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

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

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Bortezomib, Thalidomide, and Dexamethasone (VTD) Versus VTD Plus Cyclophosphamide as Induction Therapy in Previously Untreated Multiple Myeloma Patients Eligible for HDT-ASCT: A Randomized Phase 2 Trial.

Blood ◽

10.1182/blood.v114.22.2312.2312 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2312-2312 ◽

Cited By ~ 3

Author(s):

Heinz Ludwig ◽

Luisa Viterbo ◽

Richard Greil ◽

Tamas Masszi ◽

Ivan Spicka ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Response Rates ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Phase 2 Study ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2312 Poster Board II-289 Bortezomib (Velcade®) has shown substantial activity and manageable toxicity in newly diagnosed multiple myeloma (MM) in combination with thalidomide (Thalomid®) and dexamethasone (VTD) in a phase 3 study (Cavo et al, ASH 2008), and with cyclophosphamide and dexamethasone (VCD) in a phase 2 study (Knop et al, ASCO 2009). Four-drug combinations may be more effective than 3-drug regimens, but may also be associated with increased toxicity. This randomized, non-comparative, open-label, multicenter, phase 2 study was designed to evaluate the efficacy and safety of VTD and VTD plus cyclophosphamide (VTDC) as induction therapy prior to high-dose therapy plus autologous stem cell transplant (HDT-ASCT). A total of 98 previously untreated MM patients with measurable disease who were candidates for HDT-ASCT were enrolled. Additional eligibility criteria included: age 18–70 years, Karnofsky Performance Status (KPS) ≥60%, adequate hematologic, hepatic, and renal function, and no grade ≥2 peripheral neuropathy (PN)/neuropathic pain. Patients were randomized (1:1), stratified by International Staging System (ISS) disease stage (I / II / III), to receive four 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, thalidomide 100 mg daily, and dexamethasone 40 mg on days 1–4 and 9–12 (VTD), or VTD plus cyclophosphamide 400 mg/m2 IV on days 1 and 8, as induction therapy prior to HDT-ASCT. All patients received antithrombotic prophylaxis. Patients who became ineligible for HDT-ASCT or had a complete response (CR) after induction therapy could receive an additional 4 cycles of treatment. Responses were categorized using modified IMWG Uniform Response Criteria (stringent CR [sCR] were unconfirmed by immunohistochemistry) through blinded review by the principal investigator and medical monitor, using central laboratory M-protein data and local bone marrow data. The primary efficacy endpoint was combined CR rate (sCR + CR + near-CR) following induction therapy. Secondary objectives included combined CR rate post-HDT-ASCT, overall response rate (ORR: ≥partial response) post-induction and post-HDT-ASCT, time to progression (TTP), overall survival (OS), and safety. Adverse events (AEs) were graded using NCI CTCAE v3.0. Forty nine patients were randomized to each arm; median age was 57 and 58 years in the VTD and VTDC arms, respectively, 53% and 51% of patients were male, 49% and 43% had KPS ≤80%, and 24 / 45 / 31% and 18 / 47 / 35% had ISS stage I / II / III MM. All but 7 patients completed induction; these patients discontinued due to AEs (3 [6%] each arm) and disease progression (1 [2%] VTDC). Four VTDC patients received additional cycles of treatment. One patient (VTDC arm) was not evaluable for response. Response rates following induction are shown in the table. Median CD34+ stem cell yields were 8.16 (VTD; n=48) and 8.13 (VTDC; n=40) x 106/kg. At data cut-off (April 10, 2009), 47 VTD and 35 VTDC patients had undergone HDT-ASCT; response rates post-HDT-ASCT in 38 and 27 evaluable patients are shown in the table. Time-to-event data are not mature (median follow-up: 9.8 months). The 1-year survival rate was estimated to be 94% in each arm. At least one AE was reported in 98% and 96% of patients on the VTD and VTDC arms, with at least one grade ≥3 AE reported in 47% and 59%, respectively. The most common non-hematologic grade 3/4 AEs included fatigue (2% and 8%) and constipation (6% and 2%); analyses of hematology laboratory values indicated grade 3/4 AEs of lymphopenia (39% and 77%), anemia (8% and 18%), neutropenia (14% and 18%), and thrombocytopenia (6% each). PN was reported in 35% (VTD) and 29% (VTDC) of patients, including 8% grade 3 in each arm and 2% grade 4 in the VTD arm. Two patients (1 [2%] each arm) had deep vein thrombosis; one (VTDC arm) was a grade 3 SAE. At least one serious AE (SAE) was reported in 22% (VTD) and 41% (VTDC) of patients, including 6% and 14% with SAEs of infections (MedDRA SOC), and 2% and 14% with musculoskeletal-related pain. In conclusion, both VTD and VTDC are highly active induction regimens, with CR rates and ORRs among the highest reported; the efficacy profiles were similar between the arms, but there were higher rates of toxicity in the VTDC arm compared with the VTD arm. Table. Response rates following induction and post-HDT-ASCT. Post-induction n=49 n=48 Combined CR*, % 51 44 sCR†, % 27 27 ORR, % 100 96 Post-HDT-ASCT n=38 n=27 Combined CR*, % 76 78 sCR, % 39 33 ORR, % 100 100 * sCR + CR + near-CR † unconfirmed Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen-Cilag: Honoraria. Dmoszynska:Milllennium: Research Funding. Cakana:Janssen Cilag: Employment, Equity Ownership. Enny:Johnson & Johnson: Employment, Equity Ownership. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership.

