Search

In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.Lay abstract Currently, the majority of patients with multiple myeloma are not cured, and current treatments may not be helpful for patients with poor prognoses, including those with high-risk chromosomal changes, those who have impaired kidney function, those who are elderly and those who are refractory to prior treatments. In this review, we will discuss the benefits of the combination of isatuximab plus pomalidomide and dexamethasone in these difficult-to-treat patients.

The ICARIA-MM study was sponsored by Sanofi. The authors thank, Helgi van de Velde, Valérie Boutet, Shujia Dai, Deborah DiNoto, Graziella Engelvin, Olivier Fedeli, Sébastien Hugla, Dominique Mouret, Béatrice Pradeilles, and Alain Roccon, all employees of Sanofi, for their contribution to the study, technology, and comments on the manuscript. The authors thank the participating patients and their families, and the study centers and investigators, for their contributions to the study. The medical writing support was provided by John Clarke, PhD and Stephanie Brillhart, PhD of Elevate Medical Affairs, contracted by Sanofi Genzyme for publication support services.

Patients with relapsed/refractory multiple myeloma (RRMM) experience several relapses, and become refractory to successive therapies. In the ICARIA-MM trial (NCT02990338), isatuximab plus pomalidomide-dexamethasone prolonged median progression-free survival (PFS) in patients with RRMM. This subgroup analysis of ICARIA-MM assessed the treatment benefit of isatuximab by prior lines of therapy and refractory status. A total of 307 patients were randomized to isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, then every other week. Standard pomalidomide-dexamethasone doses were given. PFS was assessed by prior lines and refractory status. Overall, 102 (66 %) patients receiving isatuximab-pomalidomide-dexamethasone and 101 (66 %) patients receiving pomalidomide-dexamethasone had received 2–3 prior lines; 52 (34 %) and 52 (34 %) had received >3 prior lines, respectively. Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who received 2–3 prior lines of therapy (12.3 vs. 7.8 months) and >3 prior lines of therapy (9.4 vs. 4.3 months). Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who were lenalidomide-refractory (11.4 vs. 5.6 months), lenalidomide-refractory at last line (11.6 vs. 5.7 months), refractory to a proteasome inhibitor (PI) (11.4 vs. 5.6 months), and double-refractory (11.2 vs. 4.8 months). Overall response rate (ORR) in patients receiving isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone was 59.0 % versus 31.4 % in lenalidomide-refractory; 60.2 % versus 32.2 % in PI-refractory; and 58.6 % versus 29.9 % in double-refractory patients. Isatuximab-pomalidomide-dexamethasone improved PFS and ORR regardless of prior lines of therapy or refractory status, consistent with the benefit in the overall population. © 2021 The Authors, Amgen Bristol-Myers Squibb, BMS Pfizer Roche Sanofi Celgene Takeda Pharmaceutical Company, TPC Janssen Pharmaceuticals, SB reports honoraria from Amgen, Bristol-Myers Squibb, Celgene, and Janssen; and reports a consultancy/advisory role for Celgene, Janssen, Karyopharm, and Takeda. VV reports a consultancy/advisory role for Astellas, Biocad, Bristol-Myers Squibb, Janssen, Roche, Sanofi, and Takeda. VM reports a consultancy/advisory role for Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda. LK reports honoraria from Amgen, Celgene, Janssen, and Takeda; a consultancy/advisory role for Amgen, Celgene, Janssen, and Takeda; and travel support from Amgen and Janssen. MP reports honoraria from Celgene, Pfizer, and Takeda; consultancy/advisory role for Amgen, Celgene, Janssen, Roche, and Takeda; and research funding from Amgen, Celgene, Janssen, Pfizer, Roche, and Takeda. PGR reports a consultancy/advisory role for Amgen, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda; and research funding from Bristol-Myers Squibb, Celgene, Oncopeptides, and Takeda. LP, FV, KW, LB, and YK have no disclosures. FC, SLG, FM, and HvdV are employees of Sanofi., The ICARIA-MM study was sponsored by Sanofi . The authors thank the participating patients and their families, and the study centers and investigators for their contributions to the study. Medical writing support was provided by Stephanie Brillhart, Julian Ball, and Smitha Reddy of Elevate Medical Affairs E (Fairfield, CT, USA), and funded by Sanofi (Cambridge, MA, USA).

