scholarly journals Subcutaneous Epcoritamab in Combination with R-CHOP in Patients with Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma: Preliminary Results from a Phase 1/2 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1413-1413
Author(s):  
David Belada ◽  
Jacob Haaber Christensen ◽  
Kristina Drott ◽  
Sylvia Snauwaert ◽  
Joshua Brody ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Metabolic Response ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: In patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) that is considered high risk (revised International Prognostic Index [R-IPI]: 3-5), standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is associated with a 4-year overall survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab (DuoBody ®-CD3×CD20) is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells to induce T-cell-mediated killing. Single-agent epcoritamab demonstrated a manageable safety profile and substantial antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the first-in-human phase 1/2 trial (EPCORE NHL-1; NCT03625037). Among pts with relapsed/refractory DLBCL treated at the identified recommended phase 2 dose (RP2D) of 48 mg (n=8), the overall response rate was 88% and the complete response rate was 38% (Hutchings, Lancet, in press). These encouraging data supported initiation of the EPCORE NHL-2 phase 1/2 trial (NCT04663347), which is evaluating epcoritamab in combination with various standard of care therapies in pts with B-cell NHL. We present data from arm 1 of this trial, in which epcoritamab in combination with R-CHOP is evaluated in pts with previously untreated high-risk DLBCL. Methods: Adults with previously untreated DLBCL and an R-IPI score ≥3 received flat-dose epcoritamab in combination with standard R-CHOP for 6 cycles followed by epcoritamab monotherapy. The study includes a dose-escalation cohort (epcoritamab doses: dose level 1 = 24 mg; dose level 2 = 48 mg). Step-up dosing of epcoritamab (ie, priming and intermediate doses before first full dose) and corticosteroid prophylaxis were used as previously described (Hutchings, Lancet, in press) to mitigate cytokine release syndrome (CRS). Tumor response was evaluated by positron emission tomography-computed tomography obtained once every 6 weeks for the first 24 weeks. Results: As of July 15, 2021, 9 pts have been treated with the combination of epcoritamab + R-CHOP (4 with epcoritamab 24 mg; 5 with 48 mg). Median age was 66 years (range, 56-78). All pts had stage III-IV disease. At data cutoff, all pts remained on treatment with a median follow-up of 12.2 weeks (range, 2.2-28.2). The most common treatment-emergent adverse events were CRS (56%; all grade 1/2), anemia (56%; grade 1-3), neutropenia (44%; all grade 3/4), fatigue (33%; all grade 1/2), and peripheral neuropathy (33%; all grade 1/2). Notably, no grade ≥3 CRS events or cases of febrile neutropenia were reported. No dose-limiting toxicities have been observed. Four pts have had ≥1 response assessment, with 3 achieving complete metabolic response (CMR; all in the epcoritamab 24 mg dose-escalation cohort) and 1 pt achieving partial metabolic response (epcoritamab 48 mg cohort) by week 6; 2 of the 3 pts with CMR had response assessments at 6 months, and both remained in CMR at that time. Both dose cohorts have been cleared by the Dose Escalation Committee and Safety Committee, and the expansion part has been opened to enroll additional pts. Conclusions: These preliminary data from a small number of pts suggest that epcoritamab in combination with R-CHOP has a manageable safety profile with no new safety signals. Adverse events were similar to those previously reported for epcoritamab and R-CHOP individually. All evaluable pts achieved early responses, and all pts remain on treatment. Updated and additional data from pts treated in the expansion phase will be presented. These findings warrant further evaluation of epcoritamab for the treatment of high-risk, newly diagnosed DLBCL. Disclosures Belada: Genmab: Research Funding. Drott: Roche: Honoraria; Kyowa Kirin: Honoraria; Respiratorius AB: Membership on an entity's Board of Directors or advisory committees. Narkhede: TG Therapeautics: Research Funding; Genmab: Other: Medical writing support, Research Funding; Genentech/Roche: Research Funding; Gilead: Research Funding. Elliot: Genmab: Current Employment, Patents & Royalties: P158-US-PSP3 . Liu: Genmab: Current Employment. Cota Stirner: AbbVie: Current Employment. Abbas: Genmab: Current Employment. Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 397-397 ◽  
