A Phase I Study of DCDT2980S, an Antibody-Drug Conjugate (ADC) Targeting CD22, in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 59-59 ◽  
Author(s):  
Ranjana Advani ◽  
Daniel Lebovic ◽  
Mark Brunvand ◽  
Andy I. Chen ◽  
Andre Goy ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Antibody Drug Conjugate ◽  
Safety And Efficacy ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

Abstract Abstract 59 Introduction: CD22 is a lineage marker expressed in most B-cell lymphomas. DCDT2980S is an ADC consisting of an anti-CD22 monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a potent microtubule disrupting agent linked to the antibody via a protease-cleavable peptide linker. DCDT2980S exhibits potent anti-tumor activity in murine xenograft models of B-cell lymphoma and is being evaluated in a Phase I study to assess the safety, tolerability, pharmacokinetics (PK), and biologic activity in patients (pts) with relapsed/refractory B-cell NHL. Methods: Pts receive DCDT2980S intravenously every 21 days at dose levels 0.1 to 3.2 mg/kg until disease progression or unacceptable toxicity. Intrapatient dose escalation based on tolerability at higher doses is permitted. Following determination of the recommended Phase II dose (RP2D) based on protocol-defined dose-limiting toxicities (DLTs) occurring within 21 days of dosing, additional pts with indolent and aggressive B-cell NHL are being enrolled to further evaluate safety and efficacy based on Cheson response criteria. Here we report the RP2D and preliminary safety and efficacy results. Results: To date, 35 pts (57% male), median age 66 years (range 30–85) have been enrolled: diffuse large B-cell lymphoma (DLBCL, n=18), follicular lymphoma (FL, n=11), transformed FL (n=4), and small lymphocytic lymphoma (n=2). Enrolled patients were heavily pre-treated: 26 pts had received ≥ 3 prior regimens, all pts had received prior rituximab, and 7 pts received prior high-dose therapy followed autologous or allogenic stem cell transplantation. Overall, pts received a median of 4 doses (range 1–25) of DCDT2980S in 7 dose-escalation cohorts, and 2 expansion cohorts at the RP2D. All 3 pts treated with DCDT2980S at 3.2 mg/kg developed Grade 4 neutropenia following the first dose, one of which constituted a DLT. No DLTs were reported in the 6 pts treated at 2.4 mg/kg, which is the RP2D. Across all dose levels, the most common treatment-emergent adverse events (AE) in ≥ 20% of pts were diarrhea (34%), fatigue (34%), nausea (31%), neutropenia (26%), decreased appetite (23%), vomiting (23%), and peripheral edema (20%). Treatment-emergent Grade ≥ 3 AEs were reported in 9 (27%) pts including 5 out of 9 pts who were treated at the RP2D of 2.4 mg/kg. Overall, neutropenia (24%) was the only Grade ≥ 3 AE in ≥ 10% of pts (24%) and was the only Grade ≥ 3 AE reported in > 1 pt (n=2) treated at the RP2D. Eight (26%) pts across all dose levels experienced a serious AE (SAE) of which one Grade 3 dehydration in a pt treated at 3.2 mg/kg was attributed to DCDT2980S. Treatment discontinuation due to AEs occurred in 3 pts: Grade 3 neutropenia (n=1) and Grade 3 peripheral sensory neuropathy (n=2). No deaths were reported within 30 days of the last dose of DCDT2980S. Assessment of Cycle 1 PK after the first dose of DCDT2980S indicated that the exposure of antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE increased with dose. The clearance estimates of both acMMAE and total antibody were similar across doses from 1.0–3.2 mg/kg. The volume of distribution estimates for acMMAE and total antibody approximated plasma volume and did not change with dose and suggest dose-proportional increase of acMMAE and total antibody exposures for doses of 1.0–3.2 mg/kg. Early evidence of anti-tumor activity was observed. At the RP2D of 2.4 mg/kg, 2 of 3 pts with DLBCL had > 75% reduction in tumor sum of perpendicular dimensions (SPD) and negative PET scans; 1 partial response was noted in a pt with FL treated at 1.8 mg/kg. These 3 pts continue on study, each having received at least 8 cycles of study treatment. Two additional pts with DLBCL receiving 0.5 mg/kg and 3.2–2.4 mg/kg had > 50% reduction in tumor SPD and discontinued study treatment after 8 and 6 cycles, respectively, to undergo stem cell transplant. Conclusions: In this early experience, DCDT2980S is well tolerated, has a favorable safety profile and has evidence of anti-tumor activity in in a heavily pretreated pts with relapsed/refractory B-cell NHL. Updated clinical data will be presented. These results support additional clinical evaluation of DCDT2980S in B-cell malignancies. Disclosures: Advani: Genentech: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A. Lebovic:Genentech: Speakers Bureau. Brunvand:Genentech: Speakers Bureau. Chen:Genentech: Research Funding. Chang:Genentech: Research Funding. Ho:Genentech: Employment. Kahn:Genentech: Employment. Lu:Genentech: Employment. Su:Genentech: Employment. Chu:Genentech: Employment.