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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 ◽

10.1182/blood.v120.21.2737.2737 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2737-2737 ◽

Cited By ~ 1

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.

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Lyra: A Phase 2 Study of Daratumumab (Dara) Plus Cyclophosphamide, Bortezomib, and Dexamethasone (Cybord) in Newly Diagnosed and Relapsed Patients (Pts) with Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2018-152 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 152-152 ◽

Cited By ~ 4

Author(s):

Habte Yimer ◽

Jason Melear ◽

Edward Faber ◽

William Bensinger ◽

John M Burke ◽

...

Keyword(s):

Board Of Directors ◽

Phase 2 ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Split Dose ◽

Phase 2 Study ◽

Equity Ownership ◽

Grade 3 ◽

Line Of Therapy

Abstract Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed (ND) MM. CyBorD is another commonly used immunomodulatory drug-sparing regimen for MM. We evaluated the safety and efficacy of dara-CyBorD and administered the first dara infusion as a split dose over 2 days in pts with NDMM or relapsed MM (RMM) after 1 prior line of therapy. Methods: This is an ongoing, multicenter, single-arm, open-label, phase 2 study conducted at US community oncology centers in pts aged ≥18 years with documented MM per IMWG criteria; measurable disease; ECOG performance score (PS) of 0-2; and ≤1 prior line of therapy. Pts received 4-8 cycles (C) of dara-CyBorD (oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or IV dexamethasone 40 mg weekly) every 28 days. Dara was administered at 8 mg/kg IV in 500 ml on Days 1 and 2 of C1, 16 mg/kg weekly from C1D8 through C2, 16 mg/kg every 2 weeks (q2w) for C3-6, and 16 mg/kg q4w for C7-8. After induction, pts could undergo autologous stem cell transplantation (ASCT). All pts receive 12 cycles of maintenance dara 16 mg/kg IV q4w. The primary endpoint was the proportion of pts achieving very good partial response or better (VGPR+) after 4 induction cycles using a computer algorithm based upon IMWG response criteria. Results: A total of 101 (87 ND, 14 RMM) pts were enrolled; 100 (86 ND, 14 RMM) pts received at least 1 dose of study treatment. Median age was 63 years (63 ND, 68 RMM); most pts were white (81%), male (64%), had ECOG PS 0-1 (94%), and had IgG (57%) or IgA (17%) MM; 35% of pts had high-risk cytogenetics defined as del(17p), t(4:14), or t(14;16). Eighty-two ND pts completed at least 4 induction cycles, 55 at least 6 cycles, and 26 the maximum of 8 cycles; 28 ND pts underwent ASCT by the data cutoff date. After 4 induction cycles, 44% of ND pts achieved VGPR+ (5% CR) with an overall response rate (ORR) of 79%. The VGPR+ rate (57%), CR rate (14%), and ORR (71%) were similar in RMM pts. At the end of induction (median 6 cycles), the VGPR+ rate, CR rate, and ORR in ND pts were 56%, 9%, and 81%, respectively. With a median follow up of 7.9 months, median PFS and OS were not reached; the 12-month PFS and OS rates were 87% and 99%, respectively, in ND pts. All 100 evaluable pts experienced ≥1 treatment-emergent