Treatment for relapsed/refractory multiple myeloma (RRMM) remains an unmet need. Isatuximab, an anti-CD38 monoclonal antibody has shown efficacy and tolerability as a monotherapy and combination therapy in Phase I/II studies in RRMM. Here, we describe the design of the Phase III ICARIA-MM study (NCT02990338) which will evaluate isatuximab in combination with pomalidomide (Pom) and low-dose dexamethasone (dex) (Pom/dex) versus Pom/dex alone in RRMM. Patients will be randomized in a 1:1 ratio. The primary endpoint is progression-free survival. Response will be determined by an independent response review committee using IMWG criteria (2016) and safety will be assessed throughout. Approximately 300 patients (150 in each arm) are expected to enroll. The first patient was recruited in January 2017 and accrual is ongoing.

BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. METHODS: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (

BACKGROUND: In multiple myeloma (MM), deep responses have been associated with improvements in progression-free survival (PFS) and overall survival (OS). Response kinetic data, including renal response times, which are highly important for patients with renal impairment, are infrequently reported. We analyzed the association between depth of response, including minimum residual disease (MRD) negativity, plus response kinetics and long-term outcomes, using data from the randomized, open-label, phase 3 ICARIA-MM study. ICARIA-MM evaluated the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory MM (RRMM) after ≥2 prior lines of therapy (NCT02990338). METHODS: All patients received standard doses of Pd and those randomized to the Isa-Pd group received 10 mg/kg IV on days 1, 8, 15, and 22 (cycle 1), and days 1 and 15 in subsequent 28-day cycles. Depth and kinetics of response were analyzed for each treatment group. MRD was assessed at 10-5 (tested by next-generation sequencing in patients with complete response [CR] / stringent CR [sCR]). Time to tumor response, time to renal response (CRenal; improvement in estimated glomerular filtration rate (eGFR), using the MDRD formula, from RESULTS: Overall, 307 patients were randomized to Isa-Pd (n=154) or Pd (n=153), of whom 33/142 (23.2%) and 24/145 (16.6%) patients had eGFR 92.9% > 82.4% > 46.4%, respectively). Tumor responses occurred faster with Isa-Pd than with Pd. Among patients who achieved a response of ≥PR (93 in the Isa-Pd arm and 54 in the Pd arm), the median time to first response was shorter for Isa-Pd (1.1 months) than for Pd (1.9 months). Among patients who achieved a response of ≥VGPR (49 and 13 in the Isa-Pd and Pd arms, respectively), the time to first VGPR or better response was similar at 2.9 months for Isa-Pd and 3.0 months for Pd. Renal responses occurred faster in patients on Isa-Pd than on Pd. A CRenal was observed in 23/32 (71.9%) patients in the Isa-Pd arm (median time to response 3.4 weeks) and in 8/21 (38.1%) of patients in the Pd arm (median time to response 7.3 weeks). A sustained CRenal was observed in 10/32 (31.3%) patients in the Isa-Pd arm (median time to first response 2.4 weeks) and in 4/21 (19.0%) patients in the Pd arm (median time to first response 4.8 weeks). CONCLUSION: In the heavily pretreated ICARIA population, Isa-Pd induced more frequent and faster tumor and renal responses than Pd. Depth of response, including MRD negativity, was improved with Isa-Pd and was clearly associated with better long-term survival outcomes. Figure. PFS (A) and OS (B) by best overall response and minimal residual disease for Isa-Pd Figure Disclosures Hulin: celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Spicka:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Le-Guennec:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Beksac:Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Isatuximab is an investigational agent and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the uses under investigation.

