Patients with RR low grade NHL or MCL, who had received at least one line of immuno-chemotherapy were treated according to a 3 + 3 design with 3 dose escalation cohorts (DL1, DL2, and DL3) to identify the recommended phase 2 dose (RP2D) with an expansion cohort at the RPTD. Patients received alisertib 30mg BID (DL1 and DL2) or 40mg BID (DL3) on days 1-7, bortezomib subcutaneous 1mg/m2 (DL1) or 1.3 mg/m2 (DL2 and DL3) on days 1, 8, and 15, and rituximab 375mg/m2 on day 1 for the first 8 cycles, and subsequently q 3 months. An expansion cohort was treated at DL3. Treatment cycles were 28 days. Dose Limiting Toxicity (DLT) was defined within the first cycle of therapy. Results: A total of 24 patients at 3 sites were enrolled between 06/2013 and 02/2018, including DL1: 3, DL2: 7; DL3: 14. Median age was 64 (range 46-87). Twelve patients (50%) were male. Nineteen patients had low grade NHL, and 5 patients had MCL. Performance status was 0-1 in 22 (92%) patients, and 2 in 2 (8%) patients. Dose Escalation and Safety: The recommended phase II dose (RP2D) was DL3, with the only DLT in DL3 (prolonged grade 4 neutropenia). The most common grade 3-4 AEs at all dose levels were neutropenia (34%), thrombocytopenia (13%), anemia (8%), and fatigue (8%); grade 2 alopecia occurred in 37% (Table 1). Other grade 4 AEs included hypertension & hypotension, respiratory failure, hyperkalemia and hyperuricemia (n=1 (4%) each); one patient died of GI hemorrhage deemed unrelated to study treatment (NSAID overdose). Grade 3 neutropenia and leukopenia was seen in 4 patients and thrombocytopenia in 1. There was one grade 3 AE each of: hypertension, pulmonary hypertension, pneumonitis, fatigue, diarrhea, infusion reaction, lung infection, and febrile neutropenia. Efficacy: A total of 18 patients were evaluable for response. Five patients were not evaluable for response for the following reasons: withdrawal of consent (3, 1 each DL1, 2, 3), non-compliance (1 DL2), and death unrelated to study drug (1, DL2). For patients who were treated with at least 3 cycles of therapy, and had a restaging CT scan, the median duration of therapy was 142 days, (range 29-590). Response was seen in 7/18 evaluable patients for an overall response rate (ORR) of 38%; 4 of 18 patients (22%) had a complete response (CR), and 4 of 18 patients (22%) had a partial response (PR). An additional 8/18 patients (44%) had stable disease for a clinical benefit rate of 88%. With a median follow-up of 30.9 months, the median PFS was 6.9 months (95%CI 4.1-28.0) and median OS not reached. OS at 3 years was 64.9% (95% CI 44.1-95.3%; Fig. 1). Median duration of response was 14.1 mo (95% CI 2.63-NR). Conclusion: Alisertib in combination with bortezomib and rituximab is a well-tolerated regimen with significant and durable activity in heavily pretreated low grade NHL and MCL. The RP2D is DL3 (R + bortezomib 1.3mg/m2 and 1.8 alisertib 40mg bid). A correlation of Aurora Kinase tumor expression with clinical outcome is planned. Disclosures Barta: Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Diefenbach:Merck: Consultancy, Research Funding; Genentech: Consultancy; Incyte: Research Funding; Millenium/Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acerta: Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Denovo: Research Funding.

A phase IB safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low-grade non-Hodgkin lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8078-8078 ◽  
Author(s):  
L. Yee ◽  
M. Fanale ◽  
K. Dimick ◽  
S. Calvert ◽  
C. Robins ◽  
...  
Keyword(s):  
Stable Disease ◽  
Objective Response ◽  
Safety Data ◽  
B Cell Lymphoma ◽  
Response Assessment ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Low Grade ◽  
Non Hodgkin Lymphoma

8078 Background: Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) induces apoptosis (programmed cell death) through binding to the pro-apoptotic receptors DR4 and DR5. Preclinical studies show that rhApo2L/TRAIL selectively induces apoptosis in many cancer cell lines derived from various malignancies including NHL, while sparing most normal cells. In vivo, rhApo2L/TRAIL and Rituximab cooperate to shrink or attenuate the growth of various NHL tumor xenografts in SCID mice. RhApo2L/TRAIL is being co-developed by Genentech and Amgen as a targeted therapy for solid tumors and hematologic malignancies. Methods: Subjects were eligible to participate if they had CD20+ follicular NHL or small lymphocytic lymphoma or marginal zone B-cell lymphoma that had progressed following stable disease or an objective response lasting > 6 months duration to the most recent rituximab-contain regimen. RhApo2L/TRAIL is administered intravenously over 1 hour for 5 consecutive days every three weeks up to 4 cycles at dose levels of 4 and 8 mg/kg. Rituximab is administered intravenously at 375 mg/m2 weekly for up to eight doses. Results: Six subjects with low grade NHL (4 with follicular NHL and 2 with small cell NHL) have been enrolled and treated with 4 mg/kg rhApo2L/TRAIL and rituximab, and one subject (with follicular NHL) has been enrolled and treated with 8 mg/kg rhApo2L/TRAIL and rituximab. The enrolled subjects range in age from 39–82 years; there are 6 male and 1 females. The number of prior therapies for NHL range from 1–8. Four subjects have received all protocol specified therapy. There have been no DLTs or SAEs or Grade 3/4 adverse events reported to date. To date, five subjects have undergone tumor response assessment: there have been 2 patients with complete response, 1 with partial response and 2 with stable disease. Conclusion: The combination of rhApo2L/TRAIL at 4 mg/kg/day and rituximab appears safe and shows evidence of activity in subjects with low grade NHL that has relapsed following previous rituximab-containing therapy. Enrollment is continuing to test rhApo2L/TRAIL at 8 mg/kg plus rituximab for expanded safety data and further dose optimization. No significant financial relationships to disclose.

Managing cytokine release syndrome (CRS) and neurotoxicity with step-fractionated dosing of mosunetuzumab in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7518-7518 ◽  
Author(s):  
Nancy L. Bartlett ◽  
Laurie Helen Sehn ◽  
Sarit E. Assouline ◽  
Francesc Bosch ◽  
Catherine S. Magid Diefenbach ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
Significant Risk ◽  
Complete Response ◽  
Fixed Dose ◽  
Low Grade ◽  
Non Hodgkin Lymphoma ◽  
Car T ◽  
Toxicity Relationship ◽  
Related Reaction

7518 Background: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. We report safety results from an ongoing phase 1/1b study of mosunetuzumab in patients (pts) with R/R B-cell NHL. Methods: Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-fractionation), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy. Results: As of October 23, 2018, 114 pts who received step-fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common ones were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%) with only 1 treatment-related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), and tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step-fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL-6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts. Conclusions: Step-fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile. Clinical trial information: NCT02500407; GO29781. [Table: see text]

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