Author(s):  
Paolo Caimi ◽  
Deepa Jagadeesh ◽  
Kirsten Marie Boughan ◽  
Robert M. Dean ◽  
Brenda Cooper ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Second Line ◽  
Advisory Committees ◽  
Line Therapy ◽  
Grade 3

Abstract Introduction: Diffuse large B cell lymphoma (DLBCL) patients (pts) with relapsed or refractory (r/r) disease after front line chemoimmunotherapy have poor survival. Standard second line therapy for r/r DLBCL consists of platinum-based chemotherapy followed by autologous stem cell transplant (ASCT). Approximately 50% of pts do not respond to second line therapy, highlighting the need for increased efficacy of these regimens. The antiapoptotic protein Bcl-2 is overexpressed in approximately 30% of DLBCL cases. Preclinical and early clinical data suggest that addition of venetoclax (VEN), a potent selective Bcl-2 inhibitor, to chemoimmunotherapy augments response rates and durability in lymphoma. We conducted a phase 1 dose escalation and dose expansion study to evaluate the safety and efficacy of VEN in combination with R-ICE (rituximab, ifosfamide, carboplatin and etoposide) (VICER) r/r DLBCL pts. Here we present the results after completion of VEN dose escalation. Methods: Patients (≥18 years of age) with r/r DLBCL who failed one or two lines of therapy were enrolled. The primary objective was to determine the recommended phase 2 dose (RP2D) of VEN when combined with R-ICE. VEN was given orally on days 1 - 10 of each 21 - day cycle x 3 cycles. Dose escalation was conducted according to a 3+3 design, with 3 dose levels (400, 600 and 800mg). R-ICE was given at standard dose and schedule on days 1 - 3 of each cycle for 3 cycles. No intra-patient dose escalation was allowed. Tumor lysis syndrome (TLS) mitigation included inpatient administration, hydration, allopurinol and frequent laboratory evaluation during cycle 1. All patients received pegfilgrastim; use of prophylactic antibiotics during neutropenia was left at the discretion of the treating physician. Results: As of July 20, 2018, 18 pts with DLBCL (14 male, 4 female) were enrolled (VEN 400mg, n = 3; 600 mg, n = 3; 800 mg, n = 12). Median age of pts was 55.5 years [range 27-78]. All pts received rituximab and anthracycline containing first - line therapy, 4 patients had failed a second line of therapy. One patient experienced dose limiting toxicity (DLT) at 800 mg VEN, with acute renal failure, febrile neutropenia, sepsis and rapid tumor progression and died after cycle 1. No other DLTs were observed. Hematologic toxicity was common, with grade ≥3 anemia in 6 (33%) pts; grade ≥3 neutropenia in 14 (78%) pts and grade ≥3 thrombocytopenia in 10 (55%) pts. Five (28%) pts experienced febrile neutropenia. The most common non-hematologic all-grade treatment emergent adverse events (TEAEs) were fatigue (7 [38%] pts), nausea (6 [33%] pts); diarrhea (6 [33%] pts), anorexia (5 [27%] pts], infection (5 [27%] pts) and sensory neuropathy (5 [27%] pts). Grade ≥3 TEAEs included infection (4 [22%] pts), cholecystitis (2 [11%]) and one case each (5.5%) of peripheral edema, acute renal failure, acute coronary syndrome, atrial fibrillation, hyponatremia and hypokalemia. One case of laboratory TLS occurred, but no clinical TLS was observed. At data cutoff, the intent-to-treat (ITT) population included 13 patients that had at least one cycle of therapy and end of treatment response or had discontinued prior to response assessment; 3 pts did not complete all planned cycles of VICER: one patient died after DLT, one patient proceeded to ASCT in complete remission (CR) after 2 cycles and another withdrew after cycle 1, achieving partial remission (PR) with additional 2 cycles of R-ICE. Nine pts (69%) achieved CR and 2 (15%) achieved PR (overall response rate (ORR): 11/13 [84.6%]) (Tables 2 and 3). Figure 1 depicts tumor response data. Among 11 responding pts, 7 have undergone stem cell collection, with a median CD34 cell count of 3.73x106 cells/kg. Seven pts have completed their ASCT, with hematopoietic engraftment in all cases. Median follow up of patients in CR/PR is 6 months (range 1 - 12), none has experienced progression. Conclusions: In this Phase 1 study, VICER shows encouraging antilymphoma activity in r/r DLBCL, including double hit/double expressor lymphomas, with high rates of complete metabolic response (69% CR by PET), which is higher than historical levels reported with R-ICE alone (CR typically <45%). The RP2D of VEN is 800 mg. Hematologic toxicity - particularly neutropenia - is common, and G-CSF support as well as antibiotic prophylaxis are necessary to prevent infectious complications. Updated safety, progression-free survival and response data will be presented at the meeting. Disclosures Caimi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk or Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma (AFT-08)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2964-2964 ◽  
Author(s):  
Peter Martin ◽  
Nancy L. Bartlett ◽  
Julio C. Chavez ◽  
John L. Reagan ◽  
Sonali M. Smith ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: For patients with diffuse large B-cell lymphoma (DLBCL), resistance to standard R-CHOP immunochemotherapy remains an urgent and unmet clinical challenge. Aberrant DNA methylation likely contributes to chemoresistance and may represent a therapeutic target.In a phase I study of R-CHOP plus subcutaneous azacitidine, a DNA methyltransferase inhibitor, complete responses (CRs) were achieved in 10/11 high-risk DLBCL patients (Clozel et al. Cancer Discovery 2013), providing the rationale for this study of oral azacytidine (CC-486) plus R-CHOP. Previously reported data from the dose escalation phase of this study demonstrated promising response rates in patients with high-risk DLBCL (Martin et al. Blood 2017). Here, we present results from both the dose escalation and expansion phases after substantially longer follow-up. Methods: CC-486-DLBCL-001 (NCT02343536) is a phase I, open-label, multicenter study of CC-486 plus standard R-CHOP in patients with previously untreated DLBCL, grade 3B follicular lymphoma (FL), or transformed FL. Eligible patients were aged ≥18-80 years with no active viral hepatitis, had an International Prognostic Index (IPI) score ≥2 or DLBCL double-positive for BCL2 and c-MYC, an Eastern Cooperative Oncology Group performance status ≤2, and Ann Arbor stage II-IV disease. Patients in the dose escalation phase were enrolled sequentially into 4 dose cohorts of CC-486 (100, 150, 200, and 300 mg) using the time-to-event continual reassessment method. Additional patients were enrolled in the expansion phase to evaluate preliminary efficacy. Patients received up to six 21-day cycles. CC-486 was administered for 7 days before initiation of R-CHOP and on days 8-21 of cycles 1-5. Granulocyte-colony stimulating factor was mandated by protocol and anti-emetics were standard treatment. The primary objectives were to determine safety (per NCI CTCAE v4.03) and the recommended phase 2 dose (RP2D) of CC-486 in combination with standard R-CHOP. Secondary endpoints included pharmacokinetics and preliminary efficacy per the International Working Group criteria (Cheson et al.J Clin Oncol 2014). Results: Fifty-nine patients were enrolled as of May 31, 2018, including 40 treated at the RP2D of CC-486 300 mg. The median age in the overall population was 66 years (range, 25-80), 76% were aged >60 years, 59% were male, and 59% had an IPI score ≥3. Fifty-four patients (92%) completed all 6 planned cycles of study treatment. Thirteen patients (22%) had CC-486 dose reductions because of adverse events (AEs). Two patients discontinued CC-486 due to AEs: febrile neutropenia (n=1; 150 mg) and sepsis (n=1; 300 mg). The most common AEs were gastrointestinal, which were mainly grade 1/2; hematologic AEs were the most common grade 3/4 toxicity (Table 1). Grade 3/4 AEs related to CC-486 occurred in 36 (61%) patients, most commonly neutropenia (41%) and febrile neutropenia (20%). Febrile