bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1/2 trial of cirmtuzumab and ibrutinib: Planned analysis of phase 1 CLL cohorts.
Authors: Choi Michael Y. , Wierda William G. , Lee Hun Ju , Tzachanis Dimitrios , Ianopulos Xen , Jezior Deborah , Breitmeyer James Bradley , Jamieson Catriona HM , Kipps Thomas J. ,   CIRLL Study Group
Published: March 2020

7527

Background: Cirmtuzumab (C) is a humanized mAb that binds ROR1 and blocks Wnt5a from binding and activating ROR1 on CLL and mantle cell lymphoma (MCL); C does not bind normal adult tissues. A phase 1 trial of C showed excellent safety and inhibition of Wnt5a-ROR1 signaling. Ibrutinib (Ibr) does not inhibit the ROR1 pathway, and C+Ibr exert synergistic effects in CLL and MCL. The current clinical trial combines C+Ibr for patients (pts) with CLL and MCL. A planned analysis of the phase 1 CLL portion is presented. Methods: Eligible pts had CLL needing treatment according to iwCLL guidelines. C was given at 2, 4, 8, or 16 mg/kg q 2 wk for 8 wk, then q 28 d to 52 wk. Ibr 420 mg PO daily was started on d 28. Results: 3 pts were treated at each C dose level with age 57-86; 75% were previously treated (median 2); 3 pts had del(11q), 3 had trisomy 12, and 6 pts had unmutated IGVH genes. There were no discontinuations for toxicity and no dose limiting toxicities. Treatment with C alone and combined with Ibr was well-tolerated. One SAE occurred with C monotherapy (hospitalization for tonsillitis). Adverse events on C+Ibr were consistent with the known Ibr safety profile, with one grade 3 hyperkalemia and 1 atrial fibrillation event. All other AEs were grade 1 or 2. The overall response rate after 16-48 weeks of treatment was 67% with 1 confirmed complete response (CR) with no morphologic evidence of CLL in the marrow, 1 clinical CR, 6 partial responses (PR) and 4 stable disease. No patient had progressive disease. The typical redistributive lymphocytosis seen with Ibr was blunted, with only a 50% mean rise in ALC, rapidly returning to baseline. PRs were observed in all C dose levels. Conclusions: The combination of C+Ibr is well-tolerated and effective. CRs were observed in 2 cases, a result that would be highly unusual with Ibr monotherapy in CLL. Based on these findings, Cirm 600 mg was selected as the RP2D for the randomized phase 2 portion of this protocol, which will prospectively compare the complete response rates between C+Ibr and Ibr alone. Clinical trial information: NCT03420183.
Impact on survival of surveillance imaging after first remission in follicular lymphoma.
Authors: Mao Jimmy , Strouse Christopher Sun , Goldman Max , Chen Wanqi , Chen Zhengjia , Maurer Matthew John , Calzada Oscar , Churnetski Michael , Flowers Christopher , Cerhan James Robert , Link Brian K. , Thompson Carrie A. , Cohen Jonathon Brett
Published: March 2020

7536

Background: While most patients (pts) with follicular lymphoma (FL) achieve an initial response to treatment, the majority relapse. Recently, Goldman et al. reported that surveillance imaging (SI) in FL is not associated with improved post-relapse outcomes and is frequently associated with false positive scans (ASH 2017). The goal of this study was to validate these findings. Methods: Pts were enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), a prospective cohort of newly diagnosed lymphoma pts. All pts were followed for events including relapse, re-treatment, and death, with events verified by medical records. Pts eligible for this study had biopsy proven FL grade 1, 2, or 3a who had achieved a response after induction therapy and later relapsed. Initial and post-treatment management was per treating physician. Medical records were re-reviewed in pts with events for clinical details at relapse in relationship to planned follow-up visits and SI. Relapse detection was categorized either by clinical suspicion (CS) via history, exam, and/or labs; or by SI in an asymptomatic pt. Univariate survival analysis was conducted for each variable. The hazard ratio with 95% confidence interval based on Cox Proportional Hazard models was presented along with the log rank test p-value. Kaplan-Meier plots were produced to evaluate the difference in overall survival (OS) between groups. Results: 1121 FL pts were enrolled in MER from 2002-2015, of which 117 were eligible. Median age at diagnosis was 60 years (range 35-83), and 61% were men. Median time to relapse of the 117 pts was 26 months (range 9-125). At a median follow-up from relapse of 69 months (range 0.23-179), 26 pts died. Pts completed a median of 3 imaging studies (range 0-15) during post-induction surveillance. 63 relapses (56%) were detected based on CS; 50 (44%) were detected by SI; and 4 were unknown. There was no difference in OS from relapse for those with relapse detected via CS vs. SI (HR = 0.98 [0.45,2.12], p = 0.96). Conclusions: Routine SI does not appear to improve survival outcomes in FL after achieving first remission, and its common practice should be questioned. Further investigation of prognostic markers to identify high-risk FL pts who may benefit from SI is needed.
Early progression of disease (POD24) as survival predictor in MALT lymphoma.
Authors: Conconi Annarita , Thieblemont Catherine , Cascione Luciano , Torri Valter , Kiesewetter Barbara , Margiotta-Casaluci Gloria , Gaidano Gianluca , Raderer Markus , Cavalli Franco , Lopez-Guillermo Armando , Johnson Peter W. M. , Zucca Emanuele ,   International Extranodal Lymphoma Study Group
Published: March 2020

