Ld Arm Research Articles

Protocol and Primary Analysis of Lome: A Randomized Trial of Low- Versus Intermediate-Dose Immune Tolerance Induction with Recombinant Factor VIII (Omfiloctocog alfa, SCT800) in China

Background: Although the cohort and registry data support low-dose (LD; 50 IU/kg once every other day) and intermediate-dose (MD; 100 IU/kg daily) immune tolerance induction (ITI) are almost equally effective in inducing tolerance in people with severe hemophilia A, with inhibitors (PwHI)1-3, there has been no prospective randomized trials, especially in China. Here, we present the protocol and results of the primary analysis in LOME (ChiCTR2200056603). Methods LOME is a multicenter, prospective, randomized comparison of LD and MD ITI, in severe hemophilia A (HA) patients (FVIII level < 1%) with peak historical inhibitor ≥ 5 and < 200 Bethesda Unite (BU/ml). In the first year of recruitment (Part A), patients with age ≤ 8 years at time of randomized will be included. In the second year of recruitment (Part B), patients with age ≤ 12 years at time of randomized will be included. Patients have received ITI therapy before randomization will be excluded. Subjects were randomized 1:1 to LD or MD ITI with the first domestic recombinant factor VIII (rFVIII) (Omfiloctocog alfa, SCT800) approved in China. Factor III (FVIII) inhibitor screening, ITI monitoring and dose tapering will be based on the consensus from United Kingdom Hemophilia Center Doctors' Organization (UKHCDO)4. If (a) there is an upward trend in titer over 3-6 months period; or (b) fall in chromogenic Bethesda titer of less than 20% in 6 months period after initial peak inhibitor titer; or (c) titer ≥ 200BU/ml during ITI therapy; or (d) spontaneous bleeding > 1 monthly over 3-6 months period, modify the regimen as below: In the LD arm, increase to 100IU/kg daily;In the MD arm, rituximab 375 mg/m2 weekly × 4 weeks (maximum 600 mg) and prednisone 2 mg/kg daily × 1 month (maximum 60 mg, tapering over 3 months) would be added. Once the patient had achieved Success, taper dose as below: In the LD arm, the FVIII dose would be reduced slowly to 25IU/kg three times a week for continuing prophylaxis;In the MD arm, the FVIII dose would be reduced slowly to LD ITI, then same as LD arm. The primary endpoints are ITI outcomes (Success: negative inhibitor titer and FVIII recovery ≥ 66% of expected) and the time taken to ITI Success, in PwHI with LD ITI compared to those with MD ITI. Key secondary endpoints include annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) for any bleeds and treated bleeds; joint and bone health assessed by Hemophilia Joint Health Score 2.0 (HJHS 2.0) and ultrasound; quality of life measured by the Canadian Hemophilia Outcomes-Kids Life Assessment Tool 2.0 (CHO-KLAT 2.0) and numbers of days out of school; average consumption cost (per kg body weight) was calculated based on the intermediate number of treatment doses consumed to achieve Success. This included the cost of rFVIII and rituximab for ITI, prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) for treatment of breakthrough bleed, and intravenous immunoglobulin (IVIG) for infection prevention in patients receiving immunosuppressants. Safety was also a secondary endpoint. Results: Ten subjects were randomized into the study with median follow-up time of 1.64 [range (minimum, maximum), 0.23, 3.91] months in LD arm, and 2.66 (0.26,3.91) months in MD arm. Baseline includes age at time of randomized, age of inhibitor detection, exposure days before inhibitor detection, initial inhibitor titer, inhibitor titer at start of ITI and so on, between two arms are summarized in Table 1. Twenty percent (1/5) in MD arm achieved Success after 7 weeks of treatment and still maintained until the latest follow-up. No one achieved Success in LD arm. The bleeds between the treatment arms are summarized in Table 2. Nearly 2-fold difference in mean ABR and AJBR for treated bleeds, between treatment arms, and 3- to 4-fold in ABR and AJBR for any bleeds. Conclusions: It is planned to enroll 40 patients in Part A and 60 patients in Part B, who will be followed for up to 2 years. The study is ongoing and, currently, 10/40 (25%, in Part A) PwHI from 4 HTCs have been included. LOME study is the first, multicenter, prospective, randomized trial of LD vs MD ITI with domestic rFVIII (Omfiloctocog alfa, SCT800) in Chinese PwHI. This study is likely to contribute with the choice of optimal ITI regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Continuous induction with lenalidomide/dexamethasone versus autologous stem cell transplantation in newly diagnosed multiple myeloma: a case for response-adapted approach