adverse event (AE). AEs with incidence ≥20% included fatigue, nausea, diarrhea, cough, insomnia, vomiting, constipation, upper respiratory tract infection, dyspnea, headache, and back pain. Grade ≥3 AEs were reported for 56% of pts; the most common (≥10%) was neutropenia. Serious AEs (SAEs) occurred in 21% of pts; the most common (≥2%) were atrial fibrillation, bacteremia, pulmonary embolism, and mental status changes. AEs led to permanent treatment discontinuation in 3% of pts. Infusion reactions (IRs) occurred in 54% of pts, including 49% at C1D1 and 4% at C1D2; 2 Grade 3 IRs (hypertension, anaphylactic reaction) occurred at C1D1; no Grade ≥4 IRs occurred. The most common (≥5%) IRs were chills, cough, dyspnea, nausea, pruritus, and flushing. Median infusion time was 4.5 hours for C1D1, 3.8 hours for C1D2, and 3.5 hours for subsequent doses. Conclusion: Dara-CyBorD was active and well tolerated in pts with ND and RMM, including pts with high-risk cytogenetics. ORR, VGPR+, and CR rates improved with cycles 5-8 of induction, indicating that longer therapy with dara results in deeper response. Preliminary PFS and OS data in ND pts in the first year are comparable to dara-VMP. The safety profile was consistent with that previously reported for dara, with no new safety signals observed. Split first daratumumab dosing was feasible, reduced Day 1 infusion time, and resulted in a similar IR rate as previously described for single-dose administration. These findings indicate that dara-CyBorD, using a split-dose first infusion, can be safely administered in the community setting and may be an effective treatment option for pts with MM. www.clinicaltrials.gov identifier: NCT02951819 Figure 1. Kaplan-Meier estimate of progression-free survival (PFS) among patients with newly diagnosed multiple myeloma. Disclosures Yimer: AstraZeneca: Speakers Bureau; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Equity Ownership; Janssen: Speakers Bureau. Melear:Janssen: Speakers Bureau. Faber:Amgen: 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; Cardinal Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Burke:Gilead: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Tempus Labs: Consultancy. Narang:Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gunawardena:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Lutska:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Qi:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Ukropec:Janssen Scientific Affairs, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Lin:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Rifkin:Amgen: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Celgene: Consultancy; EMD Serono: Consultancy; Takeda: Consultancy; Sandoz: Consultancy.

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IVAC +/- R for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas: Real-World Experience in the Modern Era

Blood ◽

10.1182/blood-2020-134607 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-10

Author(s):

Michael J Buege ◽

Phuong H Dao ◽

Esther Drill ◽

Andréa C LeVoir ◽

Terry Pak ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hematologic Toxicity ◽