7548

Background: Progression of disease within two years from start of therapy (POD24) is linked with poor outcome in follicular lymphoma. It is less clear whether POD24 affects overall survival (OS) also in extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma). Methods: We analyzed the dataset of the IELSG19 clinical trial (training set) to determine whether POD24 is associated with inferior OS. The study population included 401 EMZL patients (131 randomly assigned to chlorambucil treatment, 138 to rituximab and 132 to chlorambucil plus rituximab). Reproducibility was analyzed in an independent cohort (validation set) of 218 patients who received systemic treatment (chemotherapy, immunotherapy or both). In both, training and validation sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without progression. Overall survival (OS) was calculated from disease progression in patients with POD24 and from 24 months after start of treatment in those without POD24 (reference group). Results: POD24 was observed in 69 of 401 patients of the IELSG19 study and 58 of 218 patients in the validation cohort. In the training set, the 10-year OS rates were 64% in the POD24 group and 85% in the reference group (HR = 2.42, 95%CI, 1.35-4.34; log-rank P = 0.002) and POD24 predicted poor outcome regardless of treatment type (multivariable Cox model, P = 0.003). The prognostic impact of POD24 was confirmed in the validation set, with 10-year OS rates of 48% in the POD24 group and 71% in the reference group (HR = 2.17, 95%CI, 1.20-3.93; log-rank P = 0.009). Conclusions: In patients with EMZL who received front-line systemic treatment, POD24 is associated with poorer survival and may represent a useful endpoint in future prospective clinical trial.
A phase Ib/II study of oral nanatinostat (N) and valganciclovir (VG) in subjects with Epstein-Barr virus (EBV)-associated lymphomas.
Authors: Porcu Pierluigi , Haverkos Bradley , Brem Elizabeth , Vallurupalli Anusha , Feldman Tatyana , Alpdogan Onder , Brammer Jonathan Edward , Bryan Locke Johnson , Barta Stefan K. , Obrzut Sebastian , Shen Hao , Rochford Rosemary , Baiocchi Robert A. , Casper Corey , Gutheil John , McRae Robert , Daniels Preston , Warren Marshelle Smith , Royston Ivor , Faller Douglas V.
Published: March 2020

7551

Background: Nanatinostat (N; VRx-3996) is a Class I-selective oral hydroxamate histone deacetylase (HDAC) inhibitor active against HDAC 1-3, but not HDAC 6. N induces expression of EBV thymidine kinase (TK, BXLF1) and protein kinase (PK, BGLF4) in EBV+ lymphomas. This study examines if N+VG results in tumor sensitization to antivirals (i.e., VG) and impacts EBV-induced T-cell exhaustion. Methods: The study employs a 3+3 design with expansion in patients (pts) with relapsed/refractory EBV+ lymphomas (EBER-ISH). Objectives: Maximal Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D), and efficacy. Primary endpoint: safety. Secondary endpoints: PK, response rate. Exploratory endpoints: PBMC histone H3 acetylation (Ac), quantitative plasma EBV DNA (pEBVd), and immune biomarkers. Responses (investigator-assessed and centrally-reviewed) are based on the Lugano Classification. Early safety and efficacy data are reported. Results: As of 10-Jan-2019, 15 pts (4F/11M, median age 60 yrs [19-79]) were enrolled with a median of 2 prior therapies and various lymphoma subtypes. Cohort 1 (N 10 mg BID/VG 900 mg BID) exceeded MTD (DLTs: leukopenia, neutropenia and thrombocytopenia). PK demonstrated ~2-fold higher N exposure compared to a prior study. VG levels were consistent with published data. Doses were reduced in Cohort 2 (N 5 mg BID/VG 450 mg BID) with no DLTs to date and 3 active pts. Most non-hematologic treatment-related AEs (TRAEs) were G1-2. Most G3+ TRAEs were hematologic (neutropenia, leukopenia, thrombocytopenia). Increases in creatinine occurred early and responded to reductions in VG. Among 7 evaluable pts, 4 responses were seen (2 CR, 2 PR) in PTLD, DLBCL, AITL, and plasmablastic lymphoma. Two pts had SD, and 1 PD. Of 8 pts with detectable baseline pEBVd, 7 demonstrated a reduction (median -54% [17 to -83%]). PBMC H3 Ac levels, multi-cytokine expression panel, and functional assessments in CD8+ T cells are in progress. Conclusions: N+VG appears well-tolerated at 5 mg and 450 mg BID, respectively with hematologic DLTs in a higher dose cohort. Responses are observed at all doses in both B and T cell lymphomas, with reductions in pEBVd levels and changes in T cell functionality. A RP2D will be defined prior to dose expansion. Clinical trial information: NCT03397706.
Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results.
Authors: Moreau Philippe , Attal Michel , Hulin Cyrille , Béné Marie-Christine , Broijl Annemiek , Caillot Denis , Delforge Michel , Dejoie Thomas , Facon Thierry , Lambert Jérôme , Leleu Xavier , Macro Margaret , Perrot Aurore , Zweegman Sonja , Ahmadi Tahamtan , Chiu Christopher , Pei Lixia , Vermeulen Jessica , Avet-Loiseau Herve , Sonneveld Pieter ,   on behalf of IFM and HOVON
Published: March 2020

