A Phase I/II Dose-Escalation Study of Thiotepa-Based Immunochemotherapy in Relapsed/Refractory Primary Central Nervous System Lymphoma; The Tier Trial

BACKGROUND Outcomes for patients (pts) with primary CNS diffuse large B cell lymphoma (PCNSL) have improved over recent years, largely through optimisation of first-line methotrexate (MTX)-containing protocols and dose-intensive chemotherapy consolidation. However, 30-50% of pts experience refractory or relapsed (r/r) disease, which confers very poor outcomes and short survival. By contrast to systemic DLCBL, there is no accepted standard approach for r/r PCNSL. Thiotepa is an alkylating agent highly efficient at crossing the BBB and widely incorporated within high-dose therapy and autologous stem cell transplantation (HDT-ASCT) protocols for PCNSL, but has not undergone dose-finding studies nor been incorporated within salvage regimens for PCNSL. The TIER study investigates the safety and efficacy of adding thiotepa, in a dose-escalation design, to the Rituximab, Ifosphamide and Etoposide (R-IE) salvage regimen1. METHODS TIER is an open label, phase I/II UK NCRI TAP study for pts with r/r PCNSL, previously treated with a high-dose MTX-based regimen. In phase I, the RP2D of thiotepa within the TIER combination was established using a 3+3 design, with dose escalations of 30, 40 and 50mg/m2 (dose level 2 (n=4), 3 (n=5) and 4 (n=27) respectively), given on day 5 of R-IE cycle1. The Phase II primary endpoint was overall response rate (ORR) after cycle 2 of TIER (C2) by centrally reviewed contrast-enhanced MRI2, on an intention-to-treat (ITT) basis. Further treatment and consolidation after the primary endpoint MRI was at the discretion of investigators. Key secondary end-points were 2-year PFS, EFS and OS. RESULTS Thirty-six pts were recruited from Jun 2015-Apr 2019 at 13 centres (characteristics: Table 1). The median number of prior lines was 2 (range 1-4) with 44% of patients deemed refractory to their previous line of therapy. During phase I (n=10) no dose limiting toxicities (DLTs) were observed up to and including 50mg/m2 thiotepa, constituting the RP2D (n=27). 56 cycles of TIER were administered across both phases; 5 pts had >1 dose reductions. Median time between C1D1 and C2D1 was 24.7 days (range 22-38). Relative mean dose intensity of thiotepa, ifosphamide and etoposide was 71.8 (SD 44.9), 76.4 (SD 41.6), and 76.8 (SD 41.8) respectively. Further therapy after 2 cycles of TIER was delivered to 41.7% of pts (16.7% ASCT, 22.2% TIE, and 2.8% WBRT). The most common grade 3 / 4 adverse events were thrombocytopenia and neutropenia (47.2 and 55.6% occurring in 15 and 18 pts respectively). 17 serious adverse events (SAEs) were reported in 12 pts, of which 4 were haematological. Of these, 13 were considered related to TIER. Commonly occurring non-haematological SAEs were respiratory tract infections (23.5%) and seizures (11.8%). At data lock, 10/27 pts had responded to treatment as assessed by local investigators (ORR 37%, CR rate 15%). 13 pts were non-evaluable (7 progressed prior to C2 scan, 2 withdrew consent, and 4 awaiting scans) and classed as non-responders. Following data lock, responses were reported for 3 further pts (2 by local investigators and 1 by central review), resulting in a provisional ORR of 13/27 (48%). For the ITT population, median OS time was 3.52 months (95% CI 2.50, 14.17), and median PFS 2.86 months (95%CI 2.34, 6.05) (Figure 1). 6 pts underwent ASCT consolidation after TIER, of whom 2 have relapsed. CONCLUSIONS This is an early analysis of data from the phase I/II TIER study for a heavily pre-treated group of r/r PCNSL; the first such dose-escalation study for this patient group. Phase I determined a RP2D of 50mg/m2 of thiotepa incorporated in the R-IE regimen. There were no DLTs and toxicities, consistent with an intensive ifosphamide-based regimen. ORR was 10 pts (37%) with 3 further responses reported after data lock. If confirmed by central review, the primary endpoint of activity (ORR 40%) will have been reached. However, notwithstanding the response endpoint, most pts experienced very poor survival outcomes. These data describe the feasibility of TIER as a salvage regimen for r/r PCNSL but question the utility of this approach as a standard option, given the short PFS and OS times, except for the minority of pts who received ASCT. Biological and imaging sub studies are underway to identify predictors of outcome. In the modern era of effective first line immunochemotherapy approaches, pts with r/r PCNSL remain a major area of unmet need for whom novel experimental approaches are urgently required. Disclosures Fox: Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Martinez-Calle:ABBVIE: Other: Travel support. Collins:Gilead: Consultancy, Honoraria. Ferreri:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Kite: Consultancy. Davies:BioInvent: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Bayer: Research Funding; ADCT Therapeutics: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Johnson:Roche: Consultancy, Honoraria, Speakers Bureau; Takeda: Other: Travel, accomodations, expenses. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.