neutropenia was more common among older patients (9/15 patients with this AE were aged >70 years) and those with IPI scores ≥3 versus ≤2 (31% vs 17%) but was not correlated with CC-486 dose. One patient died during the study (acute respiratory failure possibly related to study treatment). All patients were evaluable for response. The overall response rate was 95%, with 52 patients (88%) achieving a CR; response rates were generally similar in patients with IPI scores ≥3 and ≤2 and in patients treated at the RP2D (Table 2). Median progression-free survival (PFS) was not reached (median follow-up of 12 months); estimated 1-year PFS rates were similar in the overall population (86%) and in patients with IPI scores ≥3 (84%) and ≤2 (89%). Conclusions: Epigenetic priming with CC-486 before R-CHOP demonstrated promising clinical activity in patients with high-risk, previously untreated DLBCL, transformed FL, or grade 3B FL. AEs were generally consistent with the known safety profile of azacitidine and toxicities associated with R-CHOP. These results support further investigation of oral azacitidine (CC-486) in combination with R-CHOP, including patients with high-risk disease. Disclosures Martin: Gilead: Consultancy; Janssen: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy. Bartlett:Astra Zeneca: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Research Funding; Immune Design: Research Funding. Chavez:Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Humanigen: Consultancy. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding. Smith:Portola: Honoraria; BMS: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau. Jones:Celgene: Employment, Equity Ownership. Drew:Celgene Corp.: Employment. Wu:Celgene: Employment, Equity Ownership. Cerchietti:Celgene: Research Funding; Weill Cornell Medicine: Employment. Leonard:ADC Therapeutics: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; BMS: Consultancy; Juno: Consultancy; Celgene: Consultancy; Biotest: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Sutro: Consultancy; United Therapeutics: Consultancy.

scholarly journals Interim Results from the First-in-Human Clinical Trial of Adct-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 398-398 ◽  
Author(s):  
John Radford ◽  
Brad S. Kahl ◽  
Mehdi Hamadani ◽  
Carmelo Carlo-Stella ◽  
Paolo Caimi ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) represents 33% of the non-Hodgkin lymphomas (NHL) and expresses CD19, a classic B-cell marker found on B lymphocytes. ADCT-402 (loncastuximab tesirine; Lonca-T) is an antibody drug conjugate comprising a humanized antibody directed against human CD19 conjugated to a pyrrolobenzodiazepine dimer toxin. This first-in-human clinical study evaluated the safety and efficacy of Lonca-T in patients (pts) with relapsed/refractory (R/R) B-cell lineage NHL. Here we present interim results in the subgroup of pts with DLBCL. Interim efficacy and safety of Lonca-T in pts with follicular lymphoma and mantle cell lymphoma are presented in a separate abstract. Methods: Pts ≥18 years of age with R/R DLBCL who have failed or are intolerant to established therapies, or have no other treatment options available, were enrolled in this Phase 1, multicenter, open-label, single-arm study, including dose-escalation and dose-expansion parts. The primary objectives are to evaluate the safety and tolerability of Lonca-T, and determine the recommended dose(s) to use for expansion cohorts. The secondary objectives are to evaluate the clinical activity (measured by overall response rate [ORR], duration of response [DoR], progression-free survival [PFS] and overall survival [OS]), pharmacokinetics, pharmacodynamics, and anti-drug antibody activity. Pts receive 1-hour intravenous infusions of Lonca-T every 3 weeks (1 cycle), with a 3+3 dose-escalation design for the dose-escalation part of the study. No intra-pt dose escalation is allowed. Results: As of June 20, 2018, 183 pts had been enrolled on the study, including 137 with DLBCL (79 male, 58 female). Pts with DLBCL had a median age of 63 years [range 20-86], and had received a median of 3 previous therapies (range 1-10; Table). Pts received doses of Lonca-T