8003

Background: VTd is a standard of care (SoC) for TE NDMM. CD38 mAb DARA significantly reduced the risk of progression/death and improved CR and MRD-negative rates in relapsed refractory MM or transplant-ineligible NDMM in phase 3 studies. We report the primary and final analysis of Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts 18-65 y were randomized 1:1 to VTd (6 28-day cycles [C; 4 pre-ASCT induction, 2 post-ASCT consolidation] of V 1.3 mg/m2 SC BIW Week [W] 1-2; T 100 mg PO QD; d 40-80 mg/week PO or IV W 1-4 C 1-2, W 1-3 C 3-6) ± DARA (16 mg/kg IV QW C 1-2, Q2W C 3-6). Melphalan 200 mg/m2 was pre-ASCT HDT. The primary endpoint, post-consolidation sCR rate, was assessed at Day [D] 100 post-ASCT. Part 2 (maintenance) is ongoing. Results: A cohort of 1085 pts (D-VTd, 543; VTd, 542) was randomized. The D 100 post-ASCT sCR rate was significantly higher for D-VTd vs VTd (28.9% vs 20.3%; P = 0.0010; Table). At 18.8-mo median follow-up, PFS from first randomization favored D-VTd with HR 0.47 (95% CI, 0.33-0.67; P <0.0001). With median PFS NR in either arm, 18-mo PFS rates were 92.7% vs 84.6% for D-VTd vs VTd. Rates of ≥CR, ≥VGPR, and MRD negativity supported sCR results (Table). OS is immature with 46 deaths on study (D-VTd, 14; VTd, 32; HR, 0.43; 95% CI, 0.23-0.80). The most common (≥10%) grade 3/4 TEAEs (D-VTd/VTd) were neutropenia (27.6%/14.7%), lymphopenia (17.0%/9.7%), stomatitis (12.7%/16.4%), and thrombocytopenia (11.0%/7.4%). In the D-VTd arm, infusion-related reactions occurred in 35.4% of pts. Conclusions: D-VTd in induction prior to and consolidation after ASCT improved depth of response (sCR, ≥CR, and MRD negativity) and PFS with acceptable safety. The favorable benefit-risk profile supports the use of D-VTd in TE NDMM. CASSIOPEIA is the first study to demonstrate clinical benefit of DARA + SoC in TE NDMM. Clinical trial information: NCT02541383. [Table: see text]
A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Attal Michel , Rajkumar S. Vincent , San Miguel Jesus , Beksac Meral , Spicka Ivan , Leleu Xavier , Schjesvold Fredrik , Moreau Philippe , Dimopoulos Meletios A. , Huang Jeffrey SY. , Minarik Jiri , Cavo Michele , Prince H. Miles , Macé Sandrine , Corzo Kathryn Penkus , Campana Frank , Le-Guennec Solenn , Dubin Franck , Anderson Kenneth Carl ,   on behalf of the ICARIA-MM Study Group
Published: March 2020

8004

Background: The primary objective of this phase 3 trial was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti-CD38 monoclonal antibody, combined with pomalidomide (P)/dexamethasone (d) versus (vs) Pd. Methods: Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4mg PO days 1-21; 40mg [20mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity. Results: 307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36-86) yrs; median prior lines of therapy: 3 (2-11); estimated GFR: <60ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high-risk cytogenetics. At median follow-up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44-0.81), P=0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P<0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10-5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461-1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3h at 1st inf. and 2.8h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3-4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd. Conclusions: IsaPd significantly improved PFS and ORR vs Pd, with a manageable safety profile. IsaPd is an important new treatment option for the management of RRMM. Clinical trial information: NCT02990338.
Outcomes of patients with light chain amyloidosis who had autologous stem cell transplantation with three or more organs involved.
Authors: Al Saleh Abdullah , Sidiqi M Hasib , Dispenzieri Angela , Muchtar Eli , Buadi Francis , Dingli David , Lacy Martha , Warsame Rahma M. , Gonsalves Wilson I. , Kourelis Taxiarchis , Hogan William J. , Hayman Suzanne R. , Kapoor Prashant , Kumar Shaji , Gertz Morie A.
Published: March 2020

