Open-Label Phase 2 Study Of The Bispecific T-Cell Engager (BiTE®) Blinatumomab In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1811-1811 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Michael Pfreundschuh ◽  
Nicole Adrian ◽  
Martin Libicher ◽  
...  
Keyword(s):  
Dose Escalation ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Target Dose ◽  
Open Label ◽  
Large B Cell Lymphoma ◽  
Phase 2 Study ◽  
Open Label Phase ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction Blinatumomab, a bispecific T-cell engager (BiTE®) that redirects cytotoxic T cells to CD19+ B-lineage cells, has shown anticancer activity and acceptable toxicity in a phase 1 study in patients with relapsed/refractory non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Using a stepwise dose escalation treatment, the overall response rate (ORR) in patients with DLBCL was 55% (Goebeler et al. Hematol Oncol 2013;31[suppl 1]:197). This open-label phase 2 study has been initiated to investigate the efficacy and tolerability of blinatumomab in patients with relapsed/refractory DLBCL, comparing stepwise dose escalation with constant target dosing. Methods In this ongoing study, eligible patients must be ≥18 years of age, must have relapsed/refractory DLBCL and Eastern Cooperative Oncology Group performance status ≤2. Blinatumomab is administered by continuous intravenous infusion over 8 weeks. In part 1 of the study, two cohorts were evaluated using a double-step or flat dose escalation regimen, respectively, in order to achieve the target dose of 112 μg/d. Part 2 will investigate the selected treatment schedule from part 1. Data from part 1 (cohorts I and II) are presented herein. Patients in cohort I received stepwise blinatumomab dosing of 9, 28, and 112 μg/d during weeks 1, 2, and thereafter, respectively; patients in cohort II received blinatumomab at 112 μg/d throughout. After a 4-week treatment-free period, patients achieving an objective response were permitted to receive a 4-week consolidation cycle. All patients received prophylactic dexamethasone. The primary endpoint is ORR by Cheson (2007) revised response criteria for malignant lymphomas. Results To date, 11 patients have been enrolled and treated in part 1 of the study: nine in cohort I and two in cohort II. The median age was 73 years (range, 55–85); 64% of patients were women. Six (55%) patients had received ≥3 lines of previous systemic antitumor therapy; study treatment was given as fourth-line (median) systemic treatment. Three patients had received autologous hematopoietic stem cell transplantation. At the time of this analysis, seven patients were evaluable for response (cohort I, n=6; cohort II, n=1). The ORR based on independent radiological assessment was 57% (cohort I: complete response, n=1; partial response, n=2; cohort II: partial response, n=1). Three patients had progressive disease (all in cohort I). Four patients were not evaluable for ORR per protocol definition: early treatment discontinuation after <1 week on target dose in absence of disease progression, n=3; transformed DLBCL, patient only pre-treated for follicular lymphoma (patient achieved a CR), n=1. The most common adverse events (AEs) regardless of causality were tremor (64%), diarrhea (46%), and fatigue (46%). Ten of 11 patients had at least one grade ≥3 AE regardless of causality, with two patients (both in cohort II) experiencing grade 4 AEs (one patient with neutropenia and leucopenia; one with respiratory insufficiency). There were no grade 5 AEs. Ten of 11 patients had central nervous system (CNS) AEs, mostly tremor (64%), speech disorder (36%), and disorientation (27%). Five patients (cohort I, n=3; cohort II, n=2) had grade 3 CNS AEs (there were no grade 4 or 5 CNS events). The overall benefit/risk assessment revealed the dose administered in cohort I (stepwise dosing: 9, 28, 112 μg/d) to be the recommended dose for part 2 of the protocol. Conclusions In this ongoing phase 2 study, blinatumomab was tolerable and showed antitumor activity in adult, heavily pretreated patients with relapsed/refractory DLBCL. Part 1 of the study established a recommended blinatumomab dose for this patient population. The study continues to enroll patients in part 2 (cohort III). Disclosures: Libicher: Amgen Inc.: Consultancy. Degenhard:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Stieglmaier:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Zhang:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Bargou:University of Würzburg: Consultancy; University of Würzburg: Honoraria; Amgen Inc.: patent, patent Other.