A Phase I Study of the Anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A Targeting CD79b in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 56-56 ◽  
Author(s):  
Maria Corinna Palanca-Wessels ◽  
Ian W. Flinn ◽  
Laurie H. Sehn ◽  
Manish Patel ◽  
Randeep Sangha ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Target Lesion ◽  
Antibody Drug Conjugate ◽  
B Cell Malignancies ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Abstract 56 Introduction: CD79b, a component of the B-cell receptor (BCR), is expressed by nearly all B-cell malignancies including NHL. DCDS4501A is an ADC consisting of an anti-CD79b monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a microtubule disrupting agent via a protease-cleavable peptide linker. DCDS4501A exhibits potent anti-tumor activity in murine xenograft models of B-cell lymphoma. Methods: A Phase I study of DCDS4501A is being conducted to assess the safety, tolerability, pharmacokinetics (PK), and biologic activity of escalating doses of DCDS4501A in pts with relapsed/refractory B-cell NHL. Pts receive DCDS4501A intravenously every 21 days until disease progression or unacceptable toxicity. Intrapatient dose escalation based on tolerability at higher doses is permitted. Following determination of the recommended Phase II dose (RP2D) based on protocol-defined dose-limiting toxicities (DLTs) occurring within 21 days of dosing, additional pts with indolent and aggressive B-cell NHL will be enrolled to further evaluate safety and efficacy based on Cheson response criteria. Here we report the RP2D and preliminary safety and efficacy results. Results: To date, 33 pts have been enrolled (64% male), median age of 65 years (range 20–85): follicular lymphoma (FL, n=14), diffuse large B-cell lymphoma (DLBCL, n=11), MCL (n=4), MZL (n=2), transformed FL (n=1), and small lymphocytic lymphoma (SLL, n=1). Enrolled patients were heavily pre-treated: 29 patients had ≥ 3 prior regimens, all pts had received prior rituximab, and 9 pts received prior high-dose therapy followed by stem cell transplantation. Pts received a median of 3 doses (range 1–12) of DCDS4501A in 6 dose-escalation cohorts with doses ranging from 0.1–2.4 mg/kg. The protocol-specified MTD was not formally reached, however, 2.4 mg/kg DCDS4501A was determined to be the RP2D based on the overall safety and tolerability profile at that dose, which included 1 pt with a DLT of Grade 4 febrile neutropenia and pneumonia. The most common treatment-emergent adverse events (AE) occurring in ≥ 20% of pts were neutropenia (59%), diarrhea (38%), nausea (34%), hyperglycemia (31%), fatigue (31%), constipation (28%), peripheral neuropathy (28%), pyrexia (28%), leukopenia (25%), chills (22%), and cough (22%). Neutropenia (39%) and leukopenia (12%) were the only treatment-emergent Grade ≥ 3 AEs in ≥ 10% of pts. Seven of 12 pts treated at the RP2D of 2.4 mg/kg experienced a Grade 3–4 AE: Grade 3–4 neutropenia in 5 pts, and anemia, leukopenia and fatigue each in 2 pts. Eight (24%) pts across all dose levels experienced a serious AE (SAE). Four SAEs were reported in 2 pts treated at the RP2D of 2.4 mg/kg: 1 pt with atrial fibrillation, neutropenia, and pneumonia and 1 pt with cardiac failure; in both cases the SAE resolved and study treatment resumed. Treatment discontinuation due to AE occurred in 1 pt each for Grade 3 neutropenia and Grade 3 hyponatremia. One pt had a dose reduction for Grade 4 febrile neutropenia and pneumonia. No deaths were reported within 30 days of the last dose of DCDS4501A. Most cases of neutropenia were observed in the absence of growth factor support. Assessment of Cycle 1 PK after the first dose of DCDS4501A indicated that exposure of antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE, increased with dose. The clearance estimates of acMMAE and total antibody were similar across doses from 0.1–2.4 mg/kg; volume of distribution estimates of acMMAE and total antibody approximated plasma volume, which also did not change with dose. These results suggested dose proportional increase of acMMAE and total antibody exposures. Early evidence of anti-tumor activity was observed, including 5 pts with > 50% reduction in target lesion burden at the first on-treatment tumor assessment after 3–4 cycles of treatment: 2 with FL, and 1 each with DLBCL, transformed FL, and MCL; 4 pts continue on treatment with DCDS4501A (range 5–12 cycles). Two of four pts treated at 2.4 mg/kg evaluable for anti-tumor activity to date had > 80% reduction in target lesion burden at the first on-treatment tumor assessment. Conclusions: DCDS4501A, a novel ADC targeting CD79b, has demonstrated an acceptable toxicity profile and encouraging anti-tumor activity in heavily pretreated pts with relapsed/refractory B-cell NHL. Updated clinical data will be presented. These results support additional clinical evaluation of DCDS4501A in B-cell malignancies. Disclosures: Palanca-Wessels: Genentech: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A. Salles:roche: Consultancy. Morschhauser:Genentech: Honoraria. Advani:Genentech: Research Funding. Press:g: Consultancy. Ho:Genentech: Employment. Kahn:Genentech: Employment. Lu:Genentech: Employment. Su:Genentech: Employment. Chu:Genentech: Employment.

scholarly journals Preliminary Results from a Phase I Study of HMPL-523, a Selective Oral Syk Inhibitor, in Patients with Relapsed or Refractory Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2432-2432
Author(s):  
Paolo Strati ◽  
Dominik Chraniuk ◽  
Eva González-Barca ◽  
Michal Taszner ◽  
Rathi Pillai ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Publicly Traded ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