Although upfront autologous stem cell transplantation (ASCT) generally improves progression-free survival (PFS) in newly diagnosed multiple myeloma (NDMM), the overall survival (OS) benefit and optimal timing of ASCT are not well established. Patients with early response may be able to safely continue induction and avoid ASCT without compromised outcomes. We report an extended follow-up analysis of a phase 2 trial that randomized transplant-eligible patients with NDMM who responded to induction (50/65 patients) to continued induction or ASCT; median follow-up was 8.0 years. Patients had similar 8-year PFS (55% vs. 43%), 8-year OS (83% vs. 72%), and rates of at least very good partial response (72% vs. 84%) whether continuing induction of lenalidomide and dexamethasone (Ld arm) or receiving ASCT (Ld + ASCT arm) (p = 0.5). Notably, over 50% of patients receiving continuous Ld had PFS of 5–10 years. These results suggest the need for prospective trials incorporating response-adapted therapeutic approaches to NDMM. STATEMENT OF PRIOR PRESENTATION Presented in abstract form (interim analysis) at the 56th annual meeting of the American Society of Hematology (San Francisco, CA, 6 December 2014) and at the 57th annual meeting of the American Society of Hematology (Orlando, FL, 3 December 2015).

A randomized clinical trial of a booster dose with low versus standard dose of AZD1222 in adult after 2 doses of inactivated vaccines

BackgroundImmunogenicity of inactivated SARS-CoV-2 vaccine has waning antibody over time. With the emergence of the SARS-CoV-2 delta variant, which requires higher neutralizing antibody to prevent infection, a booster dose is needed. ObjectiveTo evaluate immunogenicity and reactogenicity of standard- versus low-dose ChAdOx1 nCoV-19 vaccine booster after CoronaVac in healthy adults. MethodsA double-blinded, randomized, controlled trial of adult, aged 18–59 years, with completion of 2-dose CoronaVac at 21–28 days apart for more than 2 months was conducted. Participants were randomized to receive AZD1222 (Oxford/AstraZeneca) intramuscularly; standard dose (SD, 5x1010 viral particles) or low dose (LD, 2.5x1010 viral particles). Surrogate virus neutralization test (sVNT) against wild type and delta variant, and anti-spike-receptor-binding-domain IgG (anti-S-RBD IgG) were compared as geometric mean ratio (GMR) at day 14 and 90 between LD and SD arms. ResultsFrom July-August 2021, 422 adults with median age of 44 (IQR 36–51) years were enrolled. The median interval from CoronaVac to AZD1222 booster was 77 (IQR 64–95) days. At baseline, geometric means (GMs) of sVNT against delta variant and anti-S-RBD IgG were 18.1%inhibition (95% CI 16.4–20.0) and 111.5 (105.1–118.3) BAU/ml. GMs of sVNT against delta variant and anti-S-RBD IgG in SD were 95.6%inhibition (95% CI 94.3–97.0) and 1975.1 (1841.7–2118.2) BAU/ml at day 14, and 89.4%inhibition (86.4–92.4) and 938.6 (859.9–1024.4) BAU/ml at day 90, respectively. GMRs of sVNT against delta variant and anti-S-RBD IgG in LD compared to SD were 1.00 (95% CI 0.98–1.02) and 0.84 (0.76–0.93) at day 14, and 0.98 (0.94–1.03) and 0.89 (0.79–1.00) at day 90, respectively. LD recipients had significantly lower rate of fever (6.8% vs 25.0%) and myalgia (51.9% vs 70.7%) compared to SD. ConclusionHalf-dose AZD1222 booster after 2-dose inactivated SARS-CoV-2 vaccination had non-inferior immunogenicity, yet lower systemic reactogenicity. Fractional low-dose AZD1222 booster should be considered especially in resource-constrained settings.

Elotuzumab Plus Lenalidomide/Dexamethasone (ELd) Vs Ld in Patients with Newly Diagnosed Multiple Myeloma: Phase 2, Randomized, Open-Label Study in Japan