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Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-114832 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2154-2154

Author(s):

Noa Biran ◽

Shijia Zhang ◽

Scott D. Rowley ◽

David H. Vesole ◽

Michele L. Donato ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Conditioning Regimen ◽

High Dose ◽

Advisory Committees ◽

Common Grade ◽

Grade 3 ◽

High Dose Melphalan

Abstract Background: A regimen of escalating doses of thalidomide, in combination with bortezomib and high dose melphalan (Mel/Vel/Thal) was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) in a phase I/II study. Methods: Patients received Mel/Vel/Thal as a second of tandem ASCT if they achieved <CR to their first ASCT (tandem), or as conditioning for a salvage ASCT (salvage). Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, severe organ dysfunction, Karnofsky score <70%, or painful grade 2 or greater peripheral neuropathy. Conditioning consisted of Vel 1.6 mg/m2 intravenously on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1 and was administered in a planned step-wise dose escalation of 600, 800 and 1000 mg (in cohorts of 3 pts). Dexamethasone (Dex) 10-20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE version 3. Results: Twenty-nine pts were enrolled: 9 in the phase 1 dose-escalation phase and an additional 20 pts in phase 2. In the phase I portion, all pts experienced somnolence, with grade 3 occurring in 1 pt at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with decreased severity of somnolence. No dose limiting toxicities defined as ≥ grade 4 non-hematological SAEs occurred in the phase I portion, allowing full dose escalation with 9 pts enrolled. The maximum tolerated dose for Thal was not reached and the 1000 mg dose was chosen for the phase 2 dose expansion. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after ASCT and were not attributed to Thal. The most common grade 1 and 2 non-hematologic toxicities included nausea (65.5%), mucositis (51.7%), diarrhea (48.3%), somnolence (48.3%), lethargy (27.6%), and vomiting (17.2%). The most common grade 3 non-hematologic adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and somnolence (13.8%), which increased risk of falls. SAEs included somnolence (13.8%), tumor lysis syndrome (3.4%), and engraftment syndrome (3.4%). All transplant-related SAEs resolved by day +28 after ASCT. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8-14 days), and platelet >20,000 12 days (range 9-26 days). All pts received at least one ASCT prior to enrolling on the study. Seventeen pts (59%) had interim salvage chemotherapy between their upfront and Mel/Vel/Thal ASCT (i.e. received a salvage ASCT), with median time from first to salvage ASCT 29 months. The remaining 12 (41%) went directly from an upfront ASCT Mel-based ASCT to the Mel/Vel/Thal ASCT (tandem ASCT) within 6 months of the first ASCT. Twenty-seven (93%) were Durie-Salmon stage III, and 13 (44%) had >2 prior lines of therapy. Of those who had Mel/Vel/Thal as a salvage ASCT, 70% had ≥3 prior lines of therapy. The overall response rate (ORR) was 69% with 38% complete remission. ORR for Mel/Vel/Thal compared to upfront Mel ASCT was 69% versus 62% with 11 patients achieving CR with Mel/Vel/Thal compared to 5 patients with Mel alone (Figure 1). Ten of 27 evaluable patients (37%) had an upgrade in response in the Mel/Vel/Thal salvage ASCT compared to their upfront ASCT: 2 pts (7%) went from PD to PR, 1 (4%) from SD to CR, 1 (4%) from PR to VGPR; 3 (11%) from PR to CR and 2 (7%) from VGPR to CR. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. Of those who underwent tandem Mel followed by Mel/Vel/Thal ASCT the median PFS was 14.9 months with a median OS not yet reached at time of analysis. For the 17 patients who received a salvage Mel/Vel/Thal ASCT, median PFS from their upfront ASCT was 11.9 months, compared to 9.1 months with the salvage Mel/Vel/Thal ASCT. Conclusions: High-dose Thal up to 1000 mg daily for 5 days can be safely combined with Vel and dose-intense Mel as an ASCT conditioning regimen with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Figure 1 Figure 1. Disclosures Biran: BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Phase 1 Dose-Escalation Study of Multiple Dosing Schedules of the Investigational Drug MLN4924, a Nedd8-Activating Enzyme Inhibitor, In Patients with Relapsed and/or Refractory Multiple Myeloma or Lymphoma.