Abstract Background: Spleen tyrosine kinase (Syk) plays an integral role in B-cell receptor signaling critical in the development and survival of several subtypes of lymphoma. HMPL-523 is a selective, oral Syk inhibitor that has shown strong anti-tumor efficacy in xenograft models of B-cell and T-cell lymphoma. HMPL-523 had a manageable safety profile and demonstrated anti-tumor activity in a phase I study of lymphoma patients in China (NCT02857998). Here, we report the safety and preliminary anti-tumor activity of HMPL-523 in the dose escalation phase of a phase 1 study of relapsed/refractory lymphoma patients in the United States and Europe (NCT03779113). Methods: The primary objectives of the phase I study were to evaluate the safety and tolerability of HMPL-523 and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Secondary objectives were to assess the pharmacokinetics (PK) and evaluate the preliminary efficacy of HMPL-523. Eligible patients had histologically confirmed lymphoma, exhausted all approved therapy options, and had good organ function, including creatinine clearance ≥ 40 ml/min by Cockcroft-Gault, absolute neutrophil count ≥ 1000/µL, platelet count ≥ 50,000/µL, and hemoglobin ≥ 8.0 g/dL. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (AEs) were assessed per NCI CTCAE v5.0. Treatment responses were assessed by Lugano criteria at weeks 8, 16, and 24, and then every 12 weeks. Patients received HMPL-523 treatment daily in 28-day cycles until disease progression or unacceptable toxicity. Results: As of July 15, 2021, 21 patients had been enrolled and dosed with HMPL-523 at one of six dose levels (100 to 800 mg once daily). Baseline tumor subtypes included Hodgkin lymphoma (HL; n=5); diffuse large B-cell lymphoma (DLBCL; n=4); follicular lymphoma (FL; n=4); marginal zone lymphoma (MZL; n=2); and 1 patient each with mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mixed HL/DLBCL, and Richter's transformation. Patients were predominantly Caucasian (90.5%) and male (71.4%). The median age was 61 years (range 27 to 89 years) and 71.4% had an ECOG performance status of 1. The median lines of prior therapy was 4 (range 2 to 17). The majority of patients had prior anti-CD20 antibody exposure (71.4%), and four patients (19%) received prior Bruton tyrosine kinase inhibitors. Five patients continue to receive study treatment. The most frequently reported treatment emergent AEs were aspartate aminotransferase increase (23.8%), anemia (23.8%), neutropenia (19%), hyponatremia (19%), creatinine increase (19%), and nausea (19%). The most common grade ≥ 3 AEs were neutropenia (14.3%), hyponatremia (14.3%), and anemia (9.5%). Three dose limiting toxicities were observed: 1 in the 100 mg cohort (grade 3 confusion) and 2 in the 800 mg cohort (grade 3 fever and grade 3 alanine aminotransferase increase). The dose was deescalated to 700 mg, which was determined to be the MTD and RP2D. Among 17 efficacy evaluable patients, 2 patients (1 HL, 1 FL) dosed at 600 mg and 800 mg (reduced to 600 mg due to toxicity) achieved complete response, and 1 patient (dose increased from 400 to 600 mg) achieved partial response (FL). Stable disease was observed in 5 (29.4%) patients (2 DLBCL, 1 MCL, 1 SLL, 1 PTCL). At steady state, HMPL-523 showed approximately dose proportional PK over the daily dose range of 100 to 700 mg. Conclusions: HMPL-523 was well tolerated at all dose levels within the range of 100 mg to 700 mg and demonstrated proof of activity at dose levels of 400 mg or higher in heavily pre-treated patients. The dose expansion phase of the study will evaluate safety and efficacy in patients with multiple subtypes of B-cell and T-cell lymphoma at the RP2D of 700 mg. Updated safety, PK, and anti-tumor activity will be presented. Disclosures Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. González-Barca: Roche: Honoraria, Other: Travel; Kyowa Kirin: Consultancy; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel; Takeda. Abbvie: Honoraria. Taszner: Roche, Takeda: Consultancy, Other: Travel. Pillai: HUTCHMED: Current Employment. Chien: HUTCHMED: Current Employment, Current equity holder in publicly-traded company. Nanda: HUTCHMED: Current Employment, Current equity holder in publicly-traded company, Other: Travel. Rudinski: HUTCHMED: Current Employment. Jayaprakash: HUTCHMED, Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astrazeneca: Current equity holder in publicly-traded company. Hahka-Kemppinen: HUTCHMED: Current Employment, Current holder of individual stocks in a privately-held company; Eli Lilly: Current holder of individual stocks in a privately-held company. Kania: HUTCHMED: Current Employment, Current equity holder in publicly-traded company.

A Phase II Trial of Ofatumumab In Subjects with Waldenstrom's Macroglobulinemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1795-1795 ◽  
Author(s):  
Richard R. Furman ◽  
Herbert Eradat ◽  
Julie C. Switzky ◽  
Suzanne R. Hayman ◽  
Craig C. Hofmeister ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Rapid Rise ◽  
Grade 3