8011

Background: Literature suggests that three or more organ involvement is a contraindication for autologous stem cell transplant (ASCT) in light chain amyloidosis (AL). Most centers limit transplantation to patients who have no more than two organs significantly involved. Methods: We retrospectively reviewed all patients with AL Amyloidosis involving three or more organs and who had ASCT between 1996-2015 at Mayo clinic, Rochester, Minnesota. Results: Seventy five patients underwent ASCT with three or more organs involved. Median age at diagnosis was 54 years and 67% were males. The heart was involved in 95%, followed by kidneys (84%). Thirty eight patients (51%) had no induction treatment prior to ASCT. Full dose melphalan (200mg/m2) was given in 45%, and the remaining received a reduced dose (140mg/m2). Overall response rate (hematological) was 75%. The median progression-free (PFS) and overall survival (OS) were 16.3 and 68.9 months, respectively. The 100-day mortality was 16% and overall forty four patients (59%) died during the follow up period. The most common causes of death were cardiovascular events (32%) and progressive amyloidosis (25%). On multivariable analysis, predictors for PFS were Mayo stage III/IV (RR 3.3, P = 0.0012) and hematological response (≥VGPR, RR 0.4, P = 0.012). An NT-ProBNP level of ≥2000 pg/ml was an independent predictor for shorter PFS (RR 2.6, P = 0.013). Predictors for OS included any hematological response (RR 0.1, P < 0.0001) and Mayo stage III/IV (RR 7, P < 0.0001). When looking at the NT-ProBNP, a level ≥2000 was prognostic (RR 5.5, P = 0.001). Number of organs involved (3 vs. 4-5) was not significant in either PFS or OS. Conclusions: We conclude that the high prevalence of cardiac involvement is the main driver for the poor outcome in patients who have three or more organs involved. Using selection criteria defined for safe transplantation in cardiac amyloidosis should result in low therapy-related mortality independent of the number of organs involved. The concept of considering patients with three organs involved ineligible for stem cell transplantation should be abandoned.
Clinical responses and pharmacokinetics of fully human BCMA targeting CAR T-cell therapy in relapsed/refractory multiple myeloma.
Authors: li chunrui , Zhou Jianfeng , Wang Jue , Hu Guang , Du Aihua , Zhou Xiaoxi , Meng Li , Hong Zhenya , Chen Liting , Mao Xia
Published: March 2020

8013

Background: Previous studies indicate patients with relapsed/refractory multiple myeloma (RRMM) who receive high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM. The primary objectives are to characterize the safety and tolerability in patients with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, cytokines, CAR-T cell persistence, and pharmacokinetics. Between September 21, 2018, and January 21, 2019, nine patients (including 3 patients having relapsed after being given a murine BCMA CAR-T) received CT103A in 3+3 dose-escalation trial (three doses at 1, 3, 6 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. All Patients had received a median of 4 prior lines (range 3 - 5) of MM therapy. Results: At the time of the February 4, 2019 data analysis, the overall response rate was 100% (Table), and all patients had a rapid response within 14 days, with 67% (2/3) reaching CR/sCR at the lowest dose. The pharmacokinetics of CT103A were assessed by a digital polymerase chain reaction. Robust expansions were seen even at the lowest dosage level. In addition, Cmax and AUC0-28 reached levels comparable to reported CD19 CAR-T. In the first two dose groups, the grade of cytokine release syndrome (CRS) was 0 - 2. In the 6 ×106 /kg dose group, DLT had been observed in one patient. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A. Major AEs were transient, manageable, and reversible. three patients who relapsed the murine BCMA CAR-T were treated with CT103A, two patients achieved CR, and one patient achieved VGPR. 100% ORR and a rapid response within 2 weeks, suggests CT103A could be developed as a competitive therapeutic to treat patients with RRMM. Treatment Response (Case 1,5 and 7 are patients who relapsed the murine BCMA CAR-T). Clinical trial information: ChiCTR1800018137. [Table: see text]
Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: Analysis of the CASSIOPEIA trial.
Authors: Avet-Loiseau Herve , Moreau Philippe , Attal Michel , Hulin Cyrille , Arnulf Bertrand , Corre Jill , Garderet Laurent , Karlin Lionel , Lambert Jérôme , Macro Margaret , Perrot Aurore , Sonneveld Pieter , Levin Mark-David , Klein Saskia , Chiu Christopher , Pei Lixia , De Boer Carla , Kampfenkel Tobias , Wuilleme Soraya , Béné Marie-Christine ,   on behalf of IFM and HOVON
Published: March 2020