ranging from 15 to 200 µg/kg (median cycles: 2 [range 1-13]). Treatment-emergent adverse events (TEAEs) were reported in 136/137 (99.3%) pts, and grade ≥3 TEAEs in 100/137 (73.0%) pts. The most common all-grade TEAEs (≥20% pts), regardless of relationship to study treatment, were fatigue (57 [41.6%]), nausea (44 [32.1%], peripheral edema (44 [32.1%]), anemia (39 [28.5%]), rash (35 [25.5%]), gamma-glutamyltransferase (GGT) increased (33 [24.1%]), constipation (30 [21.9%]), dyspnea (29 [21.2%]), and thrombocytopenia (28 [20.4%]). The most common grade ≥3 TEAEs (>10% pts) were GGT increased (21 [15.3%]), neutropenia (20 [14.6%]), neutrophil count decreased (19 [13.9%]), anemia (15 [10.9]), thrombocytopenia (15 [10.9%]) and platelet count decreased (14 [10.2%]. Approximately 66% and 72% of pts in the 120 and 150 µg/kg groups, respectively, tolerated at least 2 cycles before any AE leading to dose reduction/delay occurred. The figure depicts tumor response data. Out of 132 evaluable pts with DLBCL, the ORR was 40.2% (53/132 pts), comprising 29/132 (22.0%) complete responses (CRs) and 24/132 (18.2%) partial responses (PRs). Median DoR was 4.17 months and PFS was 2.79 months after a median follow-up of 5.13 months. Median DoR was not reached in pts achieving a CR and was 2.76 months in pts with a PR. In pts with non-bulky disease, the ORR was 44.2% (50/113 pts); 28/113 (24.8%) pts attained a CR and 22/113 (19.5%) pts attained a PR. The majority of pts (122/132) received doses ≥120 µg/kg; in these pts, the ORR was 41.8% (51/122 pts), with 28/122 (23.0%) pts attaining a CR and 23/122 (18.9%) pts attaining a PR. Conclusions: In this Phase 1 study, Lonca-T has demonstrated encouraging and durable single-agent antitumor activity and manageable toxicity in pts with R/R DLBCL at doses ≥120 µg/kg. Updated safety, tolerability, and efficacy results will be presented at the meeting. Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02669017. Disclosures Radford: Pfizer: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Equity Ownership; Novartis: Consultancy, Speakers Bureau; Celgene: Research Funding. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; ADC Therapeutics: Research Funding. Hamadani:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Research Funding; Cellerant: Consultancy; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy; Merck: Research Funding. Carlo-Stella:Boehringher Ingelheim Italia: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Genenta Science: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau. Caimi:Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Feingold:ADC Therapeutics: Employment, Equity Ownership. He:ADC Therapeutics: Employment, Equity Ownership. Reid:AbbVie: Research Funding; Millenium Pharmaceuticals: Research Funding; ADC Therapeutics: Research Funding. Solh:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Chung:ADC Therapeutics: Research Funding. Heffner:Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding. Ungar:ADC Therapeutics: Employment, Equity Ownership. O'Connor:ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding.

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.

A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1068-1068 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Emily M Huebner ◽  
Kaysey F. Orlowski ◽  
Bart L. Scott ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

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.

Multicenter Phase I Dose-Escalation Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma (ATL) or Peripheral T-Cell Lymphoma (PTCL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2737-2737 ◽  
Author(s):  
Naokuni Uike ◽  
Michinora Ogura ◽  
Yoshitaka Imaizumi ◽  
Norio Asou ◽  