Introduction: Elotuzumab, a humanized IgG1 monoclonal antibody that binds to SLAMF7 expressed on myeloma and natural killer (NK) cells, has a dual mode of action; it causes targeted myeloma cell death by directly activating NK cells and enhances NK cell-mediated antibody-dependent cellular cytotoxicity. Elotuzumab combined with lenalidomide and dexamethasone (ELd) has been approved in Japan for the treatment of relapsed/refractory multiple myeloma (RRMM). In a 4-y follow-up of the phase 3 ELOQUENT-2 study (NCT01239797) in patients (pts) with RRMM, ELd demonstrated a sustained 29% reduction in risk of disease progression/death and an overall survival benefit vs Ld (Dimopoulos M et al. Haematologica 2017), consistent with prior reports (Dimopoulos M et al. Br J Haematol 2017). We present the first report on the efficacy/safety of ELd vs Ld in pts with newly diagnosed multiple myeloma (NDMM).Methods: In this phase 2, open-label, multicenter study (NCT02272803) in Japan enrolling pts with NDMM ineligible for high-dose chemotherapy plus hematopoietic cell transplantation, pts were randomized 1:1 to intravenous elotuzumab (10 mg/kg weekly for Cycles 1 and 2; every 2 wk for Cycles 3-18; 20 mg/kg monthly thereafter) plus Ld or Ld alone, in a 28-d cycle until disease progression or unacceptable toxicity. All pts in the ELd arm received premedication prior to elotuzumab to mitigate infusion reactions (IRs). In the absence of IRs, infusion rate was increased from 0.5-2.0 mL/min at dose 1, and up to a maximum of 5 mL/min (per FDA/EMA labels for ELd in RRMM) by dose 3 of Cycle 1. Primary endpoint was investigator-assessed objective response rate (ORR) with ELd, per International Myeloma Working Group criteria (1-sided α=0.15 for a true response rate >71%). Secondary endpoints included difference in ORR between the arms and progression-free survival (PFS). Safety was an exploratory endpoint.Results: In total, 40 and 42 pts received ELd and Ld, respectively. At database lock (March 2017; minimum follow-up of 6 mo), 31 (78%) pts in the ELd arm and 25 (60%) in the Ld arm remained on study. At baseline, median (range) age was 72 y (65-83) in the ELd arm and 73 y (62-89) in the Ld arm. Median duration of therapy was 13.0 cycles with ELd and 11.5 cycles with Ld. The most common reason for discontinuation was: ELd (9 pts)-disease progression (4/40 pts [10%]); Ld (17 pts)-drug toxicity, adverse events (AEs) unrelated to study drug, and pt request (each with 4/42 pts [10%]). The primary endpoint was met: investigator-assessed ORR (Table) was 88% with ELd; lower bound of the 2-sided 70% CI in ORR was 80% (> threshold of 71%). The ORR in the LD arm was 74%. ORR was 13% numerically higher with ELd than Ld. Very good partial response or better was observed for 45% of ELd- and 29% of Ld-treated pts. AEs were reported in 40 (100%) and 41 (98%) pts in the ELd and Ld arms, respectively. The most common (≥20%) AEs for ELd vs Ld included constipation (43% vs 31%), pyrexia (35% vs 7%), rash (28% vs 36%), diarrhea (28% vs 21%), nasopharyngitis (25% vs 26%), dysgeusia (23% vs 19%), malaise (23% vs 2%), peripheral edema (20% vs 14%), neutropenia (20% vs 14%), leukopenia (20% vs 7%), and back pain (18% vs 21%). Grade (G) 3-4 AEs occurred in 31 (78%) and 19 (45%) pts in the ELd and Ld arms, respectively. The most common G3-4 AEs (ELd vs Ld) were neutropenia (18% vs 7%) and leukopenia (15% vs 0%). One IR was reported (ELd): G2 hypersensitivity during the first infusion (2-mL/min infusion rate); elotuzumab infusion was interrupted; the pt did not experience any IRs at subsequent infusions. Thirty-eight pts (95%) received elotuzumab at 5 mL/min (representing 1046/1176 [89%] infusions) and no IRs were reported at this increased infusion rate. Secondary primary malignancies were reported in 1 pt in each arm (of the rectum and lung with ELd and Ld, respectively). ELd had a comparable safety profile when given at 10 mg/kg weekly or every 2 wk up to Cycle 18, or at 20 mg/kg monthly from Cycle 19 onwards. PFS data are not yet mature.Conclusions: In this first report of ELd treatment of pts with NDMM, the primary endpoint of ORR was met. ELd had an acceptable safety profile in this pt population, and an increased infusion rate of 5 mL/min, which reduced infusion time and did not induce additional IRs. These data suggested that ELd with a faster infusion rate of 5 mL/min was effective and well tolerated in Japanese pts with NDMM.Study support: Bristol-Myers Squibb K.K. [Display omitted] DisclosuresOhta:Bristol-Meyer Squibb K.K., Celgene K.K., Jansen Pharmaceutical K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd: Honoraria. Hori:Celgene, Fujifilm RI Pharma, Shire Japan: Other: Post-marketing surveillance study fee. Kinoshita:Bristol-Myers Squibb K.K.: Employment. Shelat:Bristol-Myers Squibb: Employment, Equity Ownership. Miyoshi:Bristol-Myers Squibb K.K.: Employment.