8017

Background: In TE NDMM patients (pts), the CD38 monoclonal antibody DARA significantly reduced the risk of progression/death and improved stringent CR, ≥CR, and MRD-negative rates when added to VTd in the phase 3 CASSIOPEIA study. MRD status and its association with progression-free survival (PFS) was evaluated in TE NDMM pts receiving D-VTd vs VTd as pre-transplant induction/post-transplant consolidation in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts were randomized 1:1 to 4 cycles of pre-ASCT induction and 2 cycles of post-ASCT consolidation with DARA + VTd or VTd. Landmark analyses of MRD were performed on bone marrow aspirates after induction by multiparametric flow cytometry (MFC; 10–5 sensitivity threshold) and after consolidation (at Day 100 post-ASCT) by MFC (10–5) and next-generation sequencing (NGS; 10–6) for all pts, regardless of response. Results: A cohort of 1085 pts was randomized (D-VTd, n = 543; VTd, n = 542). Post-induction and post-consolidation MRD-negative rates were significantly higher for D-VTd vs VTd (Table). Post-consolidation MRD-negative rates (MFC) were consistent across pt subgroups, including ISS stage III or high-risk cytogenetics. Multivariate analyses accounting for treatment arm and MRD negativity (MFC) showed a PFS benefit in pts reaching MRD negativity (HR, 0.31; 95% CI, 0.20-0.50; P <0.0001). Based on these analyses, D-VTd showed additional PFS benefit vs VTd (HR, 0.48; 95% CI, 0.30-0.78; P = 0.0028). Analysis of MRD based on response (per IMWG criteria) will be presented. Conclusions: Adding DARA to VTd induction and consolidation deepened responses, as demonstrated by significant increases in MRD-negative rates. MRD negativity was associated with a PFS benefit regardless of treatment group. However, deepened responses with D-VTd led to improved outcomes, with MRD negativity associated with prolonged PFS, versus VTd in pts with TE NDMM. Clinical trial information: NCT02541383. [Table: see text]
Phase 1 study of elotuzumab in combination with autologous stem cell transplantation and lenalidomide maintenance for multiple myeloma.
Authors: Osman Keren , Cho Hearn J. , Chari Ajai , Parekh Samir S.
Published: March 2020

8021

Background: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients will be safe and feasible. Methods: This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must be eligible for auto-SCT, and meet inclusion/exclusion criteria. Fifteen subjects participated in this study. The treatment plan is: In addition to PBSC harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily begins with cycle 4 of elotuzumab. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab. Results: 15 subjects have been enrolled in the study. All of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 15 subjects have completed 4 of the first 5 planned elotuzumab infusions.. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. There were no delays in hematopoietic reconstitution. No AEs were attributed to PBMC reconstitution. Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy appears to be safe and feasible. The trial is ongoing and has completed accrual. The clinical results will be updated for presentation.
Maintenance with weekly carfilzomib in elderly newly diagnosed multiple myeloma (IFM 2012-03).
Authors: Bobin Arthur , Fouquet Guillemette , Duhamel Alain , Manier Salomon , Karlin Lionel , Kolb Brigitte , Tiab Mourad , Araujo Carla , Meuleman Nathalie , Malfuson Jean-Valère , Bourquard Pascal , Lenain Pascal , Jaccard Arnaud , Belhadj Karim , Attal Michel , Moreau Philippe , Avet-Loiseau Herve , Hulin Cyrille , Facon Thierry , Leleu Xavier
Published: March 2020

8029

Background: Prolonged treatments have significantly improved survival in newly diagnosed multiple myeloma (NDMM). Lenalidomide (IMiDs), is currently approved in this indication, but remains a daily treatment, although oral, and may favor side effects in the long run. Furthermore, the use of a proteasome inhibitor (PI) is warranted in certain type of MM, such as high-risk. Carfilzomib, a second generation PI, has proved active combined with an acceptable security profile but its added benefit when given continuously is unknown. We thought to study maintenance Carfilzomib for elderly NDMM (eNDMM). Methods: The IFM 2012-03 multicenter phase I KMP (Carfilzomib, Melphalan, Prednisone) weekly study for eNDMM (≥ 65 years old) determined the maximal tolerated dose of weekly Carfilzomib at 70mg/m². We focus herein on the second part of the study with IV Carfilzomib monotherapy given at 36mg/m² for 13 cycles maintenance on an every 2 weeks schedule. Results: Thirty eNDMM were recruited in IFM 2012-03. Median age is 75, with 56% R-ISS 2 or 3 and 11% high-risk cytogenetic. With K weekly from 36 to 70mg/m², OS is reported at 93.3%, including 46.7% ≥CR; median PFS is 35.8 months and median OS was not reached. Twenty-two (73%) patients started K maintenance and 16 (73%) completed it. Four patients progressed and 2 stopped for AEs (renal amylosis, sensory neuropahty) during the maintenance phase. At maintenance completion, 50% were ≥CR. From the start of maintenance, in landmark analysis, median PFS is 28.1 months and the estimated 36-months OS approximately 70%. Conclusions: Carfilzomib monotherapy can be used safely in maintenance for 1 year in eNDMM, including for patients above 75 years. K maintenance may lead to deep response rate, certainly a most relevant prognostic factor for prolonged survival. Therefore, Carfilzomib maintenance, characterized with a simple administration modality, might be considered as an alternative to Lenalidomide and integrate the armamentarium of prolonged therapy in eNDMM. Clinical trial information: NCT02302495.
Biomodulatory therapy approach with lenalidomide in combination with pioglitazone, dexamethasone, and metronomic low-dose chemotherapy with treosulfan in patients with relapsed/refractory multiple myeloma > second-line.
Authors: Heudobler Daniel , Elger Tanja , Mayer Stephanie , Hart Christina , Vogelhuber Martin , Grube Matthias , Hahn Joachim , Lüke Florian , Ditz Diana , Günther Andreas , Gramatzki Martin , Schmidt Burkhard , Ferenczy Peter , Herr Wolfgang , Rechenmacher Michael , Reichle Albrecht
Published: March 2020