scholarly journals Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

2020 ◽  
Vol 7 (7) ◽  
pp. e511-e522 ◽  
Author(s):  
Nagesh Kalakonda ◽  
Marie Maerevoet ◽  
Federica Cavallo ◽  
George Follows ◽  
Andre Goy ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Large B Cell Lymphoma ◽  
Open Label Phase ◽  
Large B Cell

A Multinational, Open-Label Phase 2 Study Of Ruxolitinib In Asian Patients (Pts) With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4086-4086
Author(s):  
Chul Won Jung ◽  
Lee-Yung Shih ◽  
Zhijian Xiao ◽  
Jie Jin ◽  
Hsin-An Hou ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Research Funding ◽  
Phase 2 ◽  
Spleen Volume ◽  
Open Label ◽  
Phase 3 ◽  
Phase 2 Study ◽  
Open Label Phase ◽  
Large Phase ◽  
Grade 3

Abstract Background Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable reductions in splenomegaly, improved MF-related symptoms and quality of life (QoL), and prolonged survival in 2 phase 3 studies comparing ruxolitinib with placebo (COMFORT-I) and best available therapy (COMFORT-II). However, no clinical trial in pts with MF had been conducted in Asian countries, and only a limited number of Asian pts or healthy volunteers had been enrolled in any ruxolitinib study. Methods This study was an open-label phase 2 study evaluating ruxolitinib in Asian pts with PMF, PPV-MF, or PET-MF who had palpable splenomegaly ≥ 5 cm below the costal margin and intermediate-2– or high-risk MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Pts received starting doses of ruxolitinib 15 or 20 mg twice daily (bid) based on baseline platelet count (100-200 or > 200 × 109/L, respectively); dose adjustments balancing safety and efficacy were allowed to titrate each pt to their most appropriate dose. The primary endpoint was met if the proportion of pts achieving ≥ 35% reduction in spleen volume from baseline at week 24 was ≥ 27.5% as measured by MRI/CT. Symptomatic response was assessed as a secondary endpoint using the 7-day modified MF Symptom Assessment Form (MFSAF) v2.0 total symptom score (TSS) and European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30). The study was conducted in China (n = 63), Japan (n = 30), Korea (n = 17), and Taiwan (n = 10). The data cutoff date for this analysis was 7 June 2013. Results Overall, 120 pts were enrolled (PMF, n = 80; PPV-MF, n = 21; PET-MF, n = 19), and their baseline characteristics were as follows: median age, 61 years (range, 25-80 years); 51.7% female; 69.2% intermediate-2 and 30.8% high risk by IWG-MRT criteria; median palpable spleen size, 15 cm (range, 5-45 cm); median spleen volume, 2159 cm3; 55.8% of pts had prior exposure to hydroxyurea. The median follow-up was 8.44 months; 22.5% of pts discontinued treatment, primarily for adverse events (AEs; 9.2%) and disease progression (7.5%). The median duration of treatment was 8.44 months (range, 0.5-21.7 months), and the median daily dose was 20.64 mg/day in the 15 mg bid group (n = 46) and 36.11 mg/day in the 20 mg bid group (n = 74). All pts were evaluable for achievement of the primary endpoint, 101 pts remained on study and were evaluable at week 24, and 96 pts had nonzero scores on the MFSAF-TSS and were evaluable for a reduction from baseline. Most pts who had assessments at week 24 (91% [92/101]) had a reduction from baseline in spleen volume (Figure). The study met the primary endpoint, with 31.7% (38/120) of all pts achieving ≥ 35% reduction from baseline at week 24. Overall, 38.3% (46/120) of pts achieved ≥ 35% reduction from baseline in spleen volume at any time on study. As measured by the 7-day MFSAF, 49% (47/96) of pts achieved ≥ 50% reduction from baseline in TSS (median reduction, 47.2%). Pts experienced an improvement from baseline at week 24 in EORTC global health status/QoL (mean change, 5.2). The most common nonhematologic AEs (≥ 10%) regardless of relationship to study medication included diarrhea (25.8%), upper respiratory tract infection (17.5%), ALT level increased (15.0%), pyrexia (15.0%), AST level increased (13.3%), cough (11.7%), herpes zoster infection (11.7%), nasopharyngitis (10.8%), constipation (10.0%), gamma-glutamyl transferase level increased (10.0%), and headache (10.0%), and most were grade 1/2. Serious AEs were reported for 24.2% of pts, and 65.8% of all pts had grade 3/4 AEs. The most common new or worsening laboratory abnormalities were low hemoglobin (all grade 3, 55.7%), low lymphocyte (grade 3/4, 19.5%), low platelet (grade 3/4, 15.3%), and low ANC (grade 3/4, 7.6%) levels. AEs observed in this study were consistent with those observed in the 2 large phase 3 COMFORT studies. Six pts (5%) died on treatment or within 30 days of discontinuation. Summary/conclusions Findings from this study demonstrated that ruxolitinib was relatively well tolerated in Asian pts with MF and provided substantial reductions in splenomegaly and modest improvements in MF-associated symptoms. The AEs observed with ruxolitinib treatment in this study are consistent with those observed in the large phase 3 COMFORT studies, and there were no new AEs associated with ruxolitinib in Asian pts with MF. Disclosures: Okamoto: Novartis: Honoraria, Research Funding. Sirulnik:Novartis: Employment. Ruiz:Novartis: Employment. Amagasaki:Novartis: Employment. Ito:Novartis: Employment. Akashi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma with the Bispecific T-Cell Engager (BiTE®) Antibody Construct Blinatumomab: Primary Analysis Results from an Open-Label, Phase 2 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4460-4460 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Georg Hess ◽  