Abstract Abstract 1795 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by a heterogeneous population of lymphocytes, plasmacytoid lymphocytes and plasma cells with variable CD20 expression. Rituximab (R) achieves an overall response rate (ORR) of 25–50% in relapsed/refractory WM and is associated with IgM flares, manifested by a rapid rise in IgM, potentially leading to complications of hyperviscosity. Ofatumumab (OFA) is a fully human monoclonal antibody that targets an epitope encompassing both the large and small extracellular loops of CD20 and effectively induces complement-dependent cytotoxicity of B-lymphoma cells. OFA is approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated clinical activity in non-Hodgkin's lymphoma. Given the efficacy of OFA in CLL, with its decreased CD20 antigen density, similar to WM where CD20 is down-regulated with differentiation of cells into plasma cells, a Phase II, open-label, single-arm trial of OFA in patients (pts) with WM was initiated to examine the safety and efficacy of OFA in this population. We report data from a planned interim analysis, which was performed to examine IgM flare, toxicity and response data. Methods: Pts (age ≥18 years) with WM requiring therapy by 2nd International Workshop on WM criteria were eligible. Pts received OFA 300 mg week 1 and 1000 mg weeks 2–4. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts who experienced grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. The primary endpoint was ORR assessed by 3rd International Workshop on WM criteria, and toxicity was assessed according to NCI-CTCAE, v3.0. Results: Fifteen pts were enrolled between March 2009 and January 2010. Median age was 59 years (range 43–85), and 9 pts were male. Pts had a median IgM level of 3.70 g/dL (range 1.21–6.62) and median hemoglobin (hgb) of 9.8 g/dL (range 5.3–11.7). Three pts were previously untreated; 12 pts had received a median of 3 therapies (range 2–5), including 11 pts who had received R, and 7 pts who had received a purine analog. Fourteen pts completed all 4 infusions of OFA. One pt withdrew from study after infusion 3 due to a drug-related serious AE (SAE). One pt had cryoglobulinemia, which interfered with IgM assessment. Of the 14 pts with evaluable IgM levels, 3 achieved partial response (PR), and 3 achieved minor response (ORR=43%) 8 weeks to 5 months after start of OFA therapy. One of 3 previously untreated pts and 5 of 12 relapsed pts responded. Four of 11 pts who had received prior R and 2 of 4 R-naïve pts responded. Five of 9 pts with IgM <4 g/dL and 1 of 5 pts with IgM >4 g/dL responded. Four pts with a median hgb of 8.0 g/dL (range 5.3–9.2) experienced ≥2.8 g/dL increase in hgb, including 3 pts who had >5 g/dL increase; median time to reach hgb ≥11.0 was 4 weeks. Infusion-related events occurred with dose 1 (300 mg) in 12 pts and with dose 2 (1000 mg) in 7 pts; all infusion events were grade 1–2 except 2 grade 3 events (rash, serum sickness). Nine pts developed 11 infections: 7 URI, 2 UTI, 1 sinusitis, 1 oral candidiasis (all grade 2). One pt developed grade 3 febrile neutropenia. Two pts developed SAEs possibly related to OFA. One pt developed grade 3 Coombs-negative hemolytic anemia after infusion 3 resulting in study withdrawal, and 1 pt with a baseline IgM level of 6.62 g/dL developed grade 3 renal insufficiency due to a rapid rise in IgM and cast nephropathy 6 weeks after starting OFA. One additional pt, with a baseline IgM level of 4.69 g/dL, developed a rapid rise in IgM and hyperviscosity symptoms. Both pts with a rapid rise in IgM underwent plasmapheresis with resolution of symptoms. No other OFA-related hematologic toxicity was observed. Conclusions: OFA has an acceptable toxicity profile, although a rapid rise in IgM requiring plasmapheresis was observed in 2 pts with high baseline IgM levels. OFA shows clinical activity in pts with WM, including those who relapse after R therapy, with rapid improvement in hgb and slower reduction of IgM levels. Based on the acceptable safety profile in this study and the dose of OFA approved for refractory CLL, the study was amended to increase the OFA dose to 2000 mg and allow a 2nd cycle of therapy for pts who do not attain PR after cycle 1. Accrual to the amended study is ongoing. Disclosures: Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Switzky:GlaxoSmithKline: Employment, Research Funding; Genmab: Employment, Research Funding. Leonard:GlaxoSmithKline: Consultancy. Liao:GSK: Employment. Shah:GlaxoSmithKline: Employment; Genmab: Research Funding. Brownell-Buttich:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Consultancy, Employment.

Integration of Rituximab and Liposomal Doxorubicin (DOXIL®) Into CODOX-M/IVAC for HIV-Negative and HIV+ Adults with Untreated Burkitt's Lymphoma (BL): Results of a Prospective Multicenter Phase II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2669-2669
Author(s):  
Andrew M. Evens ◽  
Kenneth R. Carson ◽  
Chadi Nabhan ◽  
Borko Jovanovic ◽  
Paul Barr ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Liposomal Doxorubicin ◽  
Cell Lymphoma ◽  
Survival Rates ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Grade 3 ◽  
Hiv Negative