Low Grade ◽

Advisory Committees ◽

Prophylactic Measures ◽

Grade 3

Introduction Part B of the modified Magrath regimen (ifosfamide, etoposide, and cytarabine; IVAC) with or without rituximab (R) is utilized as a standalone regimen in the management of relapsed/refractory Burkitt lymphoma and other non-Hodgkin lymphomas (NHL). There are no comparative or prospective data and a paucity of retrospective, non-comparative data to support use of this regimen. A small retrospective study described second-line IVAC use without R in a mixed cohort of patients with diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma, suggesting utility as a bridge to hematopoietic cell transplantation (HCT) (Pereira J, et al. Leuk Res. 2006 Jun;30(6):681-5). The activity of this regimen in B-cell NHL, particularly in conjunction with R, and its toxicity remain incompletely described. In this study, we describe our institutional experience with IVAC +/- R in relapsed/refractory B-cell NHL. Methods We reviewed all patients with relapsed/refractory B-cell NHL treated with IVAC +/- R between 1 January 2004 and 30 September 2019 at Memorial Sloan Kettering Cancer Center to assess efficacy and toxicity. Patients who received IVAC as part of sequential or alternating chemotherapy were excluded. Standard dosing consisted of ifosfamide 1500mg/m2 IV over 60min days 1-5, etoposide 60mg/m2 IV over 60min days 1-5, cytarabine 2000mg/m2 IV over 3 hours every 12 hours days 1-2, with or without rituximab 375mg/m2 IV day 0 or 1 in 21- to 28-day cycles (Lacasce A, et al. Leuk Lymphoma. 2004 Apr;45(4):761-7). Results Cohort and treatment characteristics are described in Table 1. Among 54 eligible patients (median age 51 years), 76% had DLBCL; 30% had lymphomatous central nervous system involvement at the time of initiating IVAC. Patients had received median 2 prior lines of therapy, with the last dose of the most recent line of therapy administered a median of 3 weeks prior to initiating IVAC. Patients received median 2 cycles of IVAC +/- R; 48% received IVAC-R. Prophylactic antimicrobials with cycle 1 were utilized in 94%. Most patients received herpesvirus- (81%) and Pneumocystis- (80%) directed prophylaxis; broad-spectrum prophylaxis with a fluoroquinolone was less common (24%). Primary granulocyte colony stimulating factor (GCSF) was utilized in 93% of patients with cycle 1; primary or secondary GCSF was utilized in 94% of cycles. Efficacy outcomes are described in Table 1. Objective response rate (ORR) among 46 evaluated patients was 48%; 17% achieved CR. ORR did not vary significantly between patients who did or did not receive R (58% vs 42%; p = 0.5) but was associated with number of IVAC cycles administered (among responders, 69% received 3-4 cycles while 31% received 1-2 cycles; p < 0.001). At median follow-up of 22 months, median progression-free survival (PFS) and overall survival (OS) were 3.1 months and 4.9 months, respectively (Figure). In Cox proportional hazard regression analysis of survival, patients who received R with every cycle (p = 0.025) and received 3 or more cycles (p < 0.001) experienced significantly longer PFS. Patients who achieved CR (p < 0.001) or PR (p = 0.003), received R with every cycle (p < 0.001), received 3 or more cycles (p < 0.001), or underwent subsequent HCT or CAR-T cell therapy (p = 0.001) experienced significantly longer OS. Toxicity outcomes are described in Table 2. Grade ≥ 3 anemia (93%), neutropenia (94%), and thrombocytopenia (100%; all grade 4) were common, regardless of number of cycles received. Febrile neutropenia (FN) occurred in 65% of patients and complicated 47% of cycles; documented infection occurred in 44%. Risk of FN and infection did not appear to be influenced by use of antimicrobial or GCSF prophylaxis. Grade ≥ 3 elevations in AST/ALT or total bilirubin were uncommon (5.6% and 9.3%, respectively). Neurotoxicity attributed to cytarabine or ifosfamide occurred in 17% of patients and was usually low-grade; hemorrhagic cystitis occurred in one patient. In patients for whom cause of death was documented (n = 37), mortality was attributed to a treatment-related complication in 19%. Conclusion IVAC-R may be a useful bridging therapy for patients with relapsed/refractory B-cell NHL who are planned for HCT. However, its potential for profound hematologic toxicity and life-threatening complications despite prophylactic measures requires careful consideration of less toxic alternatives. Disclosures Straus: Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Speakers Bureau; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽

10.1182/blood.v114.22.3866.3866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3866-3866 ◽

Cited By ~ 2

Author(s):

Maria Teresa Petrucci ◽

Igor W. Blau ◽

Paolo Corradini ◽

Meletios A. Dimopoulos ◽

Johannes Drach ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Bortezomib Treatment ◽

Best Response ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.4175.4175 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4175-4175

Author(s):

Christine I. Chen ◽

Susi Snitzler ◽

Trina Wang ◽

Harminder Paul ◽

Lisa W Le ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Treatment Phase ◽

Phase 2 ◽

Akt Inhibitor ◽

Advisory Committees ◽

Phase 2 Study ◽

Previously Treated ◽

Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Velcade, Vorinostat and Dexamethasone (V2 D) in Relapsed Myeloma: Results of the Phase 2 Muk Four Trial

Blood ◽

10.1182/blood.v126.23.1852.1852 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1852-1852

Author(s):

Matthew W Jenner ◽

Avie-Lee Tillotson ◽

Sarah R Brown ◽

Louise M Flanagan ◽

Debbie Sherratt ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Disease Progression ◽