Blood ◽

10.1182/blood.v116.21.2801.2801 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2801-2801 ◽

Cited By ~ 1

Author(s):

Jatin J Shah ◽

R. Donald Harvey ◽

Owen A O'Connor ◽

Andrzej J Jakubowiak ◽

Mitchell R Smith ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Peripheral Blood ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Advisory Committees ◽

Dose Escalation Study

Abstract Abstract 2801 Background: MLN4924 is an investigational inhibitor of Nedd8-activating enzyme (NAE), which plays an essential role in regulating the activity of the cullin-RING E3 ligases (CRLs). NAE controls the neddylation cascade that results in Nedd8 conjugation to the CRLs, which is required for ligase activity. NAE inhibition thus inhibits ubiquitination and proteasomal degradation of CRL substrates, which include proteins involved in cell-cycle regulation (p27), signal transduction (pIκBα), DNA replication (Cdt-1), stress response (Nrf-2), and other processes important to tumor cell growth and survival. In lymphoma cells, NAE inhibition with MLN4924 has been shown to result in apoptosis either through increased Cdt-1 levels, S-phase accumulation, and DNA re-replication, or via pIκBα stabilization and consequent NF-κB pathway inhibition. In vivo, MLN4924 treatment resulted in tumor growth inhibition and regressions in lymphoma xenograft models. This phase 1 dose-escalation study is the first investigation of MLN4924 in multiple myeloma (MM) and lymphoma patients. We have previously reported (Shah et al, ASH 2009) that the maximum tolerated dose (MTD) of MLN4924 on Schedule A of this study (days 1, 2, 8, and 9 of 21-day cycles) was 110 mg/m2, with dose-limiting toxicities (DLTs) including muscle cramps and febrile neutropenia. Analyses of peripheral blood mononuclear cells and skin biopsies indicated MLN4924 exerted the predicted pharmacodynamic (PD) effects in peripheral blood and skin, including inhibition of neddylated cullins and induction of pIκBα, Cdt-1, and Nrf-2. Two additional schedules of MLN4924 administration are now being investigated with the aim of increasing tolerability and the deliverable dose. Methods: Patients aged ≥18 years with ECOG performance status 0–2 and relapsed and/or refractory MM or lymphoma, including any B- or T-cell non-Hodgkin's lymphoma (NHL) and Hodgkin lymphoma (HL), following ≥2 prior lines of therapy were eligible. Primary objectives were to determine the MTD and safety profile of MLN4924 on the different dosing schedules, describe the pharmacokinetics (PK) and PD of MLN4924 in blood, and investigate PD effects in skin and tumor. Secondary objectives included evaluation of disease response. Patients received MLN4924 via a 60-minute intravenous infusion on either days 1, 4, 8, and 11 (Schedule B) or days 1 and 8 (Schedule C) of 21-day cycles for up to 12 months. Doses of 25–147 mg/m2 were investigated on Schedule A; for Schedules B and C, dose escalation started at the MTD of Schedule A, 110 mg/m2, and proceeded in 1.33-fold increments using a Bayesian continual reassessment method based on the occurrence of DLTs in cycle 1. The MTD was defined as the dose level closest to that predicted to result in a DLT rate of 25%. Adverse events (AEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results: To date, 7 patients (5 male, median age 60 years [range 48–68]) have been enrolled to Schedule B, 2 each at 110, 147, and 196, and 1 at 261 mg/m2; 2 have MM and 5 lymphoma (2 diffuse large B-cell lymphoma [DLBCL], 1 small lymphocytic lymphoma, 1 mantle cell lymphoma [MCL], 1 nodular sclerosis HL). Patients have received a median of 3 cycles (range 2–5) to date. A total of 7 patients (all male, median age 49 years [range 45–66]) have been enrolled to Schedule C, 2 each at 110 and 147, and 3 at 196 mg/m2; 4 have MM and 3 lymphoma (1 follicular lymphoma [FL], 1 MCL, 1 nodular sclerosis HL). Median number of cycles received is 4 (range 1–7). No DLTs and no grade ≥3 AEs have been reported on either schedule to date. On Schedule B, only grade 1 dyspnea and myalgia (both n=2) have been reported in >1 patient, with grade 1 diarrhea (n=3), constipation, fatigue, and nausea (each n=2) reported on Schedule C. PK data for the 110 mg/m2 cohorts of Schedules B and C are consistent with the lack of significant accumulation of MLN4924 in plasma shown on Schedule A. One patient with HL on Schedule A achieved a partial response; no responses have been reported to date on Schedules B and C though some heavily treated patients have demonstrated stable disease for 5 or more cycles (1 FL, 7 cycles; 1 DLBCL, 5 cycles; 1 MM, 5 cycles). Conclusion: Enrollment and dose escalation are proceeding on Schedules B and C (at doses above Schedule A MTD) to determine the MTD on each schedule; updated clinical data will be presented, together with data on the PK and PD of MLN4924, on these dosing schedules. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of multiple myeloma and lymphoma. O'Connor:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding, Speakers Bureau. Orlowski:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Mulligan:Millennium Pharmaceuticals: Employment. Smith:Millennium Pharmaceuticals, Inc.: Employment. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Dezube:Millennium Pharmaceuticals: Employment, Equity Ownership. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽

10.1182/blood-2019-123954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2831-2831 ◽

Cited By ~ 1

Author(s):

Swaminathan P. Iyer ◽

Brad M. Haverkos ◽

Jasmine Zain ◽

Radhakrishnan Ramchandren ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

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A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Blood ◽

10.1182/blood-2019-131045 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 348-348 ◽

Cited By ~ 6

Author(s):

Nathan H Fowler ◽

Loretta J. Nastoupil ◽

Collin Chin ◽

Paolo Strati ◽

Fredrick B. Hagemeister ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Advisory Board ◽

Indolent Lymphoma ◽

Advisory Committees ◽

Grade 3

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

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Ritumixab in Combination with Adapted-Dose of Ifosfamide and Etoposide As Salvage Treatment in Elderly Refractory/Relapsed Diffuse Large B-Cell Lymphoma Patients Non-Candidate for High Dose Therapy: A Retrospective Study of Lyon Hospital University

Blood ◽

10.1182/blood-2018-99-116734 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4215-4215

Author(s):

Guillaume Aussedat ◽

Delphine Maucort-Boulch ◽

Philippe Rey ◽

Violaine Safar ◽

Lionel Karlin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Advisory Board ◽

High Dose ◽

First Line ◽

Advisory Committees ◽

Previously Treated ◽

Grade 3

Abstract Introduction: standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) but this strategy is not appropriate for elderly DLBCL patients (pts) related to a high risk of toxicities. Multiple chemotherapy regimens had been developed for heavily pretreated elderly DLBCL patients such as R-bendamustine, R-gemcitabine-oxaliplatin (R-GEMOX) and pixantrone; the median progression free survival (PFS) of these regimens were 2, 4 and 3.5 months, respectively in prospective phase II studies for patients previously treated with R (Sehn 2017, Mounier 2013, Pettengel 2016). Adapted dose of ifosfamide and etoposide was firstly developed as sequential consolidation regimen after high-dose CHOP (ACVBP regimen) in first line therapy of young DLBCL patients (Tilly 2003). This regimen with a safe toxicity profile was then used in combination with R in Lyon University Hospital in elderly R/R DLBCL ineligible to intensive strategy. Methods: we retrospectively reviewed the efficacy and the safety profile of this regimen performed in two Lyon University Hospitals (Centre Hospitalier Lyon Sud and Leon Berard Cancer Center). Between June 2004 and March 2017, 75 pts with R/R DLBCL (63 de novo DLBCL, 12 transformed DLBCL) received R (375 mg/m2) in combination etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on day 1 (N=72, 96%) and on days 1-2 (N=3, 4%) at 2 (N=46, 61%) or 3-week (N=29, 39%) intervals. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities, responses and outcome. Results: the median age was 79 years (range, 64-92) at the beginning of R-ifosfamide/VP16 treatment with 46% of the patients over 80 years. 13% of pts had a CIRS-G grade 3 or 4 >2 categories and 35% had a cumulative CIRS-G score more than 6. The performance status according to EORTC scale was 2-4 in 37% of the pts and 93% had III-IV Ann Arbor stages. Age-adjusted IPI were 0-1 in 20 pts (27%) and 2-3 in 55 pts (73%). All patients were previously treated in first-line therapy by R in combination with chemotherapy (CHOP, N=56, 75%, low-dose CHOP, N=14, 19%, other, N=5, 6%). The patients received a median number of 1 previous line (range, 1-8) and no patient was previously treated by ASCT. The median time between initial diagnosis and R-ifosfamide/VP16 was 20 months (range 4-187). The median time between the last treatment and R-ifosfamide/VP16 was 5 months (range 0-181). A refractory disease to first-line treatment was showed in 14 pts (19%). 31% of the patients had a refractory disease to the last regimen performed before R-ifosfamide/VP16. Patients received a median of 6 cycles (1-12). At the end of treatment, the overall response rate (ORR), defined by the rate of complete response (CR) and partial response (PR) was 37%, with 18% of CR. Evaluations were assessed for 29% of the pts by TEP scanner. For toxicity, among the 387 cycles, 10 patients developed febrile neutropenia (2.6%); 15 (20%) a grade 3-4 neutropenia; 7 (9%) a grade 3-4 thrombocytopenia; 5 patients needed platelet units and 16 patients received packed red blood cell units. No grade 3-4 non-hematological toxicity was observed and no toxic death occurred. With a median follow up of 31.3 months (range, 5.0-202.8), the median progression-free survival (PFS) was 4.3 months with a 1-year PFS rate of 26.0% (95%CI, 17.7-38.3) (Figure 1A). The median overall survival (OS) was 8.2 months with a 1-year OS rate of 40.8% (95%CI, 30.9-54.0) (Figure 1B). The median duration of response was 4 months (range 1-97). The median PFS was adversely affected by response (refractory versus CR/PR) to the last treatment (3.0 months versus 5.5 months, P=0.001) (Figure 1C). Conclusions: in this retrospective study, R-Ifosfamide/VP16 regimen provided effective results in R/R DLBCL transplant-ineligible pts with 37% of ORR and a median of PFS of 4.3 months with a safe toxicity profile. This regimen could also be considered as a platform for combinations with novel targeted agents in these categories of patients. Disclosures Karlin: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarkozy:ROCHE: Consultancy. Bachy:Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding; Celgene: Consultancy; Janssen: Honoraria. Salles:Abbvie: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria. Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy.