Abstract Abstract 2669 Background: The survival of adult BL has improved with intensification of multi-agent chemotherapy, although 2-year survival rates remain <65–70%. Efforts to improve survival, as well as decrease treatment-related toxicities are needed. Further, there are no prospective clinical studies to date that have examined the addition of rituximab into the CODOX-M/IVAC regimen. Methods: Eligible patients for this investigator-initiated, 5-site phase II clinical trial included: newly diagnosed BL and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and BL (according to WHO 2008 definition) regardless of HIV status. Eligibility for HIV+ patients included: no evidence of multi-drug resistant HIV infection or concurrent AIDS defining illness and CD4 count >350/mcL. Patients were classified as low risk (LR) if they had all of the following factors present: 1) normal LDH, 2) stage I/II disease, 3) ECOG performance status (PS) <2, and 4) no mass >10 cm. All other patients were “high risk” (HR). LR patients received 3 consecutive cycles of CODOX-M, while HR patients received 4 alternating cycles of CODOX-M and IVAC. For CODOX-M, methotrexate 3.0 gram/m2 i.v. was used. Further, liposomal doxorubicin (40 mg/m2) was utilized in lieu of doxorubicin (day 1 of all CODOX-M cycles), while intravenous rituximab (500 mg/m2) was added to days 0 and day 8 of each CODOX-M cycle and days 0 and 6 of IVAC cycles. In addition, as a corollary analysis, frequent assessment of ejection fraction (EF) was performed in all patients (baseline, s/p 2 cycles, and 4 weeks after completion of therapy). Results: Twenty-five patients (22 male and 3 female) enrolled from March 2007 through April 2011. The median age was 44 years (range, 23–70 years). Furthermore, 5 (20%) patients were >60 years. All patients had classical BL, while 1 patient had concomitant BCL-2 expression. There were 20 HR and 5 LR patients; 3 of the HR and 1 LR patient were HIV+, while the remaining patients were HIV-negative. Median PS at study entry was 1, while PS=2 in 6 (24%) patients. Further, 3 (15%) HR patients had + central nervous system disease (2 parenchymal, 1 leptomeningeal). Additionally, 7 (35%) HR patients had bulky disease >10 cm (2 (10%) with dominant mass >20cm), 8 (40%) of all patients had bone marrow involvement, and 15 (75%) had an elevated LDH. 24 of 25 patients were evaluable for toxicity and response/survival. Therapy was completed at a median of 13.5 weeks (range, 11–20) for HR patients and a median of 10 weeks for LR (range, 9–12). With respect to toxicity, myelosuppression was overall comparable (58% of patients experienced grade 4 thrombocytopenia with only 4% grade 4 anemia) to prior CODOX-M/IVAC data, while the incidence of mucositis also appeared similar to prior reports (38% grade 3, 13% grade 4). Other clinically relevant grade 3 toxicities included neutropenic fever (33%), transaminitis (33%), diarrhea (8%), elevated creatinine (8%), and seizure (4%). Notably, there was no grade 3 or 4 neuropathy. After 2 cycles of therapy, two grade 2 and two grade 3 cardiac events were noted (all depressed EF, no clinical evidence of congestive heart failure). The two grade 3 events occurred in a 70-year-old and 69-year-old man, both with HR disease, and the latter with history of myocardial infarction. Among all patients, the median change in EF at baseline vs study end was: −2% (range, −22% to +11%). In terms of outcomes, the response rate after 2 cycles of therapy was 100% with a 67% complete remission (CR) rate. At a median follow-up of 24 months, the 2-year PFS and OS rates for all patients were 86% and 86%, respectively (LR 2-year PFS and OS both 100%; and HR 2-year PFS and OS both 82%). Furthermore, the 2-year PFS and OS rates for HR, HIV-negative patients were 91% and 91%, respectively (see Figure 1), while the disease-specific survival (DSS) for this subgroup of patients was 100%. Of the 3 deaths on trial, 2 were due to progressive disease in HIV+ HR patients, while the 3rd was a 71 year-old HIV-negative HR subject who died in CR at 14 months from unknown causes. Conclusions: Altogether, the integration of rituximab and liposomal doxorubicin into CODOX-M/IVAC for adult BL was feasible and associated with similar tolerability compared with prior reports. Additionally, this regimen was associated with excellent survival rates, especially for HIV-negative BL. Disclosures: Evens: Ortho-Biotec: Research Funding. Off Label Use: Doxil in the treatment of Burkitt's lymphoma. Carson:Genentech: Speakers Bureau. Nabhan:Genentech: Research Funding, Speakers Bureau. Gregory:Genentech: Advisory Board. Gordon:Genentech: Consultancy, Speakers Bureau.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