Board Of Directors ◽

Dose Reduction ◽

Response Rate ◽

Prior Treatment ◽

Phase 2 ◽

Advisory Committees ◽

Grade 3 ◽

Relapsed Myeloma

Abstract Introduction: Bortezomib (Velcade) and dexamethasone is a standard combination for relapsed myeloma. Both in vitro data and initial clinical trials signalled the efficacy of the combination of intravenous bortezomib and the oral histone deacetylase inhibitor vorinostat. Although the randomised phase 3 VANTAGE 088 trial identified an improvement in progression free survival with the combination of bortezomib and vorinostat compared to bortezomib monotherapy in relapsed myeloma, 50% of patients in the vorinostat group had at least one dose reduction compared with 25% in the placebo group, with potential impact on clinical outcomes. Subcutaneous bortezomib has now become the standard route of administration because of lower rates of peripheral neuropathy. MUK four is a single arm phase 2 multi-centre UK trial to evaluate the toxicity profile and efficacy of an alternative dosing schedule of vorinostat in combination with subcutaneous bortezomib and oral dexamethasone. We report the final analysis of toxicity and response data. Methods: Patients with relapsed myeloma treated with 1-3 prior lines of therapy received up to 8 cycles of V2 D (bortezomib 1.3 mg/m2 subcutaneously days 1, 4, 8 and 11, vorinostat 400 mg orally days 1-4, 8-11 and 15-18 and dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21 day cycle). Following completion of a minimum of 3 cycles of V2 D, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28 day cycle) until disease progression, intolerance or participant withdrawal. Responses were assessed using the modified IMWG response criteria and toxicities graded using CTCAE v4.0. Results: Between August 2013 and November 2014, 16 participants were recruited to MUK four. Median age was 69.5 years (range 50.0-78.0) and median lines of prior treatment was 1 (1-3). Prior treatment included thalidomide-based combinations in 13/16 (81.3%), bortezomib-based in 7/16 (43.8%) and lenalidomide-based in 2/16 (12.5%). 9/16 (56.3%) participants had received prior high dose melphalan ASCT. Median time from diagnosis was 38.6 months (9.3-120.4). At analysis in June 2015 8/16 (50%) participants continued on maintenance vorinostat. All 16 patients were evaluable for response within the first 8 cycles of V2 D. Overall response rate was 81.3% (13/16, 95% CI [55.4-96.0]) consisting of CR in 4/16 (25.0%), VGPR 2/16 (12.5%) and PR in 7/16 (43.8%). The remaining 3/16 (18.8%) achieved MR giving a clinical benefit response rate of 16/16 (100%). Participants received a median of 6 cycles of initial treatment with 6/16 (37.5%) receiving all 8 cycles. Treatment was discontinued in 4/8 (50%) because of disease progression, in 2/8 (25%) because of toxicity and in 2/8 (25%) for clinician discretion. Overall 12/16 (75%) participants experienced a dose reduction of either vorinostat or bortezomib or terminated treatment early as a result of toxicity. 11/16 (68.8%) reduced vorinostat and 10/16 (62.5%) reduced bortezomib. The most frequent grade 2 toxicities during the first 8 cycles were fatigue in 8/16 (50%), anaemia in 7/16 (43.8%), diarrhoea in 5/16 (31.3%), nausea in 4/16 (25.0%) and peripheral neuropathy in 4/16 (25.0%). The most frequent grade 3-4 toxicities encountered during the first 8 cycles were thrombocytopenia in 8/16 (50%), anaemia in 1/16 (6.3%), diarrhoea in 1/16 (6.3%) and fatigue in 1/16 (6.3%). During maintenance vorinostat only 1 participant experienced an adverse reaction above grade 2 (grade 3 neutropenia). Conclusion: Bortezomib, vorinostat and dexamethasone is a highly effective combination in relapsed myeloma with good response rates. Maintenance vorinostat is well tolerated. Although toxicity and dose reductions are observed with combination therapy, this study demonstrates that the combination of proteasome inhibitor, HDAC inhibitor and dexamethasone offers promise. Further data on PFS will be presented. Disclosures Jenner: Amgen: Honoraria; Takeda: Honoraria. Off Label Use: Vorinostat for treatment of myeloma. Pawlyn:Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Williams:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Davies:Array-Biopharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Onyx-Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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The Eatl-001 Trial: Results of a Phase 2 Study of Brentuximab Vedotin and CHP Followed By Consolidation with High-Dose Therapy - Autologous Stem-Cell Transplantation (HDT-ASCT) in the Frontline Treatment of Patients with Enteropathy-Associated T-Cell Lymphoma