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Systematic Reviews of the Clinical Efficacy and Safety of First-Line Treatments for Patients with Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-118685 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5868-5868

Author(s):

Neerav Monga ◽

Jamie Garside ◽

Matthew S. Davids ◽

Constantine S. Tam ◽

Katherine Ward ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Eligible Patient ◽

High Dose ◽

Efficacy And Safety ◽

First Line ◽

Advisory Committees ◽

Treatment Regimens ◽

Mantle Cell

Abstract Introduction Mantle cell lymphoma (MCL) is a rare and aggressive form of Non-Hodgkin's lymphoma (NHL) with poor survival outcomes. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended as first-line therapy in younger patients. However the comparative efficacy of such regimens, and of alternative therapy options (for patients unable to tolerate chemotherapy + ASCT), remain unclear. A comprehensive understanding of the current evidence is therefore required. Methods Two systematic reviews (SRs) were developed to identify efficacy and safety data for therapies used in the first-line treatment of MCL. One review identified randomised controlled trials (RCTs) and the other non-randomised studies (NRSs). Searches were carried out in EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Clinical Trials electronic databases. Additionally, conference materials were screened from ASH, EHA, ESMO and ASCO proceedings from the last 2 years. All review methodologies were performed according to Cochrane best practice guidelines Results The RCT SR was run in August 2017 and updated in April 2018. Overall, 2,787 abstracts were screened. The SR included 9 full-text articles and data from 2 conference proceedings, together reporting a total of 7 independent studies. Across the RCTs, the most commonly investigated treatment regimens were rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP), and bendamustine + rituximab (BR). Frequently reported primary endpoints were response rates and progression-free survival (PFS). Table 1 presents the PFS and overall survival (OS) data reported in the included RCTs. Data from the RCT reporting on intensive induction chemotherapy followed by ASCT are separated from regimens that did not include ASCT. There were notable differences in median PFS rates, between both patients receiving ASCT versus patients not receiving ASCT and also between the two ASCT treatment arms. In pharmacotherapy studies, PFS ranged from 14.4 to 35.4 months, whereas the two arms of the ASCT RCT reported 51.6 and 109.2 months, respectively. Similar trends were observed in OS: the only result for patients undergoing ASCT (117.6 months) was higher than any result reported in patients not receiving transplant (range 40 - 60 months). However, study heterogeneity may affect the appropriateness of directly comparing these results. Frequently reported grade 3-4 adverse events included anemia, infusion-related reactions, nausea, neutropenia and thrombocytopenia (four of seven RCTs reported each event). The NRS SR was run in April 2018. A total of 3,290 abstracts were screened and 75 full papers were assessed. The SR included 25 full-text articles and 6 conference proceedings, together reporting a total of 18 independent single-arm studies. Several of the NRSs investigated treatment regimens that have not been described in RCT studies, including: R-CHOP with alternating or sequential rituximab + cytarabine (maxiCHOP), and cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high dose methotrexate or cytarabine + rituximab (hyperCVAD + R). Across the NRSs, the longest median PFS was 8.5 years (102 months), in patients treated with maxiCHOP (who were young/ASCT-eligible patients). This outcome was reported in a patient population who had responded to induction therapy and were treated with consolidative ASCT. Across all studies there was heterogeneity in the eligible patient population, with some studies focusing on unfit patients and others focusing on high-dose-therapy-eligible patient populations. Many studies also reported maintenance or consolidation treatments, which would influence the long-term outcomes of the patients. Conclusions These SRs highlight the paucity of directly comparable evidence on the efficacy and safety of therapies for patients with MCL. Although there are some marked differences in patient outcomes according to therapy regimen, considerable heterogeneity in study design and patient populations make direct comparison difficult. Despite this, these SRs highlight that MCL remains a difficult subtype of NHL to treat, with short survival highlighting the high unmet need. With new and emerging therapies, additional research is essential to understand optimal regimens for first-line MCL. Table 1. Table 1. Disclosures Monga: Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Davids:Merck: Consultancy; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding; Surface Oncology: Research Funding; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ward:Janssen Pharmaceutica NV: Consultancy. Quigley:Janssen Pharmaceutica NV: Consultancy. Parisi:Janssen: Employment. Tapprich:Janssen Pharmaceutica NV: Employment.