A Phase I Open-Label, Multi-Dose Escalation Study of the Dual Syk/Jak Inhibitor PRT062070 (Cerdulatinib) in Patients with Relapsed/Refractory B Cell Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3103-3103
Author(s):  
Manish Patel ◽  
Paul Hamlin ◽  
Donald K Strickland ◽  
Anjali Pandey ◽  
Greg Coffey ◽  
...  
Keyword(s):  
Steady State ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Markers Of Inflammation ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Preclinical studies of the Syk-mediated B-cell receptor pathway and Jak-mediated cytokine pathways have demonstrated a potential therapeutic advantage for the dual inhibition of both Syk and Jak kinases in the treatment of B-cell malignancies. Cerdulatinib (PRT062070) was identified from a chemistry screen as a potent and selective inhibitor of Syk, Jak1, Jak3, and Tyk2, with minimal activity against Jak2. Cerdulatinib is efficacious in rodent models of B-cell lymphoma and autoimmune disease (Coffey et al., ASH 2012) and has demonstrated anti-tumor activity in genetically diverse B-cell lymphoma cell lines that is greater than that of Syk- or Jak- selective inhibitors alone (Ma et al., ASH 2013). Methods: This Phase 1 3+3 dose escalation study is evaluating cerdulatinib, given continuously on either a once daily (QD) or twice daily (BID) schedule, for relapsed/refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (NHL). The primary objective is to determine the maximum tolerated dose (MTD) of cerdulatinib in patients with CLL or NHL. Secondary objectives are to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cerdulatinib and to make a preliminary assessment of antitumor activity. Toxicity is graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4. Clinical response is evaluated according to published criteria (Hallek et al., Blood 2008:111:5446-5456; Cheson et al., J. Clin. Oncol. 2012: 25:579-586). The level of inhibition of Syk and Jak is determined using a variety of whole blood assays measuring signaling via receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden, including CCL3, CCL4, and other markers of inflammation, are also being measured. Results: As of 4 August 2014, twelve patients have been enrolled in once daily dose cohorts of 15 mg QD, 30 mg QD, and 45 mg QD. No dose-limiting toxicities have been reported. Grade ≥3 adverse events (AEs), regardless of causality, were: Grade 3 anemia (n=1), Grade 3 neutropenia (n=1), Grade 3 fatigue (n=1), Grade 3 hypotension (n=1), Grade 3 AST increased (n=1), Grade 3 hematochezia (n=1), and Grade 5 Pneumocystis pneumonia (PCP; n=1). The patient who experienced PCP pneumonia was a 76 year old male with CLL who had received prior therapy with bendamustine and rituximab. Cerdulatinib is well-absorbed with an average terminal elimination half-life at steady state of 14 hours. Selective inhibition of Syk and Jak in whole blood assays was observed post-treatment, with IC25-IC50 (Cmin to Cmax at steady-state) against these targets achieved at the 15 mg dose level, and IC50-IC80 (Cmin to Cmax at steady-state) achieved at the 30 mg and 45 mg doses. Reductions of >50% in serum markers of inflammation, as well as in CCL3 and CCL4, were noted at all dose levels post-treatment. Two patients treated at the 15 mg dose (1 CLL, 1 follicular lymphoma [FL]) remained on study for >230 and >200 days, respectively, with stable disease (SD) prior to disease progression. One patient treated at the 30 mg dose (diffuse large B-cell lymphoma [DLBCL], who did not respond to prior R-CHOP therapy), remained on study with SD for 140 days. One patient treated at the 30 mg dose (CLL) experienced a >60% decrease in peripheral lymphocyte count prior to coming off study for PCP pneumonia. Another patient treated at the 30 mg dose (CLL) experienced early lymphocytosis and a 33% reduction in lymph node size at the end of Cycle 2 and remains on study in Cycle 3. One patient treated at the 45 mg dose (FL) experienced a 40% decrease in lymph node size at the end of Cycle 4 and remains on study in Cycle 5. Conclusions: Cerdulatinib has been well tolerated in the initial cohorts of this Phase 1 study, with no dose-limiting toxicities and preliminary evidence of anti-tumor activity. Dose escalation continues and Phase 2 expansion cohorts are planned in CLL, DLBCL and FL. Disclosures Hamlin: Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding. Strickland:SCRI Development Innovations: Employment. Pandey:Portola Pharmaceuticals, Inc.: Employment; Portola Pharmaceuticals, Inc.: Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals, Inc.: Employment. Levy:Portola Pharmaceuticals: Employment; University of Michigan: Patents & Royalties. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership; Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership. Wagner-Johnston:Gilead: Consultancy; Gilead: Speakers Bureau; Celgene: Research Funding. Flinn:Portola Pharmaceuticals, Inc.: Research Funding.

scholarly journals Safety and Anti-Tumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2807-2807
Author(s):  
Craig H. Moskowitz ◽  
Mariana Bastos-Oreiro ◽  
David Ungar ◽  
Ilva Dautaj ◽  
Matko Kalac
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Stock Options ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Fixed Dose ◽  
Mantle Cell ◽  
Anti Tumor Activity ◽  
Large B Cell

Introduction: Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 antibody (Ab) conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 1, first-in-human ADCT-402-101 clinical study, Lonca demonstrated single-agent anti-tumor activity with manageable toxicity in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Durvalumab is a human monoclonal Ab of the immunoglobulin G-1 kappa subclass that blocks the interaction of programmed death-ligand 1 (PD-L1) with PD-1 on T-cells and with CD80 (B7.1) on other immune cells. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. Preclinical data, as well as early results from clinical trials combining ADCs and checkpoint inhibitors, show potentially increased effectiveness of these therapeutics when used in combination and provide the rationale for the current trial. Study Design and Methods: This is a Phase 1b, open-label, dose escalation (Part 1) and expansion (Part 2) trial of Lonca combined with durvalumab in patients with R/R DLBCL, MCL, or FL (NCT03685344). The key inclusion and exclusion criteria for the ADCT-402-104 study are reported in Table 1, and the dosing schema is presented in Figure 1. This trial will evaluate the safety and tolerability, preliminary anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of Lonca combined with durvalumab. Patients will receive Lonca once every 3 weeks for 2 doses in total, and durvalumab every 4 weeks for up to 1 year. Patients with only partial response or stable disease at the second disease evaluation may receive 2 additional doses of Lonca given once every 3 weeks. During Part 1, the dose of Lonca will be escalated using a classic 3+3 design with a fixed dose of durvalumab. Part 2 will consist of up to 3 expansion cohorts, one for each of the DLBCL, MCL, and FL populations. All patients in Part 2 will receive the dose of Lonca determined in Part 1, with a fixed dose of durvalumab. The trial opened in February 2019 and recruitment is ongoing. Study sponsored by ADC Therapeutics SA with the support of MedImmune Limited, a wholly-owned subsidiary of AstraZeneca Pharmaceuticals PLC, which supplies durvalumab (http://clinicaltrials.gov/show/NCT03685344). Disclosures Moskowitz: ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ungar:ADC Therapeutics: Employment, Other: Stock options. equity interest. Dautaj:ADC Therapeutics: Employment, Other: Stock options.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4082-4082
Author(s):  
Beth A. Christian ◽  
Ying Huang ◽  
Sabarish Ayyappan ◽  
Robert A Baiocchi ◽  
Jonathan E Brammer ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Advisory Committees ◽  
Oral Agents ◽  
Grade 3 ◽  
Aggressive B Cell Lymphoma