8037

Background: Nowadays, therapy for relapsed or refractory multiple myeloma (rrMM) usually consists of multi-targeted combination regimens for achieving complete remission. In this context, resistance resembles a therapeutic challenge that may be overcome by novel biomodulatory therapies communicatively reprogramming dysregulated cellular and intercellular homeostasis in neoplasia. Methods: The present, prospective phase II, one-arm, one-stage multi-center, open label trial, following phase I, focused on reprogramming myeloma and adjacent stroma cells in order to control rrMM beyond > 2nd-line treatment and following lenalidomide resistance in prior line. Adults with rrMM were eligible for receiving continuously, oral, daily dexamethasone 1mg, pioglitazone 45mg, low-dose treosulfan as metronomic chemotherapy ( 250mg bid) and lenalidomide 15mg, respectively, until disease progression. Results: Thirty-nine patients (mean time since diagnosis, 5.7 years; 66.7% with age > 60 years) had received a median of 5.5 (range 2 to 10) prior treatments. 89.5% of the patients were refractory to last therapy (all IMiD resistant), and 48.7% had received autologous stem-cell transplants. The overall response rate (CR, VGPR) was 17.9%. Eighteen patients (46.2%) had partial response or better; ten patients (25.6%) had stable disease. The disease control rate (DCR) was 71.8%. Time-to-progression was not significantly different between IMiD refractory patients and those relapsing following prior IMiD therapy or between high-risk versus non-high-risk cytogenetics. The median progression-free survival (PFS) and overall survival was 5.6 months (95% confidence interval [CI], 3.8 to 8.5) and 17.6 months (95% [CI], 14.9 to 39.2), respectively. The major AE (NCI-CTCAE grade) with grade ≥ 3 and relation to study drugs was hematologic toxicity (N = 31, 67.4%). Due to scheduled dose reductions, this was associated with only 7 (15.2%) grade ≥ 3 infections. Conclusions: The favorable safety profile, encouraging efficacy and equivalent median PFS between biomodulatory and modern targeted therapy in a historic comparison reveal a proof of concept of combined biomodulatory therapy in patients with heavily pretreated and IMiD-resistant rrMM, which should be further evaluated. Clinical trial information: NCT001010243.
Continued improvement in survival in multiple myeloma (MM) including high-risk patients.
Authors: Nandakumar Bharat , Binder Moritz , Dispenzieri Angela , Kapoor Prashant , Buadi Francis , Gertz Morie A. , Lacy Martha , Dingli David , Hwa Lisa , Leung Nelson , Hayman Suzanne R. , Gonsalves Wilson I. , Kourelis Taxiarchis , Muchtar Eli , Warsame Rahma M. , Go Ronald S. , Hobbs Miriam A. , Kyle Robert A. , Rajkumar S. Vincent , Kumar Shaji
Published: March 2020

8039

Background: Treatment of MM has evolved significantly over the past decade, with increasing use of multi-drug combinations for initial therapy. In addition, supportive care approaches have also improved. We examined how these improvements have translated to survival outcomes in patients with newly diagnosed MM. Methods: Patients (n=3449) with a diagnosis of MM made between 2004 and 2017 and seen at Mayo Clinic within six months of the diagnosis, were included in this analysis. Patients were divided into three groups based on the year of diagnosis; group 1- 2004-07 (n=831), group 2-2008-12 (n=1161), and group 3-2013-17 (n=1457). Survival of the groups were estimated using Kaplan-Meier method, and compared using log rank test. Results: The median age was 64 years (22 to 96); 60% were male and 40% were female. 14% were >75 years, 33% were aged 65-75 and 53% were <65 years. The median overall survival for the whole cohort was 5.7 years (95%CI; 5.4, 6.3). The median OS for the groups 1, 2 and 3 were 3.9, 6.3 and NR, respectively; p<0.001. The 4-year survival estimates were 50%, 62%, and 75%, respectively. We then explored the improvements in patient subgroups. While all patients experienced improvements in OS over time, improvement in group 3 was most prominent for those >75 years. In patients <65 years, the 4-yr OS for groups 1, 2 and 3 were 57, 71, and 79% respectively. In patients 65-75 years of age, the 4-yr OS for groups 1, 2 and 3 were 48, 60, and 75% respectively. In patients >75 years, the 4-yr OS for groups 1, 2 and 3 were 24, 35, and 56% respectively. While patients with high-risk disease did not see as much benefit in the earlier period, substantial progress was seen in the last group. The 3-yr OS for patients with high-risk cytogenetics were 52, 55, and 73% for groups 1, 2 and 3 compared to 67, 75, and 85% for standard-risk cytogenetics respectively. 2067 patients were staged according to the International Staging System and the median OS for stages 1, 2 and 3 were 6.5, 4.6 and 2.4 in group 1; 9.2, 6.6 and 3.5 in group 2 and NR for any of the stages in group 3. Conclusions: The results confirm continued improvement in survival of newly diagnosed multiple myeloma patients, including elderly and high-risk MM.
Stem cell (SC) yield and transplantation results from transplant-eligible newly diagnosed multiple myeloma (TE NDMM) patients (pts) receiving daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in the phase 3 CASSIOPEIA study.
Authors: Hulin Cyrille , Moreau Philippe , Attal Michel , Belhadj Karim , Benboubker Lotfi , Caillot Denis , Facon Thierry , Garderet Laurent , Kuhnowski Frederique , Stoppa Anne-Marie , Kolb Brigitte , Tiab Mourad , Sonneveld Pieter , Jie Kon-Siong , Westerman Matthijs , Pei Lixia , Kampfenkel Tobias , De Boer Carla , Vermeulen Jessica , van de Donk Niels W.C.J. ,   on behalf of IFM and HOVON
Published: March 2020