Antibody Based Three-Drug Regimens for Multiple Myeloma - a Systematic Review of Phase II and Phase III Clinical Trials

Antibody Based Three-Drug Regimens for Multiple Myeloma - a Systematic Review of Phase II and Phase III Clinical Trials

Efficacy of Elotuzumab Based Combinations in Patients with Multiple Myeloma - a Systematic Review

Introduction Multiple myeloma afflicted cells express signaling lymphocytic activation molecule family member 7 (SLAMF7). Elotuzumab; a monoclonal antibody (mAb), targets SLAMF7 and fights myeloma cells by stimulating phagocytic action of natural killer (NK) cells and via antibody‐dependent cell‐mediated cytotoxicity (ADCC) pathway. This study focuses on the clinical utility and tolerability of elotuzumab based combinations in patients (pts) with multiple myeloma (MM). Methods Literature search of PubMed, Embase, Clinicaltrials.gov, Cochrane and Web of Science was performed from inception to June 12, 2019 for elotuzumab based combinations in MM patients. Total of 06 phase II and phase III clinical trials were selected for systematic review out of 292 studies. Results Elotuzumab (E) based combinations were evaluated in 1075 patients (pts) out of 1115 enrolled pts. 119 were newly diagnosed (ND) and 956 were relapsed/refractory (RR) patients. Newly Diagnosed MM patients: Takezako et al. 2017; in phase II trial, showed overall response rate (ORR) of 88% (complete response [CR] 3% + stringent CR [sCR] 5% + partial response [PR] 43% + very good partial response [VGPR] 38%) with ELd (E-Lenalidomide-dexamethasone) arm vs 74% in Ld arm in 82 ND pts. Progression free survival (PFS) at 1 year (y) was 93% versus (vs) 91%. Grade (G) ≥3 adverse events (AEs) included neutropenia (18%) and leukopenia (15%). Relapsed/Refractory MM patients: E-Bortezomib(B)-d arm in a phase II trial by Jakubowiak et al. (2016) showed 1 y PFS of 39% vs 33% in Bd arm in 152 RR pts (Hazard ratio [HR]: 0.72; p = .09) with 28% decrease in progression or death with EBd vs Bd arm. Objective response rate (ORR) was 66% (4% CR+ 33% VGPR + 30% PR) vs 63%. OS (overall survival) at 1 y was 85% (EBd) and 74% (Bd) (HR: 0.6). G≥3 AEs were infections (21%), thrombocytopenia and peripheral neuropathy (9% each). Mateos et al. (2016) in phase II trial (n=40) evaluated E-T (thalidomide)-d with or without Cy (cyclophosphamide) in heavily pre-treated RR pts. Pts received Cy if they failed to achieve PR by the 5th cycle or because of progressive disease (PD). Responses were better with ETd vs ETdCy. ORR was 38% (95% CI: 23-54) in ETd vs 9% (95% CI: 0-41) in ETdCy. Entire study yielded median PFS (mPFS) of 3.9 months (mo) (95% CI: 2.79%-9.43%) with 1-y PFS of 30% and mOS of 16.3 mo (95% Cl: 8.87%-25.66%) with 1-y survival rate of 63%. G≥3 AEs were lymphopenia (50%), anemia (20%), leucopenia (20%) and respiratory tract infections (RTI) (8%). Dimopoulos et al. 2018 studied E + pomalidomide (P) + d (EPd) for RR pts with ≥2 prior therapies in phase II ELOQUENT-3 trial (n=117). EPd arm yielded mPFS of 10.2 mo vs 4.6 mo in Pd arm [HR: 0.54 (95% CI: 0.34-0.86; p=0.008)], i.e. 46% lower risk of progression or death in EPd vs Pd arm. ORR was 53% (CR 5% + sCR 3% + PR 33% + VGPR 12%) in EPd vs 26% in Pd arm (odds ratio [OR]: 3.25 (1.49-7.11). G≥3 AEs were anemia (10%), neutropenia and infections (13% each). Phase III ELOQUENT-2 trial randomized 646 RR pts. PFS at 4 y was 21% vs 14% (HR: 0.71, 95% CI: 0.59-0.86; p= .0004), favoring ELd with 29% reduction in myeloma progression or death. With VGPR of 30%, ORR was 79% vs 66 % (ELd vs Ld) with HR: 0.77; 95% CI: 0.62-0.95; p = 0.0176. OS at 4 y was 50% vs 43% (HR: 0.78; 95% CI: 0.63-0.96). G≥3 AEs included lymphocytopenia (79%), neutropenia (36%), anemia (20%) and thrombocytopenia (21%). (Dimopoulos et al, 2018). Newly Diagnosed &amp; Relapsed/Refractory MM patients: Phase II trial (n=70) by Berenson et al. (2017) studied G≥3 infusion reactions (IRs) using ELd in ND (n=37) and RR (n=33) pts. ORR was 78% (95% CI: 62%‐90%) for ND and 61% (95% CI: 42%‐77%) for RR pts. Other response rates were CR 6%, VGPR 27% and PR 37% in all patients. G3 AEs included anemia in 10% pts (no G3 IRs were seen). Conclusion: Elotuzumab based combinations showing promising outcomes in terms of ORR, PFS and OS for ND and RR MM patients with tolerable toxicity profile. More clinical studies with elotuzumab in unique and newer combinations need to be tested in prospective trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Final Results of a Randomized Phase 2 Trial Evaluating Lower-Dose Versus Higher-Dose Pomalidomide as Therapy for Corticosteroid-Refractory Chronic Gvhd