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Induction Therapy with Everolimus in Combination with DHAP (Dexamethasone, High-Dose AraC, Cisplatinum) in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma: A Randomized, Placebo-Controlled Phase I/II Trial (HD-R3i)

Blood ◽

10.1182/blood-2018-99-117291 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2912-2912 ◽

Cited By ~ 1

Author(s):

Bastian von Tresckow ◽

Andreas Hüttmann ◽

Vladan Vucinic ◽

Horst Mueller ◽

Annette Plütschow ◽

...

Keyword(s):

Placebo Group ◽

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Induction Therapy ◽

Research Funding ◽

High Dose ◽

Classical Hodgkin Lymphoma ◽

Advisory Committees ◽

Support Research

Abstract Introduction: Induction chemotherapy followed by BEAM high dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSC transplant) is standard of care for transplant-eligible patients with relapsed or refractory classical Hodgkin lymphoma (rrHL). However, approx. 50% of patients relapse and therefore, this strategy must be improved. As response to induction therapy is predictive of the outcome after HDCT, this trial aimed at improving the response to induction therapy by adding oral everolimus to time-intensified standard DHAP (Ever-DHAP). Methods: We included patients with histologically confirmed rrHL aged 18-60 years in this phase I/II trial. Dosage of everolimus was pre-determined in the phase I part with 10 mg/day given parallel to DHAP for 14 days within each of two cycles. The phase II part started as a randomized controlled trial comparing 50 patients in the everolimus group to 50 patients in a placebo group. The primary endpoint of the phase II part was the CT-based complete remission (CR-) rate after two cycles of Ever-DHAP. This CR-rate would be expected to be ≥ 40% if adding everolimus was effective. Secondary efficacy endpoints of the trial were PET-based CR-rate after two cycles of induction, progression-free and overall survival. Secondary feasibility endpoints were time to recovery, CTC-based adverse events, duration of induction therapy, discontinuation rates and the rates of successful PBSC collection. The trial was registered at ClinicalTrials.gov with ID NCT01453504. Results: From 7/2014 to 3/2018 we recruited a total of 59 patients in the phase II part. Because of poor recruitment the placebo group was closed in 9/2015 after 9 patients were randomized. These patients are analyzed in a descriptive way only. Of 50 patients in the everolimus group two were not evaluable because of retracting consent and not starting therapy; three additional patients discontinued Ever-DHAP because of toxicity. PBSC collection was successful in 37/39 documented patients receiving Ever-DHAP (95%). After two cycles of therapy we observed a CT-based CR in 12/45 patients of the everolimus group (27%) and in 2/9 patients of the placebo group (22%). A PET-based CR was achieved by 19/38 patients of the everolimus group (50%) and by 4/5 patients of the placebo group. In the everolimus group two patients had refractory disease (4%) and two died (4%), 3 and 4 months after starting but not related to Ever-DHAP. Final results and additional analyses will be presented. Conclusions: Adding everolimus to time-intensified DHAP is feasible, however, the Ever-DHAP regimen failed to show an improved efficacy. Disclosures von Tresckow: Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD: Honoraria, Other: Travel support, Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Viardot:Amgen: Consultancy; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

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Preliminary Results of Ibrutinib Followed By Ofatumumab Consolidation in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL): GELLC7 Trials from the Spanish Group of CLL (GELLC)

Blood ◽

10.1182/blood-2019-128470 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4296-4296

Author(s):

Pau Abrisqueta ◽

Eva González-Barca ◽

Christelle M Ferra ◽

Eduardo Ríos Herranz ◽

Margarita Fernandez ◽

...