Svenja Neumann ◽  
Michael Pfreundschuh ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
Board Of Directors ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Primary Analysis ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Treatment of relapsed or refractory DLBCL can be challenging and little progress has been made in recent years. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct, engages CD3+ cytotoxic T cells, resulting in T-cell expansion and lysis of CD19+ B cells. In a prior phase 1 study, blinatumomab treatment resulted in an overall response rate (ORR) of 55% in a subset of patients with diffuse large B-cell lymphoma (DLBCL). In the present phase 2 study, we compared stepwise versus flat dosing of blinatumomab, and evaluated its efficacy in patients with relapsed/refractory (r/r) DLBCL. Methods: Eligible patients were ≥18 years of age, had an Eastern Cooperative Oncology Group performance status ≤2 and had DLBCL; patients were refractory to treatment, had relapsed following autologous HSCT, or had relapsed and were ineligible for autologous hematopoietic stem cell transplantation (HSCT). Blinatumomab was administered over 8 weeks by continuous intravenous infusion. In stage 1, stepwise dosing (cohort I: 9, 28, and 112 μg/day after weeks 1, 2, respectively) was compared to constant dosing of 112 μg/day (cohort II). Based on the benefit/risk assessment from stage 1, stepwise dosing (9, 28, and 112 μg/day) was chosen for cohort III in stage 2. Patients achieving response after 8 weeks of treatment could receive a 4-week consolidation cycle after a 4-week treatment-free period. All patients received prophylactic dexamethasone (2 × 20 mg before infusion start and at infusion start; 3 × 8 mg/day for the first 2 days after infusion start and at dose step). The primary endpoint was ORR by Cheson revised response criteria for malignant lymphomas. Response was evaluated by independent radiologic assessment. Results: As of the primary analysis, 25 patients have been enrolled and treated: 9, 2, and 14 in cohorts I, II, and III, respectively. Fifty-six percent of patients were men, and the median age was 66 years (range, 34–85). Seven (28%) patients had received prior autologous HSCT. Blinatumomab was received as a fourth-line systemic therapy following a median (range) of 3 (1-7) prior treatments. Median (interquartile range) duration of exposure for stepwise dosing (cohorts I and III) was 46.8 (22.1−76.9) days. Twenty-one patients were evaluable for response (cohort I, n=7; cohort II, n=1; cohort III, n=13). Four patients were not evaluable for ORR per protocol definition due to early treatment discontinuation (<1 week on target dose in absence of disease progression): 1 discontinued due to investigator’s decision and 3 discontinued due to AEs. Fourteen patients have died (cohort I, n=5; cohort II, n= 1; cohort II, n=8). Eleven deaths were due to disease progression, one patient died of cardiogenic shock and one from organ failure following transplantation; no cause of death was reported for one patient. Among the evaluable 21 patients, 9 patients responded (4 CRs, 5 PRs) resulting in an ORR of 43%. All patients who responded did so within the first 8-week cycle. Among responders (n=9), median duration of response was 11.6 months. All patients experienced ≥1 adverse event (AE). Regardless of causality and grade, the most common AEs were tremor (52%), pyrexia (44%), diarrhea (24%), fatigue (24%), edema (24%), and pneumonia (24%). Twenty-four (96%) and 5 (20%) patients had grade 3 and 4 AEs, respectively. Serious AEs occurred in 23 (92%) patients, regardless of causality; the most common were pneumonia (24%), device-related infection (16%), and pyrexia (16%). Two patients had fatal on-study AEs (pneumonia and disease progression), assessed as unrelated to blinatumomab. Seven patients (cohort I, n=3; cohort II, n=2; cohort III, n=2) had grade 3 neurologic AEs (grade 3 AEs occurring in >1 patient were disorientation, encephalopathy, aphasia, and epilepsy [n=2 each]). There were no grade 4 or 5 neurologic events. Conclusions: In this phase 2 study, a stepwise dosing regimen (9, 28, and 112 μg/day) was established as the preferred dosing for blinatumomab in DLBCL. Treatment with blinatumomab showed an acceptable safety profile and resulted in objective and durable responses in heavily pretreated patients with r/r DLBCL. Disclosures Viardot: Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Travel support Other; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel support, Travel support Other; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Travel support Other. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Libicher:Amgen Inc.: Consultancy. Degenhard:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Stieglmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Zhang:Amgen Inc.: Employment. Nagorsen:Amgen Inc.: Blinatumomab-related Patents & Royalties, Employment, Equity Ownership. Bargou:Amgen Inc.: Consultancy, Honoraria.