8042

Background: High-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is the standard of care in TE NDMM. In the phase 3 CASSIOPEIA study, D-VTd significantly improved stringent complete response (sCR), ≥CR, and minimal residual disease (MRD)-negative rates and reduced the risk of progression/death vs VTd in TE NDMM pts. We assessed SC yield and transplantation results among pts receiving D-VTd vs VTd induction prior to HDT/ASCT in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts ages 18-65 y were randomized 1:1 to 4 pre-transplant induction and 2 post-transplant consolidation cycles of DARA + VTd or VTd alone. After induction, pts underwent SC mobilization with cyclophosphamide 3 g/m2 (recommended dose) and GCSF. Peripheral blood SCs were harvested based on response to mobilization. Plerixafor was given if SC collection failed at first attempt and in accordance with institutional practice. Melphalan 200 mg/m2 IV was given as HDT prior to ASCT. Results: A total of 1085 pts were randomized (D-VTd, 543; VTd, 542). Among pts who completed mobilization (D-VTd, 506; VTd, 492), more pts receiving D-VTd vs VTd received plerixafor during mobilization (21.7% vs 7.9%). Pts underwent a median (range) of 2 (1-6) vs 1 (1-4) days of apheresis for D-VTd vs VTd. The median number of CD34+ cells collected was lower for D-VTd vs VTd (6.3×106/kg vs 8.9×106/kg). Nevertheless, a similar percentage of ITT pts receiving D-VTd vs VTd underwent ASCT (90.1% vs 89.3%). The median number of CD34+ cells transplanted for D-VTd vs VTd was 3.3×106/kg vs 4.3×106/kg. Hematopoietic reconstitution rates were high and similar for transplanted pts receiving D-VTd vs VTd (99.8% vs 99.6%). For D-VTd vs VTd, a median (range) of 13.0 (6-54) vs 13.0 (4-43) days was required to achieve sustained ANC > 500 cells/mm3, and a median (range) of 14.0 (2-56) vs 12.0 (1-47) days was required to achieve sustained platelets > 20,000 cells/mm3 without transfusion. Conclusions: SC mobilization and collection was feasible with D-VTd induction. Adding DARA to VTd allowed successful transplantation in pts with TE NDMM. Clinical trial information: NCT02541383.
Local activator and T cell engager (LocATE) selectively blocks PD-L1 at the cytolytic synapse for deeper responses in multiple myeloma.
Authors: Leisner Christian , Borras Leonardo , Jungmichel Stephanie , Richle Philipp , Scheifele Fabian , Schleier Thomas
Published: March 2020

8045

Background: The BCMA-targeting bispecific T-cell engager AMG420 emerged as the first bispecific that achieved responses similar to CAR-T therapies in patients with relapsed/refractory (RR) multiple myeloma (MM). Despite improved ORR, the median duration until relapse is currently limited to approximately 12 months. Persistent minimal residual disease drives relapse and is characterized by increased expression of PD-1/PD-L1. Efficacy with checkpoint inhibitors is compromised by 1) their activity not been targeted specifically to the immune synapse between T cells and cancer cells, and 2) dose-limiting broadly distributed immune-related adverse events, which has halted several clinical trials. This underscores the need for localized checkpoint inhibition within the cytolytic synapse. We developed a Local Activator and T cell Engager (LocATE) antibody that combines binding to CD3 and BCMA with selective blockade of PD-L1 at the immune synapse in just one scaffold. Selectivity is achieved via low afffinity for PD-L1 and high affinity for BCMA. Methods: Antibody mediated Cytotoxicity (LDH assay) and T cell activation (IL-2 release) was measured in vitro using MM cell lines together with isolated human CD3+ T cells. Human ex vivo T cell activity and redirection was evaluated on fresh bone marrow biopsies from MM patients with different disease stages by automated microscopy (pharmacoscopy) and image analysis. Results: The LocATE antibody showed a 5-fold increase in T cell activation and MM cell killing in vitro compared to a BCMAxCD3 BiTE. Furthermore, patient-derived MM cells showed up to a 19-fold increase in T cell activation as compared to a BCMAxCD3 BiTE or a combination of BiTE and PD-L1 inhibitor, while no activity was observed on healthy cells. Conclusions: These results suggest that T cell redirection with simultaneous checkpoint inhibition in the synapse is highly potent while minimizing off-tumor toxicity, therefore, has high therapeutic potential for patients with relapsed MM.
Veliparib (Vel) in combination with chemoradiotherapy (CRT) of carboplatin/paclitaxel (C/P) plus radiation in patients (pts) with stage III non-small cell lung cancer (NSCLC) (M14-360/AFT-07).
Authors: Kozono David E. , Stinchcombe Tom , Salama Joseph Kamel , Bogart Jeffrey , Petty William J. , Guarino Michael J. , Bazhenova Lyudmila , Larner James Mitchell , Weiss Jared , DiPetrillo Thomas A. , Feigenberg Steven J. , Hu Beibei , Nuthalapati Silpa , Luo Yan , Vokes Everett E.
Published: March 2020