INTRODUCTION: Multiple myeloma (MM) is most frequently diagnosed among people aged 65-74, and approximately one-third of patients (pts) are aged ≥75 years. Advanced age has a negative effect on the prognosis of pts with MM. The randomized, open-label, active-controlled, multicenter phase 3 ICARIA-MM study (NCT02990338) compared treatment with the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) with Pd. Pts had relapsed/refractory MM (RRMM) after ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. This subgroup analysis of ICARIA-MM examined efficacy and safety in elderly pts (≥75 years) compared with younger pts. METHODS: Pts were randomized (1:1) to receive Isa-Pd or Pd. Isa (10 mg/kg IV) was given on days 1, 8, 15, and 22 (cycle 1), and days 1 and 15 in subsequent 28-day cycles. All pts received pomalidomide 4 mg on days 1-21 of each cycle and dexamethasone 40 mg (20 mg for pts ≥75 years old) on days 1, 8, 15, and 22 of each cycle. The primary endpoint was progression-free survival (PFS), assessed by an independent response committee. Subgroup analyses were conducted for pts aged RESULTS: Overall, 307 pts were randomized to Isa-Pd (n=154) or Pd (n=153) and included in the intent-to-treat population. The median age of pts was 68.0 years in the Isa-Pd arm and 66.0 years in the Pd arm. In the Isa-Pd and Pd arms, there were 54 (35%) and 70 (46%) pts In the overall population, PFS was significantly improved with Isa-Pd versus Pd (median 11.53 vs 6.47 months; hazard ratio [HR] 0.596; 95% confidence interval [CI] 0.436-0.814; p=0.001). Consistent with this, pts ≥75 years of age had a median PFS of 11.40 with Isa-Pd vs 4.47 months with Pd (HR 0.479; 95% CI 0.242-0.946). Similarly, in the Isa-Pd and Pd groups, pts 65-74 years of age had a PFS of 11.57 and 8.58 months (HR 0.638; 95% CI 0.385-1.059); in pts Overall response rate (ORR) for all pts was 60.4% with Isa-Pd and 35.3% with Pd with an odds ratio (OR) of 2.80 (95% CI 1.72-4.56). ORR by age group in pts receiving Isa-Pd vs Pd was: 53.1% and 31.0% in the ≥75 years group (OR 2.52; 95% CI 0.79-8.26); 64.7% and 38.9% in the 65-74 years group (OR 2.88; 95% CI 1.29-6.46); and 59.3% and 34.3% in the At least a very good partial response (≥VGPR) was achieved by 31.8% of pts with Isa-Pd and 8.5% with Pd, with an OR of 5.03 (95% CI 2.51-10.59). Rates of ≥VGPR by age in pts receiving Isa-Pd vs Pd was: 31.3% and 0% in the ≥75 years group (OR not calculated); 32.4% vs 13.0% in the 65-74 group (OR 3.21; 95% CI 1.17-9.70); and 31.5% and 8.6% in the At the time of analysis, overall survival (OS) data are not yet mature. However, in the elderly population, 8/32 (25%) pts in the Isa-Pd arm had died with median OS not reached, and in the Pd arm, 15/29 (51.7%) had died with a median OS of 10.25 months (HR 0.404; 95% CI 0.171- 0.956). In the Isa-Pd arm, the incidence of all-grade treatment-emergent adverse events (TEAEs) across age groups was: CONCLUSION: The addition of Isa to Pd improved PFS, ORR, ≥VGPR, and OS in elderly pts, consistent with the benefit observed in the overall study population. There was a consistent trend toward higher rates of SAE and discontinuation due to TEAEs in elderly pts in both the Isa-Pd and Pd arms, but with no increase in fatal AEs in the Isa-Pd arm. Disclosures Schjesvold: Celgene: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; SkyliteDX: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Facon:Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Spencer:Janssen Oncology: Other: Consulting/advisory role, Research Funding, Speakers Bureau; Amgen: Other: Consulting/advisory role, Research Funding; AbbVie: Other: Consulting/advisory role, Research Funding; Servier: Other: Consulting/advisory role; Takeda: Other: Consulting/advisory role, Research Funding; Secura Bio: Other: Consulting/advisory role; Haemalogix: Other: Consulting/advisory role; Celgene: Other: Consulting/advisory role, Research Funding, Speakers Bureau; Sanofi: Other: Consulting/advisory role; Specialised Therapeutics Australia: Consultancy, Honoraria. Sunami:Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Alexion-pharma: Research Funding; GSK: Research Funding; Janssen: Research Funding; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Le-Guennec:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Bensfia:Sanofi: Employment. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy.

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: -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.

The aim of this post hoc analysis of the VELOUR study (ClinicalTrials.gov NCT00561470) was to investigate the treatment effect of adding aflibercept to second-line infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who had failed any prior oxaliplatin-containing regimen. Adjuvant rapid relapsers (ARR), who were enrolled directly following relapse during or within 6 months of completion of oxaliplatin-containing adjuvant chemotherapy (N = 124, including 17 patients who also received bevacizumab as part of their adjuvant therapy), were excluded from the original VELOUR intention-to-treat (ITT) population (N = 1226). After exclusion of the ARR, overall survival (OS) in the ITT minus ARR (ITT-ARR) population (N = 1102) was longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm [hazard ratio (HR) 0.78, 95 % confidence interval (CI) 0.68–0.90; median survival difference 1.87 months]. In the subgroup of patients assigned to the prior bevacizumab stratum at randomization, OS was numerically longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm (HR 0.81; 95 % CI 0.63–1.04; median survival difference 2.14 months). Comparison of the post hoc analysis results with the primary analysis from VELOUR suggests that the inclusion of the directly enrolled ARR may have understated the aflibercept treatment benefit for both bevacizumab-pretreated and bevacizumab-naive patients in the strictly second-line setting although no definitive conclusion may be inferred. The benefit associated with the addition of aflibercept to second-line FOLFIRI in patients with mCRC was observed whatever the timing of first-line disease progression. There were no unexpected safety concerns.