scholarly journals Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma

Blood ◽  
2016 ◽  
Vol 127 (11) ◽  
pp. 1410-1416 ◽  
Author(s):  
Andreas Viardot ◽  
Marie-Elisabeth Goebeler ◽  
Georg Hess ◽  
Svenja Neumann ◽  
Michael Pfreundschuh ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Large B Cell Lymphoma ◽  
Phase 2 Study ◽  
Key Points ◽  
Bispecific T Cell Engager ◽  
Bite Antibody ◽  
Large B Cell

Key Points Among evaluable patients with relapsed/refractory DLBCL who received blinatumomab 112 μg/d, overall response was 43% (CR was 19%). Blinatumomab continuous infusion was feasible with weekly stepwise dose escalation (9-28-112 μg/d) and dexamethasone prophylaxis.

scholarly journals Combination of Nivolumab, Lenalidomide and Rituximab in Relapsed/Refractory Non-Germinal Center Diffuse Large B Cell Lymphoma: Results from a Dose-Escalation Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4100-4100
Author(s):  
Tarsheen Sethi ◽  
Alexandra E. Kovach ◽  
Emily F Mason ◽  
Heidi Chen ◽  
Tamara Moyo ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Germinal Center ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Grade 3 ◽  
Large B Cell

Background: Ten to 15% of diffuse large B cell lymphoma (DLBCL) patients exhibit primary refractory disease (nonresponse or relapse within 3 months of therapy) and an additional 20-25% relapse following initial response. There is an unmet need for effective therapeutic regimens in relapsed/refractory (R/R) DLBCL. Lenalidomide is an immune modulator that reverses T cell dysfunction and also inhibits the NFκB pathway, which is constitutively active in non-germinal center (non-GCB) DLBCL. Lenalidomide and nivolumab, an anti-PD-1 antibody, each have single agent activity in R/R DLBCL. Here, we report the results of the dose-escalation cohort of this investigator-initiated, single-arm open-label study of the combination of nivolumab, lenalidomide and rituximab (NiLeRi) in R/R non-GCB DLBCL. Methods: Adult patients with R/R non-GCB DLBCL, as determined by the Hans algorithm, with adequate organ function and an ECOG performance status of ≤2 were eligible for the study. The primary objective was to evaluate the safety of NiLeRi, and determine the maximum tolerated dose (MTD) of lenalidomide in combination with fixed doses of rituximab and nivolumab, using a 3+3 dose escalation design. The secondary objectives were to determine efficacy in terms of overall response rate (ORR), progression free survival (PFS), and overall survival (OS) of patients treated with NiLeRi. All patients received nivolumab IV 3 mg/kg on days 1 and 15 and rituximab IV 375mg/m2 on day 1 of each 28-day cycle. Lenalidomide was initiated at 5 mg po once daily on days 1-21. Additional planned dose levels were 10 mg, 15 mg and 20 mg. Patients were evaluable for toxicity if they received all doses of nivolumab and rituximab and at least 16 doses of lenalidomide during cycle 1 or if they experienced a dose limiting toxicity (DLT), regardless of the number of doses. NiLeRi was given for 8 cycles and patients with partial response could receive lenalidomide and nivolumab for an additional 4 cycles. Response was assessed by PET-CT after 2, 5 and 8 cycles and defined by