Keyword(s):

Pleural Effusion ◽

Adverse Events ◽

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Hematological Toxicity ◽

Induction Phase ◽

Advisory Committees ◽

Preliminary Results

Introduction. Despite the high proportion of prolonged remissions obtained with ibrutinib in patients with CLL, complete responses (CR) are rarely observed. For the purpose of increasing the deepness of response, ibrutinib has been tested in combination with other drugs that exert a different mechanism of action. Thus, monoclonal antibodies (mAbs) have been concomitantly combined with ibrutinib in untreated or R/R CLLs. Nonetheless, several data derived from both in vitro and clinical studies do not support a synergistic effect of the concomitant administration of ibrutinib with anti-CD20 mAbs. Herein, we present the preliminary results of a multi-center, non-randomized phase 2 study aimed to determine the efficacy and safety of the sequential treatment of CLL patients with ibrutinib followed, in those not attaining CR, by a consolidation phase with ofatumumab (GELLC-7, EudraCT number 2016-004937-26). Patients and methods. Patients aged ≥18 years, physically fit (CIRS score < 6) with treatment-naïve CLL were enrolled in this study. Patients received an induction phase consisting of 12 cycles (28-day) of ibrutinib in monotherapy at 420 mg once daily. Patients attaining a CR after this induction phase were kept on ibrutinib until progression. In contrast, patients not obtaining a CR also continued on ibrutinib but received a consolidation treatment with 7 doses of ofatumumab (300 mg D1 and 1000mg D8 of C13, 1000 mg D1 of C14-C18). The primary endpoint of the study was the CR rate assessed after 20 cycles of treatment (2 months after completing ofatumumab consolidation). Results. 84 patients with a median age 69 years (range 38-84 yrs), 71% male, were included in this study. At inclusion, 83.3% had Binet stage B/C, 61% unmutated IGHV status, and 19% high risk genetic aberrations (7.6% 17p deletion and/or TP53mut, and 11.4% 11q deletion). At the interim data cut-off (June 2019), 7 patients had discontinued the study (progression to Richter transformation, n=1; patient withdrawal, n=3; adverse events [AE], n=3, including one G5 AE), 5 of them during the first 12 cycles of treatment. Sixty-seven patients received the induction phase with 12 cycles of ibrutinib, whereas 22 patients completed 20 cycles of treatment and were evaluable for the primary endpoint of the study. After 12 cycles of ibrutinib, 3 patients (4.5%) were in CR, 54 patients (80.5%) in PR, 6 patients (9%) in PR with lymphocytosis, and 4 patients (6%) in SD. In 20 patients receiving the consolidation with ofatumumab an improvement in response was observed, with 8/20 patients (40%) attaining a CR (7 patients converted PR to CR, and one patient SD to CR), whereas the remaining 12 patients were classified as PR. Two patients that were already in CR at cycle 12 maintained the CR under ibrutinib monotherapy. MRD was undetectable in blood (<10-4 by flow cytometry) only in one of the 22 patients. With a median follow-up of 15 months (2 - 20.2 months), the estimated 12-months PFS and OS was 98%. Grade ≥3 adverse events (AEs) were experienced by 26 patients (31%), whilst 22 serious AEs were observed in 16 patients (19%) (14 infections, 1 febrile neutropenia, 3 dyspnoea, 1 anemia, 1 edema/pleural effusion, 1 renal insufficiency, 1 squamous carcinoma). The most common G3/4 AEs were hematological toxicity (neutropenia [7.1%], anemia [4.5%], thrombocytopenia [2.4%]) and infections (8.5%). The Gr 5 AE consisted of a severe peripheral edema and pleural effusion leading to death. The great majority of SAEs (67%) and G3/4 AEs (66%) were observed during the first 12 cycles of treatment with ibrutinib monotherapy. Conclusions. The preliminary analysis of the GELLC7 trial showed that the addition of consolidation with ofatumumab after 12 cycles of prior treatment with ibrutinib was well tolerated and elicited a deeper response. These results support the potential role of a sequential therapeutic strategy in CLL, where the addition of a consolidation with mAbs in patients with low tumor burden might improve the quality of the response. Finally, more mature results will be further presented at the meeting. Disclosures Abrisqueta: Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. González-Barca:Kiowa: Consultancy; Celgene: Consultancy; Takeda: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celtrion: Consultancy. Terol:Roche: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Consultancy; Astra Zeneca: Consultancy; Gilead: Research Funding. Baltasar Tello:GILEAD: Honoraria; JANSSEN: Consultancy, Honoraria; ABBVIE: Honoraria; ROCHE: Honoraria. de la Serna:Roche, AbbVie, Gilead, Janssen, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, AbbVie, Janssen, Gilead: Speakers Bureau. Ramirez Payer:GILEAD SCIENCES: Research Funding. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Bosch:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Ibrutinib followed by Ofatumumab Consolidation