Chronic graft-versus-host disease (cGvHD) is the leading cause of late non-relapse morbidity and mortality after allogeneic HCT. There is no standard therapy for steroid-refractory disease. Thalidomide, an immune-modulating drug, showed some activity in advanced sclerotic cGvHD but was difficult to tolerate at active doses. Pomalidomide (Pom) is related to thalidomide, but with higher potency and a more favorable toxicity profile. A pilot study suggested Pom was effective in cGvHD, however doses >2 mg/day were poorly tolerated (Pusic et al, BMT, 2016;51:612). In this randomized phase 2 trial we aimed to determine the optimal dose and to evaluate the efficacy of Pom (NCT01688466).Methods: Subjects were randomized to a low-(LD) 0.5 mg/d or a high-dose (HD) cohort with a starting dose 0.5 mg/d increasing to 2 mg/d over 6 w. Dose reductions for ≥Grade-3 non-hematologic or ≥Grade-4 hematologic adverse events (AEs) on HD-cohort were allowed. There was no crossover. Concomitant stable or tapering systemic therapy for cGvHD was permitted. Venous thrombo-embolism prophylaxis was ASA 325 mg/d. Response was assessed by 2005 NIH response criteria (Filipovich AH et al, 2005;11:945). Primary endpoint was overall response rate (ORR) at 6 mo. Responders could continue at their assigned dose for 6 more mo. Secondary endpoints were safety, PKs and immune studies. The cohort with the higher response rate would be chosen for further evaluation, or if a tie, the LD arm would be favored.Results: From 02/2013 to 05/2016, 32 subjects were randomized (LD, n=16; HD, n=16). Median age was 48 y (range, 20-73 y), 21 (66%) male, median time from transplant 4.1 y (1.5-9.7 y), median time from onset of cGvHD 3.2 y (0.6-8.5 y). Thirty subjects had Global Score Severe. The most severely affected tissues/organs were skin (n=30, 94%), eyes (n=6, 19%) and joints/fascia (n=11, 34%). Most had ≥ 20% body surface area deep sclerosis (n=24, 75%). Pts had received a median 5 (2-9) prior systemic therapies. Baseline characteristics were similar in the two cohorts.Peak/trough levels of Pom were measured at 0.5, 1, 1.5, 2 mg doses and CMax increased in a dose-proportional manner (r2=0.9997), suggesting linear PKs. The most frequent AEs were lymphopenia, infection and fatigue (Table). Six subjects in the HD cohort were dose reduced to 1.5 mg/d because of fatigue (n=3), elevated ALT/AST (n=1), bradycardia (n=1) and neutropenia (n=1), and 2 subjects reduced further to 1 mg/d. There was 1 death in the LD cohort from pneumonia. 9 subjects discontinued ≤ 6 mo because of AEs (n=5) or withdrawal (n=4). More subjects in the HD cohort discontinued early; (HD, n=7; LD, n=2).ORR at 6 mo in an intent-to-treat analysis was 47% (n=15, PR). ORR increased to 71% in 21 evaluable subjects. ORR in LD and HD were similar 50% (n=8/16) and 44% (n=7/16) respectively. 9 evaluable subjects (43%) had improvement in NIH joint/fascia scores (p=0.004) and median decrease of 10% body surface area involvement with cutaneous cGvHD (p=0.0027 by Wilcoxon signed rank test). Among the NIH response measures, the strongest association with response was the 11-point health care provider severity, median improvement 2 points (p=0.0055 by Jonckheere-Terpstra test), as well as improvements in restrictions in range of motion at elbow (p=0.023) and wrist (p=0.032). 67% (10/15) of the responders also reported clinically significant improvements in self-reported cGvHD symptom bother (Lee scale) and SF-36 physical component summary scores (p<.001).Median decreases in prednisone dose compared to baseline were 13% (0-67) at 6 mo and 63% (17-81) at 12 mo of Pom. More subjects completed the planned 12 mo of Pom in the LD- vs. HD- cohort (7 vs. 4). After 12 mo of Pom, 3 subjects in the LD arm had progressed cGvHD. Two of those subjects had SD after restarting Pom. A 3rd responded and continued Pom for an additional 12 mo.Conclusion: This phase 2, randomized trial demonstrates that Pom is an effective salvage therapy for persons with severe, corticosteroid-refractory cGvHD, including sclerotic skin disease. Response rates were similar with 0.5 and 2 mg/d but there were more early discontinuations with 2 mg/d. Organs with most improvement were skin and joints suggesting an anti-fibrotic effect. Pom is a promising new therapy for refractory cGvHD. As HD Pom was less well tolerated without a significant improvement in response, Pom 0.5 mg/d is recommended. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Eloquent-2 Update: A Phase 3, Randomized, Open-Label Study of Elotuzumab in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma - 3-Year Safety and Efficacy Follow-up