Lugano criteria. Results: Six patients with non-GCB subtype of DLBCL were enrolled in this study. The median age was 60.5 years (range 28-79), and 5 patients were male. The median number of prior lines of therapy was 4 (range 2-5), and the median IPI score was 3. None of the patients had bone marrow involvement. One patient each had been treated with autologous stem cell transplant (Auto-SCT) and CAR-T cell therapy. One patient withdrew consent before completing cycle 1 and was not evaluable for safety or efficacy. Safety: Five out of the six enrolled patients were evaluable for safety. All patients received lenalidomide 5 mg dose. Two patients experienced DLTs (grade 3 rash) resulting in lenalidomide discontinuation during cycle 2. The most common grade 3/4 toxicities were fatigue (20%), neutropenia (60%), thrombocytopenia (40%), and rash (40%). A total of 3 patients experienced grade 1/2 diarrhea and elevated liver enzymes. One patient experienced a grade 1 infusion reaction with rituximab. Efficacy: Patients who completed at least 1 cycle of therapy were evaluable for response, and this included 5 out of the 6 enrolled patients. The ORR and complete response (CR) rate were both 40%. Patients who responded did so early, with one patient achieving CR after 2 cycles and another patient achieving CR after 5 cycles. The best response seen in patients with primary refractory disease was PR. At a median follow up of 9.5 months, median PFS was 8.4 months (95% CI; 4.3 to not reached), and median OS was not reached. Discussion: This is the first study reporting the safety results of the combination of lenalidomide, nivolumab and rituximab in non-Hodgkin lymphoma. Rash was the most common DLT, limiting dose escalation of lenalidomide above 5mg in this cohort of patients. Two patients experienced durable CR early in the study after 2 and 5 cycles, respectively. This ORR and CR rate of 40% each in this small cohort of patients who had relapsed after multiple prior lines of therapy is encouraging. Correlative studies, including whole exome sequencing of patient samples, are underway, in an attempt to explore predictive markers for response and toxicity. Figure. Disclosures Mason: Sysmex: Honoraria. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Morgan:Biogen: Equity Ownership; Eli Lilly: Equity Ownership; Vertex: Equity Ownership; Zoetis: Equity Ownership; Pfizer: Equity Ownership; Novo Nordisk: Equity Ownership; Gilead: Equity Ownership; Johnson and Johnson: Equity Ownership; Merck: Equity Ownership. Reddy:Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; KITE Pharma: Consultancy. OffLabel Disclosure: Nivolumab and lenalidomide are not FDA approved for use in diffuse large B cell lymphoma

scholarly journals Safety and Efficacy of Vibostolimab and Pembrolizumab in Patients with Relapsed or Refractory Hematologic Malignancies: A Multicohort, Open-Label, Phase 2 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2484-2484
Author(s):  
Rushdia Yusuf ◽  
Thomas Jemielita ◽  
Patricia Marinello
Keyword(s):  
Cell Lymphoma ◽  
Safety Data ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Phase 2 ◽  
Open Label ◽  
Expansion Phase ◽  
Phase 2 Study ◽  
Open Label Phase ◽  
To Receive