Atae Utsunomiya ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 2737 Introduction: ATL is prevalent in Japan and has the worst prognosis among T-cell malignancies. PTCL also has a poor prognosis with currently available chemotherapeutic regimens, and both would benefit from better treatment modality. Lenalidomide is an immunomodulatory agent with direct tumoricidal and antiproliferative activity, and is approved for multiple myeloma (MM) in combination with dexamethasone after at least 1 prior therapy and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion. We conducted a phase 1 study of lenalidomide in patients with relapsed ATL or PTCL to establish the recommended dose and schedule for a subsequent phase 2 study. Patients and Methods: This multicenter, phase 1, dose-escalation study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed advanced ATL or PTCL. Dose-escalation was conducted according to the standard 3+3 design. Up to one PTCL patient was allowed to be included in each cohort of 3 patients. Patients in Cohort 1 received oral lenalidomide 25 mg daily on Days 1–21 of a 28-day cycle. Patients in Cohorts 2 and 3 received 25 and 35 mg/day, respectively, on each day of the 28-day cycle. Dose-limiting toxicity (DLT) was defined as febrile neutropenia lasting 5 or more days; thrombocytopenia (platelets <10,000/uL or bleeding requiring platelet transfusion); ALT/AST elevation of Grade 4 or that of Grade 3 lasting 7 or more days; and/or clinically unacceptable Grade 3 or higher other non-hematological adverse events (AEs). Treatment was continued until the development of unacceptable toxicity or progressive disease (PD). Response was assessed by internationally accepted standard criteria for ATL and PTCL. Results: From July 2010–June 2012, 13 Japanese patients (9 ATL and 4 PTCL; age 32–74 years [median, 64]; 1–11 prior therapies [median, 1]) were enrolled: 3 in Cohort 1, 6 in Cohort 2, and 4 in Cohort 3. The 3 patients in Cohort 1 received lenalidomide for 21, 103, and 637 days, respectively, until PD with no instances of DLT. In Cohort 2, 1 patient experienced DLT (thrombocytopenia, platelets <10,000/uL) and 4 patients received lenalidomide for 37, 56, 138, and 387 days, respectively, until PD in 3 patients and unrelated death in one. The sixth patient is still receiving lenalidomide for 28+ days without a DLT. In Cohort 3, 2 patients had DLTs (thrombocytopenia, platelets <10,000/uL in one patient and Grade 3 prolongation of QTc interval in one patient on concomitant fluconazole with preexisting cardiac disease and grade 1 QTc prolongation at baseline), 1 patient received lenalidomide for 71 days before withdrawal of consent, and 1 patient is still receiving lenalidomide for 323+ days without a DLT. Based on these results, 25 mg daily per 28-day cycle was regarded as the MTD. Other Grade 3/4 non-DLT AEs occurring in 2 or more patients included neutropenia (n=8), lymphocytopenia (n=7), thrombocytopenia (n=3), skin rash (n=3), hyperbilirubinemia (n=2), and increased ALT/AST (n=2). Among the 9 ATL patients, 3 achieved partial responses (PR) with hematological complete response in 2 patients, including the disappearance of skin lesions in 1 patient. These responses occurred between 54 and 57 days, and lasted for 92, 279+ and 505 days. Among the 4 PTCL patients, 1 achieved a PR at day 106 with >75% reduction in lymph nodes, which lasted for 282 days. PK profiles of patients in the study were generally consistent with that observed in Japanese MM patients. Plasma exposure of lenalidomide increased with increasing dose with a mean Cmax on Day 1 for 25 mg and 35 mg of 493 ng/mL and 628 ng/mL, respectively, and a mean AUC24 of 2774 ng/mL and 3062 ng/mL, respectively. There was no evidence of accumulation following multiple dosing for 8 days. Conclusions: This phase 1 study identified lenalidomide 25 mg daily per 28-day cycle as the dose and schedule for a subsequent phase 2 study in patients with ATL or PTCL. Based on the preliminary evidence of antitumor activity in ATL and PTCL patients, a phase 2 study in patients with relapsed ATL in Japan is planned. Disclosures: Off Label Use: Lenalidomide (CC-5013) is an investigational agent in Japan; this abstract assesses its use in adult ATL patients. Tobinai:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Zenyaku: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomedics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solasia Pharma: Clinical trials, Clinical trials Other, Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Chugai/Roche: Research Funding; Takeda: Clinical trials, Clinical trials Other, Research Funding.