Eloquent-2 Update: A Phase 3, Randomized, Open-Label Study of Elotuzumab in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma - 3-Year Safety and Efficacy Follow-up

Interim Analysis of a Randomized Phase II Trial Comparing Continuous Lenalidomide and Dexamethasone to Autologous Stem Cell Transplantation in Multiple Myeloma Patients Responsive to Lenalidomide and Dexamethasone Induction

Background: The aggressive approach to first-line treatment of multiple myeloma (MM) incorporating autologous stem cell transplantation (ASCT) remains widely prevalent, although it is not without controversy in the current era of novel effective agents. Some trials and meta-analysis comparing ASCT to non-myeloabaltive standard therapy or delayed ASCT have failed to show an overall survival (OS) difference between the two arms [Fermand et al. Blood 92:3131-3136 (1998); Koreth et al. BBMT 13:183-196 (2007); Kumar, et al. Cancer 118(6):1585-92 (2012)]. On the other hand, analysis of transplant-eligible patients receiving lenalidomide and dexamethasone induction on the E4A03 trial and then either undergoing ASCT or continuing lenalidomide and dexamethasone showed that ASCT conferred improved OS (Blood 2010;116:38a). This controversy lead us to design a phase II clinical trial comparing continuous lenalidomide and dexamethasone (Ld) versus ASCT followed by lenalidomide maintenance, in patients responding to four cycles of Ld.Methods: Patients with newly diagnosed symptomatic MM as defined by IMWG criteria were enrolled. Patients deemed to be in urgent need of aggressive therapy (e. g. symptomatic bone disease, acute renal failure, hyperviscosity syndrome, etc÷) were not eligible. Patients received induction with lenalidomide (L) 25 mg PO daily on days 1-21, and dexamethasone (d) 40 mg PO daily on days 1,8,15, and 22 of a 28-day cycle with standard prophylaxis. Patients with POD during induction or SD after four cycles of Ld were taken off study. All other patients had stem cells harvested after four cycles of Ld and were randomized to either the continuous (Ld) arm (L at the last tolerated dose during induction, continued indefinitely until progression or toxicity; and d at 20mg weekly for one year) or the ASCT arm (using melphalan conditioning followed by L maintenance started three months post-ASCT at 10mg daily, escalated to 15 mg daily six months post-ASCT and continued indefinitely until progression or toxicity).Results: Fifty seven patients have been registered to the trial. Two patients did not initiate therapy, one because of a concurrent diagnosis of amyloidosis and the other due to aggressive disease mandating alternative therapy according to the treating physician. At this time, four patients are still receiving induction therapy and are not available for response assessments. Among the 51 remaining patients, the response to initial induction therapy includes 12% CR (n=6), 2% uCR (n=1), 4% nCR (n=2), 14% VGPR (n=7), 51% PR (n=26), 6% SD (n= 3), 4% POD (n=2), and 8 % inevaluable (n = 4 who did not receive at least two cycles of Ld). Thirteen patients were removed from the trial prior to randomization due to POD (n=2), SD after four cycles (n=3), toxicity (n=4), physician discretion (n=2), and withdrawal of consent (n=2). Among these 13 patients, one was lost to follow-up, two continued lenalidomide therapy off protocol (one patient refused ASCT, and one patient had inadequate stem cell collection), and 10 proceeded to alternative induction. All 12 patients achieved a response [25 % CR (n=3), 42 % VGPR (n=5), and 33 % PR (n=4)]; 10 patients proceeded to ASCT without event. Thirty-eight patients were randomized, 20 to Ld and 18 to ASCT. Improvement of response by at least one level occurred in 45% and 65% of patients on the Ld and ASCT arms, respectively. The median follow-up for all surviving patients from time of randomization is 38.3 months. The 1- and 3-year PFS in the Ld arm were 100% and 66%, respectively. The 1- and 3-year PFS in the ASCT arm were 89% and 68%, respectively. The 2- and 3-year OS in the Ld arm were 100% and 92%, respectively. The 2- and 3-year OS in the ASCT arm were 100% and 85%, respectively. Considering the entire population of 51 patients, with a median follow-up of 38 months, the median PFS has not been reached.Conclusions: This interim analysis, with relatively short follow-up, suggests that in transplant-eligible patients responsive to Ld during induction, continuous Ld results in similar PFS and OS compared to patients who undergo ASCT followed by L maintenance. Furthermore, this overall approach based on response-adapted treatment results in 100% of patients reaching at least PR at completion of first-line therapy. The trial remains ongoing. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lenalidomide and Dexamethasone Alone Is Equivalent To Lenalidomide and Dexamethasone With Autologous Stem Cell Transplant In Newly Diagnosed Multiple Myeloma: Interim Study Results Of a Randomized Trial