Blood ◽

10.1182/blood-2021-153709 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 136-136

Author(s):

David Sibon ◽

Sherine Khater ◽

Julie Bruneau ◽

Chantal Brouzes ◽

Ludovic Lhermitte ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Board Of Directors ◽

Gene Rearrangement ◽

Cell Lymphoma ◽

Brentuximab Vedotin ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Frontline Treatment

Abstract Background Enteropathy-associated T-cell lymphoma (EATL), previously designated type 1 EATL, is a neoplasm of intraepithelial T cells that occurs in individuals with celiac disease (CD). It is a rare lymphoma, accounting for approximately 3% of all peripheral T-cell lymphomas (PTCLs). EATL may be preceded by refractory CD (RCD), defined as persistent or recurrent symptoms and signs of malabsorption with villous atrophy despite a strict gluten-free diet for more than 12 months. Currently, RCD is categorized into 2 types, based on immunophenotypic and molecular criteria. In RCD-II, intraepithelial lymphocytes (IELs) have an aberrant phenotype and a clonal TCR gene rearrangement. RCD-II is considered a low-grade lymphoma of intraepithelial T cells, with a high risk of transformation into EATL. CD or RCD may be diagnosed prior to or concomitant with EATL. EATL has a poor prognosis due to perforation or obstruction of the bowel, sepsis, malnutrition and treatment resistance, with 2-year OS of 20% (de Baaij, CCR 2015). An EATL prognostic index (EPI) has been developed, that can distinguish 3 risk groups (de Baaij, CCR 2015). Optimal treatment of EATL is an unmet need, and novel therapeutic approaches are required. Most EATLs are CD30+ and could be targeted by brentuximab vedotin (BV). Based on the encouraging activity and manageable safety profile of BV and CHP (cyclophosphamide, doxorubicin and prednisone) combination in CD30+ PTCLs, the EATL-001 phase 2 trial was initiated to assess the efficacy and safety of BV-CHP followed by HDT-ASCT for the frontline treatment of patients (pts) with EATL (ClinicalTrials.gov No. NCT03217643). Here we report the first results of the EATL-001 trial. Methods EATL-001 is an Investigator Initiated-Sponsored Research phase 2 study, on behalf of the CELAC (French NCI-labeled network of Centers of Expertise for Lymphomas Associated with Celiac disease). Key inclusion criteria were as follows: Newly diagnosed CD30+ (≥10% of neoplastic cells by central review) EATL (WHO 2016 criteria), 18-65 years, PS 0-3. Response was assessed according to the Lugano classification. Pts were scheduled to receive 4 cycles of BV+CHP as induction. Responding pts received 2 cycles of Etoposide (200 mg/m2) + Methotrexate (3 g/m2) followed by HDT-ASCT (BEAM conditioning regimen). The primary endpoint was 2-year PFS per investigator. Underlying CD/RCD diagnosis was based on uninvolved duodenal histology (including CMF and TCR gene rearrangement analysis of IEL), serology and HLA typing. Results A total of 14 pts were included between February 2018 and February 2021. The median age was 54 years (range, 34-65) and 64% were male. 11 pts (79%) had initial surgery for bowel obstruction (n=6) or jejunal perforation (n=5). All pts had CD, diagnosed prior to (n=4) or concomitant with (n=10) EATL. 9 pts (64%) had RCD-II. CD30 expression ranged from 10% to 100%, nine cases having 100% positivity. EPI was high-risk in 4 pts (29%), intermediate-risk in 6 pts (43%), and low-risk in 4 pts (29%). Preliminary results by investigator assessment show an overall response rate following completion of the induction of 79% (11/14) with 64% (9/14) achieving a complete response. 3 pts had primary progressive disease (all had high-risk EPI), of which 2 died of the lymphoma. The 11 responding pts, still in response before intensification, underwent HDT-ASCT. 2 pts died of septic shock during HDT-ASCT. With a median follow-up of 2.1 years, there was no relapse and the 2-year PFS and OS for all pts were 63% and 68%, respectively. The incidence of AEs was consistent with the known safety profiles of BV-CHP regimen. Conclusions EATL-001 is the first prospective phase 2 study dedicated to EATL. BV-CHP was well tolerated and induced high response rates, allowing the majority of patients to be transplanted. This novel therapeutic approach shows promising efficacy compared to historical controls. Disclosures Sibon: Takeda: Consultancy; Roche: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; iQone: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Morschhauser: Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; Roche: Consultancy, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Hermine: Takeda: Consultancy. OffLabel Disclosure: Brentuximab vedotin is not approved in Europe for EATL.