8510

Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.
The tumor microenvironment in EGFR-driven loco-regional lung adenocarcinoma can predict higher risk of recurrence.
Authors: Khalil Maya , Elkhanany Ahmed , Yang Yuanquan , Glenn Sean , Papanicolau-Sengos Antonios , Morrison Carl , Dy Grace K.
Published: March 2020

8521

Background: The role of EGFR tyrosine kinase inhibitors (TKIs) as adjuvant therapy in EGFR-mutated NSCLC is still controversial. Identifying biomarkers associated with increased risk of recurrence may help stratify pts & guide adjuvant therapy. We hypothesized that tumor immune microenvironment (TME) alterations could predict disease-free survival (DFS) in these pts. Methods: The Cancer Genome Atlas (TCGA) lung Adenocarcinoma (LUAD) data at Genomic Data Common (GDC) was accessed for pt phenotype, updated outcome & normalized gene expression profile (RNA seq). Immune landscape data was obtained from PANCAN. We chose to focus on 54 key TME genes, identified from a commercially available immune report card from OmniSeq (Inc.). Pt groups were divided via K-mean clustering. Group comparison was done via Likelihood Ratio (LR, categorical), Mann Whitney (continuous), log-rank (survival) & Cox regression (outcome). Bonferroni correction was used to correct for multiple comparisons. Results: 877 pts with LUAD were identified, 32 of whom had EGFR mutations and were at stages I to III. The mutations were mostly in the TK domain, involving exons 18 (12%), 19 (27%), 20 (6%), & 21 (33%). Only 3% harbored the T790M mutation. None of the pts received adjuvant TKI. Analysis of the impact of individual genes on DFS yielded a group of 8 genes whose high expression was associated with improved DFS: IL10 (HR 0.58, p 0.029), BTLA (HR 0.66, p 0.07), CD8A (HR 0.6252, p 0.099), CD39 (HR 0.454, p 0.037), CCR2 (HR 0.729, p 0.039), CSF1R (HR 0.70, p 0.087), ICOS (HR 0.66, p 0.062), & CD4 (HR 0.67, p 0.059). K-mean clustering of the pts using these genes demonstrated 2 groups with distinct immune profiles. Group 1 was characterized by higher leukocyte and stromal fractions, lymphocyte infiltration score, macrophage regulation, TGF-ß response, & T cell richness with less proliferation, pointing towards a more “inflamed” phenotype. Significant difference between the two groups in the immune subtypes was found (LR 10, p = 0.039). 90% of pts in the inflamed group had tumors with IFN-γ dominant, inflammatory, and TGF-ß dominant subtypes, while 45% of the “non-inflamed” group had lymphocyte depleted & wound healing signatures. DFS was significantly longer in the inflamed group (median DFS 1480 vs 772 days, p = 0.002). Conclusions: In pts with resected EGFR-mutated LUAD, an inflamed TME is associated with prolonged DFS. Identifying these pts may help select those who would benefit from adjuvant therapy.
Updated survival date of phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non-small cell lung cancer.
Authors: Horiike Atsushi , Kawano Yuko , Sasaki Tomonari , Yamaguchi Hiroyuki , Hirano Katsuya , Satouchi Miyako , Hosokawa Shinobu , Morinaga Ryotaro , Komiya Kazutoshi , Inonue Koji , Fujita Yuka , Toyozawa Ryo , Kimura Tomoki , Takahashi Kosuke , Nishikawa Kazuo , Kishimoto Junji , Nakanishi Yoichi , Okamoto Isamu
Published: March 2020

8529

Background: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC). Methods: Patients between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. In the phase II part of the study, patients received weekly nab-paclitaxel at 50 mg/m2 together with weekly carboplatin at an area under the curve (AUC) of 2 mg mL–1 min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. The primary end point of the phase II part of the study was progression-free survival (PFS). Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0 to 49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1% to 76.8 %). The median PFS was 11.8 months (60% CI, 10.6 to 16.8 months; 95% CI, 8.2 to 21.0 months). The overall response rate was 76.8% (95% CI, 64.2% to 85.9%), and the disease control rate was 94.6% (95% CI, 85.4% to 98.2%). Subgroup analysis according to histology or age revealed no significant differences in median PFS or OS. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). Pneumonitis of grade 3 was observed in two patients during the study period. No treatment-related deaths occurred. Conclusions: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 mg mL–1 min in patients with locally advanced NSCLC. Clinical trial information: UMIN000012719.