The current standard of care for patients with newly diagnosed multiple myeloma (MM) aged less than 65 years is high-dose chemotherapy combined with autologous stem cell transplantation (ASCT) based on improved progression free survival (PFS) and overall survival (OS) compared with conventional chemotherapy. The introduction of novel agents, for example lenalidomide and bortezomib over the last decade, has substantially improved MM outcomes providing similar response rates to ASCT. As a consequence, the role of upfront ASCT has become more controversial. Therefore, this randomized clinical trial aims to determine the role of upfront ASCT in patients with newly diagnosed MM patients receiving lenalidomide and low-dose dexamethasone as induction therapy.Patients enrolled into the study were aged ≥18 years with newly diagnosed MM, transplant eligible, and meeting CRAB criteria. Patients were randomized to receive 4 cycles of lenalidomide (25 mg days 1–21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22) followed by ASCT conditioned with 200 mg/m2 melphalan (Arm A; LD+ASCT) or 8 cycles of lenalidomide plus low-dose dexamethasone (Arm B; LD alone). Both groups received lenalidomide maintenance therapy 10-15 mg for up to 2 years. Patients in both treatment arms received stem cell collection after 4 cycles of lenalidomide plus dexamethasone if at least a partial response was achieved. Patients with stable disease or progressive disease (PD) went off study. The primary objective was to compare the best response between patients treated with lenalidomide plus dexamethasone followed by ASCT and patients treated with lenalidomide plus dexamethasone alone. Secondary objectives were to compare the duration of response (DOR), PFS, and OS between the two treatment arms and to evaluate the secondary malignancies in both arms.Fifty patients with newly diagnosed MM were randomized between February 2008 and May 2013, and 47 patients were eligible for evaluation in this interim analysis; 25 patients randomized to Arm A (LD+ASCT) and 22 patients randomized to Arm B (LD alone). Overall, patients had a median age of 61.6 years (range 48–75), 60% were male, 34% ISS Stage I, 49% ISS Stage II, 17% ISS Stage III. The data were analyzed according to the IMWG response criteria (Blood. 2011 May 5;117(18):4691-5). In an intention-to-treat analysis, there was a trend towards improved overall response rate (ORR) in patients receiving LD+ASCT (96%) compared with patients receiving LD alone (77%; p=0.08) (Table 1). After a median follow-up of 36.8 months (range 1.1–62.7), the median DOR was 13.9 months (95% confidence interval [CI] 4.0–34.1) in the LD+ASCT group compared with 21.2 months (95% CI 11.0–22.9) in the LD group. Overall, 18 patients have PD (10 patients in the LD+ASCT arm and 8 patients in LD arm), and 8 patients have died (4 patents in the LD+ASCT arm and 4 patients in the LD arm). Median PFS for LD+ASCT versus LD was 17.0 months (95% CI 15.5–not estimable) versus 25.2 months (95% CI 9.0–not estimable; p=0.94). Median OS for LD+ASCT versus LD was 57.6 months (95% CI 48.0–not estimable) versus not reached (p=0.94). Two patients in the LD alone arm developed a secondary malignancy, including 1 patient with myelodysplastic syndrome (MDS) 13 months after the start of therapy.This interim analysis of an ongoing randomized clinical study comparing lenalidomide plus low-dose dexamethasone induction with and without upfront ASCT in patients with newly diagnosed MM suggests that addition of ASCT resulted in a trend towards improved ORR. This did not result in a significant difference in terms of PFS or OS between the two treatment arms. In contrast there was a trend of better DOR in the LD alone arm. The data show that LD alone can achieve similar results as LD+ASCT, however careful interpretation is required due to the low patient number and relatively short follow-up. The incidence of secondary malignancy was low, including the development of 1 MDS. Disclosures:Schecter:Celgene: Honoraria, Speakers Bureau. Mapara:Celgene: Research Funding, RO1 Other. Lentzsch:Celgene: Research Funding.Table 1Best response and survivalBest response, n (%)Arm A (LD+ASCT) (n=25)Arm B (LD alone) (n=22)Stringent complete response1 (4.0)1 (4.6)Complete response4 (16.0)5 (22.7)Very good partial response8 (32.0)6 (27.3)Partial response11 (44.0)5 (22.7)Stable disease1 (4.0)5 (22.7)Progressive disease00Overall response rate24 (96.0)17 (77.3)

A prospective trial for defining a subset of patients with limited metastatic gastric cancer who may be candidates for bimodal treatment strategies: FLOT3.