Abstract Background: The T-cell immunoglobulin and ITIM domain (TIGIT) is highly coexpressed with programmed cell death 1 (PD-1) on both CD4 and CD8 T cells in cancers. Blockade of TIGIT with vibostolimab (MK-7684) has demonstrated antitumor activity in multiple preclinical tumor models. Inhibition of the PD-1 pathway with pembrolizumab has demonstrated efficacy and safety in several hematologic malignancies. Enhanced antitumor activity with anti-TIGIT and anti-PD-L1 combination therapy has been seen in a preclinical model. A multicohort, open-label, phase 2 study will evaluate the safety and efficacy of MK-7684A, a coformulation of vibostolimab and pembrolizumab, in patients with relapsed or refractory (r/r) hematologic malignancies. Study Design and Methods: This two-part phase 2 study includes a signal-finding phase (part 1) with the option for a dose-expansion phase (part 2), depending on the observed risk-benefit profile from part 1. Patients must have confirmed diagnosis of r/r disease, including classical Hodgkin lymphoma (cHL; cohort A or B), primary mediastinal B-cell lymphoma (PMBCL; cohort A or B), follicular lymphoma (FL; cohort C), diffuse large B-cell lymphoma (DLBCL; cohort D), multiple myeloma (MM; cohort E), or non-Hodgkin lymphoma (NHL; cohort F) (Table 1). Three hundred thirty participants are expected to enroll in part 1 (signal finding) and part 2 (cohort expansion). In part 1, patients in cohorts A-F will receive MK-7684A (vibostolimab 200 mg + pembrolizumab 200 mg) by IV infusion every 3 weeks (Q3W) for up to 35 cycles. Patients will continue treatment until investigator-determined PD, start of new anticancer treatment, documented complete response, or completion of maximum 35 cycles of treatment. Safety data from the first 12 treated patients from any cohort will be collected. Dose-limiting toxicities (DLTs) will be monitored for the first 6 weeks of continuous treatment. If ≥5 of the 12 patients experience DLTs during this period, enrollment may be discontinued. After the DLT review period, safety data will be collected every 6 months for all enrolled patients. Efficacy assessments will be performed Q3W, with the initial tumor imaging performed ≤28 days after enrollment and repeated at 12 weeks (cohorts A-D, F) or 4 weeks (cohort E) after enrollment. Adverse events (AEs) will be monitored throughout the study, and severity will be graded according to the guidelines outlined in NCI CTCAE version 5.0. Each patient will be monitored for AEs and serious AEs for 30 day and 90 days, respectively, after discontinuation of study intervention. The primary end point for part 1 is the number and proportion of patients with DLTs, AEs, and discontinuations from study treatment due to AEs. Safety and tolerability will be assessed by clinical review. Secondary end points include investigator-assessed objective response rate, investigator-assessed duration of response, disease control rate, and pharmacokinetic end points. Overall survival, progress-free survival, health-related quality of life assessments, and molecular assessments will be exploratory. In the part 2 dose-expansion phase, the plan is to enroll approximately 120 patients from cohorts B-E to receive up to 35 cycles of MK-7684A Q3W; 30 additional patients may be enrolled in a cohort expansion (cohort G) to receive vibostolimab monotherapy Q3W for up to 35 cycles. Cohort G will include patients with cHL or PMBCL with PD after ≥2 or ≥3 prior therapies, FL after ≥2 prior therapies, DLBCL after ≥2 prior therapies, and/or MM after ≥3 prior therapies. Figure 1 Figure 1. Disclosures Yusuf: Merck & Co., Inc.: Current Employment. Jemielita: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder.