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Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Blood ◽

10.1182/blood-2021-152603 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 623-623

Author(s):

Bradley M. Haverkos ◽

Onder Alpdogan ◽

Robert Baiocchi ◽

Jonathan E Brammer ◽

Tatyana A. Feldman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Lymphoma ◽

Phase 2 ◽

Advisory Committees ◽

Phase 1B

Abstract Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from <1 to 90% in 42 tumor biopsies with central lab review. The most common treatment-emergent adverse events (TEAEs) of all grades were nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3/4 TEAEs in >10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

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Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

Blood ◽

10.1182/blood-2020-136917 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-21

Author(s):

Vittorio Stefoni ◽

Paolo Corradini ◽

Lorella Orsucci ◽

Stefano Volpetti ◽

Lisa Argnani ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Cell Lymphoma ◽

Single Agent ◽

Progression Free Survival ◽

T Cell Lymphoma ◽

Phase 2 ◽

Advisory Committees ◽

Not Otherwise Specified ◽

Phase 2 Study

Options are limited for patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) for whom the median overall survival (OS) and progression free survival (PFS) are less than 6 months. Patients who are candidates for allogeneic stem cell transplantation can be cured should they achieve adequate response to salvage therapy prior to transplant. Patients who relapse after transplant or who are not transplant candidates are often treated with sequential single-agent therapies with non-curative intent. Only four agents are FDA-approved for the treatment of R/R PTCL including pralatrexate, romidepsin and belinostat. The objective response rate to each of these agents is only 25-30% and duration of response (DOR) is limited. For a specific subtype of PTCL, namely systemic anaplastic large-cell lymphoma, single-agent brentuximab vedotin (BV) treatment resulted in an 86% overall response rate (ORR) and a 57% complete response (CR) rate in R/R disease. A phase 2 study evaluated the efficacy and safety of BV in angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified reporting an ORR of 41% (Horwitz et al, Blood. 2014). We conducted a phase 2 study to determine the antitumor efficacy of single-agent BV (1.8 mg/kg administered intravenously every 3 weeks for a maximum of 16 cycles) as measured by the ORR in R/R CD30+ PTCL patients (PTCL not otherwise specified, AITL and transformed mycosis fungoides). Secondary objectives were to assess duration of tumor control, including duration of response and progression-free survival, overall survival and the safety and tolerability of BV in this setting. ClinicalTrials.gov Identifier: NCT02497131. From September 2015 and September 2019, 25 patients were enrolled and 23 (population for the final analysis) received at least one BV infusion (median 5, range 2-16). There were 10 females, 18 patients were in stage IV and 16 subjects were refractory to the last therapy. Median number of therapies received prior to BV was 2 (range 1-6). Final ORR was 30.4%, with 4 CR. CR patients were 3 PTCL not otherwise specified and 1 AITL with response duration of 2.8, 3.3, 4.5 and 10.7 months, respectively. Best response was achieved at the III cycle. PFS was 4.3% at 12 months (median reached at 4.4 months), OS at 12 months was 49.8% (median reached at 11.4 months) and median DOR was 3.4 months. No correlation between CD30 expression per central review and response was observed. Twenty-one hematological toxicities occurred, 14 of them were grade ≥3 (10 thrombocytopenia and 4 neutropenia, all resolved or improved during BV therapy). Among extra-hematological toxicities (n=26, 3.5% grade ≥3), 7 were serious adverse events. To note, 6 of them (23.1%) were lung infection/pneumonia. Only one peripheral neuropathy (grade 1) occurred. In terms of response, the ORR and PFS in this trial are comparable to those in similar populations studied with both other recently approved agents, such as pralatrexate and romidepsin, and with the other phase 2 study on BV. The ORR of 30% and the OS of in the present study places BV among the active agents for PTCL. Safety concerns emerged about infections, claiming for a strict monitoring for these toxicities. Disclosures Corradini: Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Zinzani:Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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