Introduction: Venetoclax, a BCL2 inhibitor, has demonstrated efficacy both as a single agent and in combination with rituximabin several subtypes of B-cell non-Hodgkin lymphoma (NHL). The combination of obinutuzumab and lenalidomide has demonstrated safety and preliminary efficacy in follicular lymphoma (Fowler et al., JCO 2015; 35: 7531). We conducted a phase I study of obinutuzumab, venetoclax, and lenalidomide to determine the safety, maximum tolerated dose, and preliminary efficacy of the combination. Methods: Patients with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell (HGBCL), marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous (ASCT) but not allogeneic stem cell transplant were permitted. Prior lenalidomide 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. Treatment consisted of obinutuzumab 1000 mg on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6 with escalating doses of lenalidomide days 1-21 and venetoclax days 1-28 of a 28 day cycle (Table 1). A 3+3 dose escalation schema was followed. The DLT period was 1 cycle and patients had to receive 80% of the doses of the oral agents and all doses of obinutuzumab to be considered evaluable for DLT. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection; grade 3 infection that fails to resolve within 7 days; and grade 3 or 4 non-hematologic toxicity. Patients without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed by CT or PET/CT every 3 months for 12 months and then every 6 months until disease progression. Results: 22 patients were treated. Median age was 61 years (range 31-78 years) with 16 males. Median prior therapies was 2 (range 1-10) and included 5 patients who had relapsed after chimeric antigen receptor T-cell therapy and 2 patients relapsed after ASCT. Median baseline lactate dehydrogenase was 259.5 U/L (range 147-5133, ULN 190 U/L). 16 patients had aggressive B-cell lymphoma including DLBCL, HGBCL, primary mediastinal and transformed FL, 5 patients had FL and 1 patient had marginal zone lymphoma. At dose level (DL) 1, one patient experienced a DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. No further DLTs occurred at DL 2-4. DL 4 was expanded and was determined to be the MTD. Four patients, 1 in each dose level, were not evaluable for DLT and were replaced including 3 who did not receiving 80% of the oral agents due to required dose reductions and 1 patient for disease progression. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n=20, 90.9%), thrombocytopenia (n=5, 22.7%), and anemia (n=3, 13.6%). Grade 3-4 infections (n=6, 27%) included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. Other grade 3-4 AEs occurring once each included dysgeusia, dyspnea, nausea, vomiting, and hyperhidrosis. No clinically significant tumor lysis has occurred. Patients have received a median of 3 cycles (range 1-12) of treatment. Three patients remain on therapy and 5 patients are on follow up. Dose reductions of lenalidomide occurred for 17 patients (77%) and of venetoclax for 11 patients (50%). Nine patients have achieved a response (41%), including 8 complete (CR) and 1 partial responses (PR). Responses have occurred at each DL and include 4 patients with FL (2 CR, 2 PR), 4 patients with aggressive lymphoma (4 CR) and 1 patient with MZL (CR). 14 patients are off of the study, 9 with progression, 2 for alternative therapy, and 1 each for DLT, physician preference, and a diagnosis of MDS in a patient with 3 prior lines of chemotherapy. Conclusions: Combined treatment with obinutuzumab, venetoclax, and lenalidomide administered up to 12 cycles is feasible with activity in multiple subtypes of relapsed NHL. Enrollment in expansion cohorts of FL and aggressive B-cell lymphoma is ongoing. Disclosures Christian: Celgene: Research Funding; Janssen: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding. Baiocchi:Prelude: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy. Awan:Gilead: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Sunesis: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Obinutuzumab - off label use in relapsed aggressive B-cell lymphoma and indolent B-cell lymphoma Venetoclax - off label use in relapsed B-cell lymphoma

scholarly journals Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma: Report on an Ongoing Phase II Trial (GOAL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5392-5392 ◽  
Author(s):  
Georg Hess ◽  
Andreas Hüttmann ◽  
Reinhard Marks ◽  
Mathias Witzens-Harig ◽  
Martin H. Dreyling ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Grade 3