Everolimus for Relapsed/Refractory Classical Hodgkin Lymphoma: Multicenter, Open-Label, Single-Arm, Phase 2 Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2740-2740 ◽  
Author(s):  
Patrick B. Johnston ◽  
Lauren Pinter-Brown ◽  
Jaqueline Rogerio ◽  
Ghulam Warsi ◽  
Quincy Chau ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Disease Progression ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Study ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2740 Background: Historically, treatment options for the approximately 30% of patients with Hodgkin lymphoma (HL) who have primary refractory disease or relapse after experiencing initial response have been limited to high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT). Development of novel therapeutic options is needed to improve outcomes in patients whose disease is refractory to or relapses after initial chemotherapy or subsequent high-dose chemotherapy with AHSCT. The oral mammalian target of rapamycin inhibitor everolimus showed promising efficacy and acceptable toxicity in 19 patients with heavily pretreated HL enrolled in a phase 2 study of everolimus monotherapy for relapsed, rare lymphomas (Johnston et al. Am J Hematol 2010;85:320-4). To confirm the efficacy and safety of everolimus monotherapy in patients with relapsed/refractory classical HL, we conducted a multicenter, open-label, 2-step, phase 2 study. Methods: Adults with classical HL that progressed after high-dose chemotherapy with AHSCT or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen received everolimus 10 mg/day until disease progression or unacceptable toxicity. Response was assessed every 12 weeks via computed tomography with contrast or integrated positron emission tomography/computed tomography with contrast. The primary study endpoint was the overall response rate (ORR) evaluated according to the modified response criteria for malignant lymphoma (Cheson et al. J Clin Oncol 2007;25:579-86). Secondary endpoints included the disease control rate (DCR), duration of overall response, duration of disease control, progression-free survival (PFS), and safety. Results: A total of 57 patients were enrolled in this study; 57.9% were women, the median age was 32.0 years, 57.9% were pretreated with AHSCT, and 100% were pretreated with gemcitabine, vinorelbine, or vinblastine. Overall, 66.7% of patients experienced disease progression during previous therapies or discontinued previous treatment due to progression. At the time of analysis, 48 patients discontinued study treatment, most commonly due to disease progression (n = 25). The ORR and DCR were 42.1% and 77.2%, respectively (Table). The median time to response was 57 days. Median PFS was 9.0 months. Adverse events experienced by >25% of patients were fatigue (56.1%), thrombocytopenia (47.4%), cough (38.6%), rash (38.6%), pyrexia (31.6%), anemia (29.8%), dyspnea (28.1%), back pain (26.3%), and diarrhea (26.3%). Grade 3/4 adverse events were observed in 33 patients (57.9%); the most common were thrombocytopenia (21.1%) and anemia (12.3%). Stomatitis was experienced by 14 patients (24.6%) and was of grade 3 severity in 2 patients (3.5%). Pneumonitis was observed in 6 patients (10.5%) and was of grade 1 severity in 2 patients (3.5%) and grade 2 severity in 4 patients (7.0%). Conclusions: In this phase 2 study, everolimus monotherapy demonstrated favorable efficacy and a short time to response in patients with heavily pretreated, relapsed/refractory classical HL. The overall safety profile was consistent with that previously observed for everolimus in patients with HL and other cancers. The results of this study confirm previous results and support the further evaluation of everolimus in patients with classical HL. Disclosures: Johnston: Novartis: Consultancy. Off Label Use: Everolimus is an mTOR inhibitor indicated in the US for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with letrozole after failure of letrozole or anastrozole; adults with progressive pancreatic neuroendocrine tumors that are unresectable, locally advanced, or metastatic; adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; adults with renal angiomyolipoma and tuberous sclerosis complex not requiring immediate surgery; and adults and children aged 3 years or greater with subependymal giant cell astrocytoma associated with tuberous sclerosis complex who require therapeutic intervention but are not candidates for curative surgical resection. Pinter-Brown:Millennium: Consultancy. Rogerio:Novartis: Employment; Novartis: Equity Ownership. Warsi:Novartis: Employment; Novartis: Equity Ownership. Chau:Novartis: Employment. Ramchandren:Seattle Genetics: Honoraria.

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