Summary Background Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas. Methods We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0–2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m 2 plus cisplatin 75 mg/m 2 or intravenous infusion of placebo plus cisplatin 75 mg/m 2 every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517. Findings Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9–33·2) in the placebo group and 30·5 months (20·7–37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45–2·69] vs 1·41 [1·38–1·58] months; hazard ratio 0·76 [95% CI 0·59–0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group. Interpretation The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas. Funding Sanofi.

Assuming that human exposure to BSE was through beef mechanically recovered meat (MRM) consumed as burgers and other meat products, we estimated the French consumption of different food items containing beef MRM, and compared these consumptions for French and British populations. To estimate consumption of meat products containing bovine MRM, we used dietary data from national individual and household food surveys conducted between 1980 and 1995. After reconciliation of consumption data between the available surveys and calendar year adjustments, we simulated consumption of one-thousandth of the French population. Consumption was estimated by birth cohort and gender, and for the periods 1980-89 and 1990-95 separately. Data showed that burgers (including manufactured minced meat) represented around 75-80% of the individual consumption of meat products containing MRM, and that consumption of burgers increased by 40% over the 1980-95 period. In all age groups, consumption was higher in males than in females. In both genders, the 1940-69 birth cohort had the highest mean consumption of burgers and other beef products containing MRM. Similar findings have been reported for the UK population. Estimated consumption of bovine MRM per calendar year increased markedly over the study period, concomitantly with an increase of bovine carcasses imported from the UK. Comparison of the 1980-1995 pattern of bovine MRM consumption in the UK and France indicated that this consumption peaked later in France than in the UK. This difference might result in different temporal pattern of vCJD incidence.

TPS8057 Background: Treatment for refractory or relapsed and refractory multiple myeloma (MM) remains an unmet need. Isatuximab (ISA), an anti-CD38 monoclonal antibody with multiple mechanisms of tumor killing, has shown efficacy and an acceptable tolerability profile in Phase 1/2 studies in patients with refractory or relapsed and refractory MM (RRMM) (Richter et al. ASCO 2016; Vij et al. ASCO 2016). Methods: This Phase III, prospective, multicenter, randomized, open-label study (NCT02990338; ICARIA-MM) is being conducted to evaluate the clinical benefit of ISA in combination with Pom and low-dose Dex (Pom/Dex) versus Pom/Dex for the treatment of adult patients with RRMM and demonstrated disease progression within 60 days of the last therapy, and who have received at least 2 prior lines of therapy, including lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) alone or in combination. Patients will be randomly assigned in a 1:1 ratio to either ISA (10 mg/kg IV on Days 1, 8, 15, and 22 in the 1st cycle; Days 1 and 15 in subsequent cycles) plus Pom (4 mg on Days 1–21) and Dex (40 mg for patients < 75 years of age and 20 mg for patients ≥75 years of age, on Days 1, 8, 15, and 22) or Pom and Dex. Treatment cycles will be 28 days each. Patients will continue therapy until disease progression, occurrence of unacceptable adverse events (AEs), or their decision to discontinue the study, whichever comes first. The primary endpoint is progression-free survival (PFS), i.e. time from randomization to progressive disease or death from any cause. Response will be determined by IMWG criteria (2016). Key secondary endpoints include overall response rate and overall survival (OS). Safety evaluations include treatment-emergent AEs/serious AEs (including infusion-associated reactions), laboratory parameters, vital signs and assessment of physical examination. Statistical analyses will be conducted according to a pre-specified plan; approximately 300 patients (150 in each arm) are expected to be enrolled in this study. The first patient was recruited in January 2017. Study funding: Sanofi. Clinical trial information: NCT02990338.