Abstract Background: Prognosis of diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphoma entities has improved with the advent of Rituximab, and R-CHOP-21 and variants is SOC. Nevertheless, a substantial proportion of patients fail first line treatment. Salvage therapies are often effective. However, no more than 25-50% achieve a long term remission even when consolidative high dose chemotherapy (HDT) followed by hematopoietic stem cell transplantation (SCT) is applied. In case of failure or intolerance to HDT, regimen like Gemcitabine/Oxaliplatin are applied but show limited efficacy, indicating the need for new treatments. Obinutuzumab (GA101) is a type II anti-CD20 antibody. Superiority of Obinutuzumab could be demonstrated in xenograft models of mantle cell lymphoma and DLBCL. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclins from higher treatment lines. With Pixantrone, a drug structurally related to anthracyclines and especially anthracenediones, a re-exposition against this drug class has been shown to be feasible. In 70 heavily pre-treated patients, a best ORR of 40% (20% CR/CRu) was observed (Pettengell et al). Experiences from further antibody drug combinations lead to the assumption that the effects of Pixantrone will be augmented by a monoclonal antibody without increasing toxicity. We thus initiated a trial combining both agents for the first time. The trial has opened in Q4/2015 and recruitment is ongoing. Overall, a total of up 70 patients will be enrolled for a number of 64 evaluable patients. Primary endpoint will be the objective overall response rate, with secondary endpoints being safety, PFS and OS. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven DLBCL, FL grade IIIb or transformed indolent lymphoma, CD20 positive disease, no curative option available, relapsed disease, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. There was no upper limit or prior treatment lines. Treatment consisted of Pixantrone 50mg/m² day 1, 8 and 15 of each cycle, Obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. A total of 6 cycles was planned with interim staging after 3 cycles. Results: 24 patients (pts) have been included until now. Concerning clinical characteristics, all were caucasian, 12 were female and the other 12 male and median age was 75 years. Most of the patients suffered from DLBCL (18 pts, 82%). Median number of prior therapies was 2 (1 to 6). Until now 55 evaluable cycles of chemotherapy (median 2 cycles (0 to 6)) have been performed. At this time, the treatment seems to be well tolerated, with no unforeseen side effects. Observed toxicity was predominantly hematologic. The following hematologic adverse events of grade 3/4 were noted: leukopenia (4 pts, 17%), neutropenia (6 pts, 25%), granulocytopenia (1 pts, 4%), as well as thrombocytopenia (2 pts). Non-hematologic grade 3/4 adverse events were observed in at least two patients: hypertension (2 pts) and pelvic pain (2 pts). Response: currently, best responses were 4 PR, 1 SD, and 8 PD in 13 patients evaluable so far. Four patients died, all after progression of lymphoma. Summary: the combination of Obinutuzumab and Pixantrone seems to be feasible and safe with early signs of efficacy. Updated results of this trial in progress with a focus on safety will be presented. Disclosures Hess: Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Roche: Honoraria. Marks:Pfizer: Honoraria. Witzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Viardot:Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Roche: Honoraria; Takeda: Other: travel support; Pfizer: Honoraria. Keller:Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Phase I/II study of Bortezomib Alone and Bortezomib with Dose-Adjusted EPOCH Chemotherapy in Relapsed or Refractory Aggressive B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1385-1385 ◽  
Author(s):  
Kieron Dunleavy ◽  
John Janik ◽  
Juan Gea-Banacloche ◽  
Margaret Shovlin ◽  
Therese White ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Patient Characteristics ◽  
Fixed Dose ◽  
Microarray Profiling ◽  
Gi Toxicity ◽  
Grade 3 ◽  
Age Range ◽  
Dose Levels

Abstract Activation of NF-kB is a possible mechanism of drug resistance in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Bortezomib is a proteasome inhibitor that inhibits NF-kB activation and has promising activity in some lymphoma subtypes. We hypothesized that bortezomib may be active in ABC DLBCL and enhance the efficacy of chemotherapy. The effect of bortezomib on NF-kB and other pathways in serial tumor samples will be examined by microarray and correlated with outcome. The study employs a sequential treatment design. Patients first receive bortezomib alone (Part A), unless they require chemotherapy due to disease, and then cross over to DA-EPOCH-bortezomib (Part B) if they do not achieve a CR. In Part A, the dose of bortezomib is 1.3 mg/m2 IV d 1, 4, 8, 11 q21days. In Part B, bortezomib is escalated over 4 dose levels, in an accelerated design, of 0.5, 1, 1.5 and 1.7 mg/m2 on d 1,4 with DA-EPOCH, q21days. Of 32 patients enrolled, there are 16 on Part A and 26 on Part B. Patient characteristics include median age (range) 54 (19–76); stage III/IV 29 (91%); median 4 (1–8) prior regimens and; 25 (83%) refractory to the last therapy. Part A response in 15 (1 TE) patients includes 1 PR, 3 SD and 11 (73%) PD. Toxicity over 35 cycles includes 2 (6%) grade 3 neutropenia; 2 and 3 grade 3/4 thrombocytopenia, respectively; and 3 grade 3 GI toxicities. Part B response in 25 (1 TE) patients includes 2 (8%) CR, 4 (16%) PR, and 20 (80%) NR. Twenty-three patients enrolled at bortezomib 1.7 mg/m2 (max dose). Toxicity over 58 cycles includes 31 (53%) grade 4 neutropenia; 13 (22%) grade 4 thrombocytopenia and; 12 (21%) fever/neutropenia. Transfusions were required with red cells on 22 (38%) and platelets on 18 (31%) cycles. Other toxicity included grade ≥ 3 sensory neurotoxicity in 2 (8%) patients and grade ≥ 2 GI toxicity on 32 (55%) cycles. Comparison of hematological toxicities of DA-EPOCH-bortezomib with fixed dose EPOCH in relapsed patients (JCO18:3633, 2000) was similar with fever/neutropenia 21% vs. 18%; grade 4 neutropenia 53% vs. 48% and; grade 3/4 thrombocytopenia 51% vs. 27%, respectively. GI toxicity appears higher with ≥ grade 2 on 55% vs. 14% of cycles. Neurotoxicity ≥ grade 2 was 8% vs. 22%, but patients on the present study received fewer cycles of treatment. Bortezomib alone is ineffective in relapsed/refractory DLBCL. Bortezomib can be safely combined with combination chemotherapy but does not appear to increase the efficacy of DA-EPOCH chemotherapy in relapsed/refractory DLBCL. However, compared to our previous study of EPOCH alone, most patients on the current study entered with chemotherapy-refractory disease. Results of microarray profiling are pending. Accrual continues.

Sign in / Sign up

Export Citation Format

Share Document