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Low-Dose Azacitidine, Pioglitazone and All-Trans Retinoic Acid Versus Standard-Dose Azacitidine in Patients ≥ 60 Years with Acute Myeloid Leukemia Refractory to Standard Induction Chemotherapy (AMLSG 26-16/AML-ViVA): Results of the Safety Run-in Phase I

Blood ◽

10.1182/blood-2019-129977 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1382-1382 ◽

Cited By ~ 4

Author(s):

Daniel Heudobler ◽

Sebastian Klobuch ◽

Florian Lüke ◽

Joachim Hahn ◽

Matthias Grube ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

Advisory Committees ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Refractory Aml

Introduction: Patients (pts) with acute myeloid leukemia (AML) who are refractory to intensive frontline treatment have a dismal outcome. In case of ineligibility for allogeneic stem cell transplantation (HSCT), the median survival of chemo-refractory AML is about 2 months and less than 5% of these pts are alive after 1-year (retrospective analysis from the AMLSG database). To date, there is no universally accepted standard approach for the treatment of chemo-refractory AML in older pts. Several retrospective studies have assessed the role of hypomethylating agents in this patient group, but complete remission (CR) rates were disappointingly low (≤10%) when compared to first line treatment. The presented study represents a novel approach focusing on hematopoietic tissue reprogramming (i.e. anakoinosis) (ClinicalTrials.gov Identifier: NCT02942758). Methods: The initial dose-finding phase I of the study evaluated the combination of azacitidine (AZA) 75 mg/d s.c. for 7 days, repeated every 28-days, pioglitazone 45 mg/d p.o. continuously from day 1 and all-trans retinoic acid (ATRA). A modified 3+3 design has been used to establish the maximum-tolerated dose of ATRA. Patients have been enrolled at an ATRA dose of 45 mg/m²/d from day 1 to day 28 and 15 mg/m²/d continuously thereafter if no dose limiting toxicity (DLT) occurred until start of next cycle on day 29. The safety DLTs were defined as toxicities attributable to ATRA, expected or unexpected, except if these are likely associated with another cause. Eligible patients had confirmed diagnosis of AML refractory to induction therapy and were not eligible for further intensive induction therapy or were not immediate candidates for allogeneic HSCT. The severity of adverse events was graded using the Common Terminology Criteria for Adverse Events (CTCAE) V. 4.03. The response to treatment was evaluated using standard criteria defined by the expert panel on behalf of the European LeukemiaNet and international working group (IWG) response. Results: Ten pts were enrolled in the safety-run-in phase I (one pt withdrew informed consent on day 9 of cycle 1). Among all treated pts, the median age was 67 years (range, 62-76 years), and the majority of pts (70%) had an ECOG PS of 1 (see table 1). Two pts had secondary AML; another two pts had therapy-related AML (t-AML). Eight pts had a complex karyotype. Concerning safety, hematological adverse events (AEs) were the most common toxicities observed. Because pts with baseline cytopenia were included (leukopenia n=8; 80%; thrombocytopenia n=9; 90%), occurrences of many hematological AEs began before study drug initiation and were attributed to underlying hematologic disease. Common 3°/4° AEs included neutropenia (50%), anemia (50%), thrombocytopenia (30%), and infections (40%). 50% of pts experienced a serious AE; one 5° AE (gastric hemorrhage) occurred. No DLTs were observed. Five pts discontinued the study, with progressive disease (PD) or relapse being the most common reason for discontinuation. Concerning efficacy, 3 pts (30%) achieved a CR and one pt a long-lasting stable disease (14 months). Morphologic review showed signs of differentiation of blasts in responding pts, which has already been shown in in-vitro analysis. In line with this observation, one pt demonstrated resolution of fungal pneumonia during the study. Conclusions: In summary, the low-intensity, biomodulatory regimen of low-dose AZA, pioglitazone, and ATRA demonstrated a tolerable safety profile and encouraging signals for efficacy in pts with AML refractory to standard induction chemotherapy warranting further investigation. S.T. and A.R. contributed equally to this abstract as senior co-authors. Disclosures Paschka: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Abbvie: Other: Travel expenses; Amgen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Other: Travel expenses; Takeda: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AROG, Bristol Myers Squibb, Pfizer: Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria. Thomas:Celgene: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Medigene AG: Consultancy, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Other: Travel support; Janssen: Other: Travel support.

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