Background: This open-label, randomized phase III trial evaluated larotaxel/cisplatin versus gemcitabine/cisplatin as first-line treatment for locally advanced (T4b) or metastatic urothelial tract or bladder cancer. Methods: Patients were randomized to larotaxel 50 mg/m2 with cisplatin 75 mg/m2 every 3 weeks (larotaxel/cisplatin) or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 with cisplatin 70 mg/m2 on day 1 every 4 weeks (gemcitabine/cisplatin). The primary endpoint was overall survival (OS). Results: The trial was prematurely closed following the sponsor's decision to stop clinical development of larotaxel (n = 337 randomized). The larotaxel dose was reduced to 40 mg/m2 and cisplatin to 60 mg/m2 following a data monitoring committee safety review of the first 97 patients. At the time of analysis, the median OS was 13.7 months [95% confidence interval (CI) 11.2-17.1] with larotaxel/cisplatin and 14.3 months (95% CI 10.5 to not reached) with gemcitabine/cisplatin [hazard ratio (HR) 1.21; 95% CI 0.83-1.76; p = 0.33]. The median progression-free survival (PFS) was 5.6 months (95% CI 4.1-6.2) with larotaxel/cisplatin and 7.6 months (95% CI 6.6-9.1) with gemcitabine/cisplatin (HR 1.67; 95% CI 1.24-2.25). More myelosuppression was observed with gemcitabine/cisplatin. Conclusion: There was no difference in OS. Although the trial was closed prematurely, PFS appeared worse with larotaxel/cisplatin, suggesting that larotaxel/cisplatin does not improve outcomes versus cisplatin/gemcitabine.

e14510 Background: In a phase 1 study investigating ziv-aflibercept (Z, known as aflibercept outside the United States) with FOLFIRI, an analysis was performed to evaluate safety and activity in colorectal cancer (CRC) patients previously treated with irinotecan (I). Methods: The first part of the study was an open-label, dose-escalation stage in which patients with advanced solid tumors received Z at doses of 2, 4, 5, or 6 mg/kg on day 1, followed by FOLFIRI q2wks. The second part of the study was an expansion stage at the recommended dose of Z (4 mg/kg). This analysis is limited to CRC patients previously treated with I and receiving a dose of Z ≥4 mg/kg in either part of the study. Results: Of the 61 patients in the overall study with a planned dose of Z ≥4 mg/kg, 37 CRC patients previously treated with I received an actual dose of Z ≥4 mg/kg (56.8% men; mean age 57.6 years; 94.6% with ECOG performance status 0-1). Table shows response rates for the prior I efficacy population (n=36) and overall study ...

10506 Background: Ombrabulin (AVE8062) is a vascular disrupting agent that damages established tumor vasculature and has demonstrated synergistic antitumor activity with cisplatin in vivo. In a phase I study, ombrabulin 25 mg/m² plus cisplatin 75 mg/m² was identified as the recommended dose in pts with solid tumors (AACR 2008; Abs 08-AB-4925). This phase III study evaluated the efficacy and safety of ombrabulin plus cisplatin in pts with advanced soft-tissue sarcoma (NCT00699517). Methods: Pts (aged ≥18 yrs, ECOG PS ≤2) with metastatic soft-tissue sarcoma who had received prior anthracycline and ifosfamide, with ≤2 prior chemotherapies for advanced disease, were randomized (1:1) to receive either ombrabulin 25 mg/m² or Pbo plus cisplatin 75 mg/m² every 3 weeks. The primary objective was to compare progression-free survival (PFS) between arms; secondary objectives included overall survival (OS) and safety. Results: Overall, 355 pts (median age 52 yrs; 51.5% male) were randomized (176 ombrabulin, 179 Pbo) in 44 centers worldwide. Median duration of follow-up was 27.9 and 30.5 months in Pbo and ombrabulin arms, respectively. PFS analysis showed a statistically significant improvement with ombrabulin (median 1.54 vs 1.41 months Pbo; HR=0.76, 95% CI 0.59–0.98; p=0.0302), with 3- and 6-month rates in favor of ombrabulin vs Pbo: 35.4% vs 24.9% and 19.3% vs 10.6%, respectively. A trend for an improvement with ombrabulin was observed in 3 of the 4 prespecified histology strata: liposarcoma, leiomyosarcoma, and “other”, but not for pleomorphic. Analysis of OS did not show statistically significant improvement with ombrabulin (median 11.43 vs 9.33 months Pbo, HR=0.85, 95% CI 0.67–1.09). OS rates at 1 year were in favor of ombrabulin (48.6% vs 42.4% Pbo). Grade 3/4 TEAEs more frequently seen with ombrabulin included neutropenia (19.2% vs 7.9% Pbo) and thrombocytopenia (8.5% vs 3.4% Pbo). Conclusions: Although this trial met its primary efficacy endpoint, the combination of ombrabulin and cisplatin did not demonstrate sufficient clinical benefit in pts with advanced soft-tissue sarcoma to warrant further study. Clinical trial information: NCT00699517.