4090 Background: The utility of surgery for metastatic gastric cancer is debated. A prospective trial was performed to evaluate a prognostic model for selecting patients (pts) treated with systemic chemotherapy (ct) who may also be candidates for surgical intervention. Methods: Using a predefined algorithm pts with untreated gastric cancer were prospectively stratified into 3 groups: operable (OD), limited metastatic (LD), or extensive metastatic (ED) disease and treated with 5-FU, oxaliplatin, leucovorin and docetaxel (FLOT). LD was defined as: distant intra-abdominal lymph node metastases only or/and a maximum of 1 organ involved, normal serum alkaline phosphatase, &lt; 5 liver lesions, no visible carcinomatosis (peritoneum or pleura), and ECOG ≤ 1. All other metastatic pts were ED. Pts with OD received 4 preoperative ct cycles followed by surgery and 4 postoperative cycles. Pts with LD received 8 cycles with surgery allowed for complete macroscopic resection. Pts with ED received 8 cycles with surgery allowed for palliation only. The study had 80% power to detect a HR of 0.55 for overall survival in favor of the LD group (vs. ED group; 2-sided log-rank p=0.05). Results: 238 of 252 pts included were eligible (OD/LD/ED: 51/60/127). LD pts had distant lymph nodes only (41%), liver (22%), lung (17%), localized peritoneal involvement (7%), or others (13%). A median of 8 ct cycles was applied to all groups. Median OS was 22.9 vs. 10.7 months in pts with LD vs. ED, respectively (HR 0.37; 95% CI, 0.25 – 0.56; p &lt;0.001). LD was the strongest predictor of OS in the multivariate analysis including all single determinants of LD status (p=.002). Surgical resection was conducted in 96%, 62%, and 12% in the OD, LD, and ED groups, of which R0 resection (primary) was achieved in 82%, 81% and 33%, respectively. Within the LD arm, operated pts had better outcome than non-operated pts (median OS 31.3 vs. 15.9 months; p=.004) and pts with lymph node only involvement had best outcome. Conclusions: This clinical model identifies a subset of pts with (limited) metastatic gastric cancer who have a favorable outcome and who may be candidates for bi-modal treatment strategies.

Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2)

The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients.

A Phase II Study (FINDER 2) Comparing Three Dosing Regimens of Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer.

Abstract Background: The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive (ER+) advanced breast cancer (FINDER) 2 study investigated the efficacy, safety, and pharmacokinetic (PK) profile of 3 fulvestrant dosing regimens in postmenopausal women with ER+ advanced breast cancer, recurring/progressing after prior endocrine therapy.Objectives: Primary: to evaluate the objective response rate (ORR). Secondary included assessment of: time to progression (TTP), clinical benefit rate (CBR), duration of response (DOR), tolerability, and PK parameters.Methods: This randomized, double-blind, parallel-group, multicenter, Phase II study, evaluated patients (pts) randomized 1:1:1 to different doses of fulvestrant: 250 mg (approved dose [AD]; given on Days 0, 28 and every 28 days thereafter), 250 mg plus loading dose (LD; 500 mg on Day 0, then 250 mg on Days 14, 28 and every 28 days thereafter), and 500 mg (high dose [HD]; Days 0, 14 and 28 and every 28 days thereafter). Treatment continued until disease progression, or until any other criterion for discontinuation was met.Results: In total, 144 pts were randomized from 34 centers in 8 countries and 143 received treatment: fulvestrant AD (n=47); LD (n=50); HD (n=46). ORRs were: 8.5% (95% confidence interval [CI] 2.4-20.4%), 5.9% (1.2-16.2%), and 15.2% (6.3-28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI 19.1-47.1%), 47.1% (32.9-61.5%), and 47.8% (32.9-63.1%) for the AD, LD, and HD arms, respectively. Median TTP was numerically longer for the HD (6.0 months) and LD (6.1 months) arms vs the AD arm (3.1 months). The low number of responders in all treatment arms prevented DOR assessment. The incidence of adverse events (AEs) was similar in all groups (76.6% AD, 72.0% LD, 69.6% HD); few pts experienced serious AEs (4 pts AD, 9 LD, 4 HD) with no clustering of event type. AEs with an incidence of ≥10% (in any arm) were back pain, arthralgia, fatigue, injection-site pain, nausea, dyspnea, cough, and hot flash. Concentrations in the AD arm approached steady state in the 3rd month of dosing and within the 1st month for LD and HD. Exposure (AUC, Cmin and Cmax) appeared to be linear across the dose range studied and, for the 250mg arms, similar to that previously reported in Western populations (Studies 9238IL/0020 &amp; 0021).Conclusion: No statistically significant differences in efficacy could be proven between AD, LD and HD given the widely overlapping CIs for median TTP. The tolerability profile was similar across the three dosing regimens. Steady-state concentrations were achieved earlier with LD and HD. A parallel study in Japanese pts will be used for comparisons of fulvestrant efficacy and tolerability in Japanese and non-Japanese pts. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4095.