scholarly journals Open-Label, Phase 2 Study of Blinatumomab after First-Line Rituximab-Chemotherapy in Adults with Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4077-4077 ◽  
Author(s):  
Deborah A. Katz ◽  
Michael P. Chu ◽  
Kevin A. David ◽  
Catherine Thieblemont ◽  
Nicholas J. Morley ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Metabolic Response ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Background: Rituximab combined with chemotherapy (R-chemotherapy) is the standard of care first-line treatment for diffuse large B-cell lymphoma (DLBCL). Despite success with R-chemotherapy, 30% to 50% of patients with high-risk DLBCL will relapse, and outcomes are poor among patients who relapse within one year of diagnosis. Given the challenge of successful salvage, novel first-line therapies are needed. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that directs cytotoxic T cells to lyse CD19-expressing B cells, has shown efficacy as salvage therapy in patients with relapsed or refractory DLBCL. This open-label, multicenter, phase 2 study (ClinicalTrials.gov, NCT03023878) assessed the efficacy and safety of blinatumomab after first-line R-chemotherapy for patients with newly diagnosed, high-risk DLBCL. Methods: Patients (≥18 y) had proven high-risk DLBCL (International Prognostic Index [IPI] 3−5 and double/triple hit or double MYC/BCL2 expressor) and Eastern Cooperative Oncology group performance status ≤2. To be eligible for blinatumomab, patients were required to achieve complete metabolic response (CMR), partial metabolic response (PMR), or stable metabolic response by PET/CT after a run-in period with 6 cycles of R-chemotherapy (R-CHOP, R-DA-EPOCH, or R-CHOEP). Blinatumomab was given by continuous intravenous infusion in a single 84-day cycle 1 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 42 days, followed by a 28-day treatment-free interval) and an optional 28-day cycle 2 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 14 days) for patients without progressive metabolic disease (PMD). The primary endpoint was the incidence and severity of adverse events (AEs). Additional endpoints were objective response rate (ORR [CMR + PMR]) per Lugano criteria, minimal residual disease (MRD) by plasma cell−free circulating tumor DNA, overall survival (OS), and pharmacokinetics (PK). Results: Of 47 patients enrolled, 17 (36%) discontinued R-chemotherapy run-in (protocol criteria, n=6; patient request, n=5; disease progression, n=3; ineligibility, n=1; AE, n=1; death, n=1) and 30 (64%) completed the run-in (2 did not proceed to blinatumomab). Of 28 patients who received blinatumomab, 26 (93%) had high or high-intermediate IPI; 8 (29%) were double/triple hit and 10 (36%) were double protein expressors (Table). In total, 26 (93%) patients completed cycle 1; ten of 11 (91%) patients completed optional cycle 2. Blinatumomab PK were consistent with those in previous studies. After the R-chemotherapy run-in before starting blinatumomab, 24 patients had objective metabolic responses and 4 had no metabolic response (NMR). After blinatumomab treatment, the ORR (within 12 weeks of starting blinatumomab) was 89% (25/28 patients; 95% CI, 72−98; Table). The 4 patients with NMR before blinatumomab had objective responses after blinatumomab treatment. Three patients with objective responses before blinatumomab relapsed after blinatumomab. Twenty-six (93%) patients were still alive with a median follow-up time of 8.6 months; 2 died (disease progression; n=1; infection not related to treatment, n=1). Nine of 13 (69%) patients during the R-chemotherapy run-in were MRD positive, all of whom converted to MRD negative after treatment with blinatumomab. After treatment with blinatumomab, 17 of 18 (94%) patients were MRD negative; the MRD positive patient had PMD. During blinatumomab treatment, 11 (39%) patients had grade ≥3 AEs, and 5 (18%) had grade ≥4 AEs. Two (7%) patients discontinued treatment due to AEs (grade 3 neurotoxicity; grade 4 neutropenia). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 17 (61%) patients, including 3 (11%) with grade 3 NEs and 1 (4%) with NEs leading to treatment discontinuation. No patients had grade ≥3 cytokine release syndrome. Other grade ≥3 events of interest included neutropenia and febrile neutropenia (n=4; 14%) and infection (n=3; 11%). Conclusions: In patients with newly diagnosed, high-risk DLBCL, blinatumomab monotherapy after first-line R-chemotherapy led to an 89% ORR, and safety was consistent with that in earlier studies in DLBCL. Thus, blinatumomab is a potential treatment option for patients with newly diagnosed disease. Disclosures Katz: Stemline: Speakers Bureau; Dova: Consultancy. Chu:Celgene: Honoraria; Teva: Consultancy; AstraZeneca: Honoraria; Amgen Inc.: Honoraria; Gilead: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Chen:Amgen Inc.: Employment, Equity Ownership. Kalabus:Amgen Inc.: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Avilion:Amgen Inc.: Employment, Equity Ownership. González-Barca:Takeda: Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

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