ALBERT

Description: Abstract 102 Background: Radioimmunotherapy (RIT) has proven to be highly active in relapsed follicular lymphoma (FL) and the best single agent efficacy results in frontline therapy of FL were obtained with Iodine-131 Tositumomab (Bexxar™) (Kaminski et al NEJM 2005); albeit half of the patients had low tumor burden. In patients with higher tumor burden, using more than one fraction of RIT increases the overall radiation dose over that of a single fraction of treatment, thereby potentially improving both the response rates and survival (Illidge et al, Blood 2009). Methods: We conducted an international, multicenter phase 2 trial to evaluate the efficacy and toxicity of Fractionated 90Y Ibritumomab tiuxetan (Zevalin™) RIT as an initial therapy of Follicular Lymphoma. Eligible patients had untreated follicular lymphoma (grade 1, 2, or 3a) and at least one criterion of high tumour burden - one lymphoma lesion greater than 7 cm or three separate nodes of 3 cm or more; symptomatic splenic enlargement; raised serum concentrations of either lactate dehydrogenase or β2-microglobulin; compressive syndrome; or the presence of B symptoms. Treatment consisted of two doses of 90Y-ibritumomab tiuxetan (11.1 MBq/kg) given 8–12 weeks apart. Patients with greater than 20% bone marrow involvement (BM) with lymphoma received 4 weekly infusions Rituximab (375 mg/m2) and proceeded to fractionated RIT only if a repeat BM biopsy demonstrated clearing of lymphoma with less than or equal to 20% involvement. The primary endpoint was end of treatment response (EOR) of the intent-to-treat (ITT) population according to IWC 1999, assessed 12 weeks after last 90Y Ibritumomab tiuxetan infusion (21 weeks after treatment start). Secondary objectives were safety and progression free survival (PFS). Results: 74 patients with a median age of 61 years (28−80), including 58 (78%) with stage III–IV stage, 23 (31%) intermediate risk FLIPI 2 and 34 (46%) with high risk FLIPI 3–5; were included between June 2007 and June 2010 in 7 centres. Thirteen (18%) patients with 〉20% BM involvement required rituximab pre-treatment, 2/74 did not qualify for RIT, meaning 72 received the first 90Y Ibritumomab tiuxetan infusion and 55 (76%) completed the full treatment schedule. The 2nd infusion of RIT was withheld secondary to hematologic toxicity with 1st infusion (n=12, 17%) or human anti murine antibodies positive testing (n = 4; 5.6%) or other (n = 1, 1.4%). Two out of 72 patients did not have recorded response data and the EOR was 95.7% (67/70) with CR/CRu of 57.1% (40/71). Six patients subsequently improved response making an ORR of 97.1% (68/70) (95% CI 90.0% – 99.7%), and CR/CRu of 64.3%% (45/70) (95% CI 51.9% – 75.4%). For the subset of 17 patients who only received a single 90Y Ibritumomab tiuxetan infusion, ORR (CR/CRu) was 100% (76,5%). At a median follow-up of 1.52 years (range 0.13 – 3.69 years) the PFS is 67 %, 20 patients have progressed and 12 of these have required further treatment (8 chemotherapy, 2 radiotherapy, 2 other). Updated data with median follow-up of more than 2 years will be presented. Ten patients experienced at least one SAE during the treatment period, with 3 related to study treatment (one case of rigors associated with the first infusion of rituximab and 2 cases of neutropenic sepsis both associated with the second RIT dose. The most common toxicity was hematologic: after the first 90Y Ibritumomab tiuxetan dose, related G3-4 hematological AEs were transient neutropenia (20.8%, 18 days median duration) and thrombocytopenia (20.8%; 20 days median duration). After the second 90Y Ibritumomab tiuxetan dose, related G3-4 hematological AEs increased to 36.4% for neutropenia (31days median duration), 14% for anemia (8/55 required transfusion) and 56.4% for thrombocytopenia (40 days median duration). There has been one case of MDS diagnosed 26 months after treatment and one death due to metastatic breast cancer diagnosed 9 months post last dose of 90Y Ibritumomab tiuxetan Conclusion: Fractionated RIT using 90Y-ibritumomab tiuxetan is an effective frontline treatment of advanced-stage follicular lymphoma in patients with high tumor burden requiring treatment and delivers high response rates. The treatment was well tolerated by patients with few infectious episodes and AE's and manageable hematologic toxicity. Disclosures: Illidge: Bayer Schering Pharma: Honoraria, Research Funding, Speakers Bureau. Morschhauser:Roche: Consultancy, Honoraria.

Description: Betalutin (177Lu-satetraxetan-lilotomab) is an antibody radionuclide conjugate (ARC) in development for the treatment of Non-Hodgkin's lymphoma (NHL). The FACT-Lym is a validated health related quality of life instrument specifically designed to assess lymphoma patients. This questionnaire has been used previously to demonstrate significant reductions in the quality of life of patients undergoing treatment, likely as a result of treatment related toxicities (Hlubocky FJ, et al, Lymphoma 2013). Methods Patients with relapsed incurable NHL of follicular grade I-IIIA, marginal zone, mantle cell, lymphoplasmacytic and small lymphocytic subtypes who had received at least one prior treatment regimen were eligible for enrolment. All patients received a single dose of 15 MBq/kg of 177Lu-satetraxetan-lilotomab. The FACT-Lym instrument used in the study has 42 questions grouped into 5 subscales (physical, social/family, emotional and functional well-being and additional concerns). Questionnaires were completed by all subjects in the phase 2 stage of the study during screening, at month 3 and month 12. Responses were categorised on a 5-point Likert scale from "0- not at all" to "4-very much" with a higher score indicating a better quality of life. The analysis is conducted as part of a protocol specified interim analysis of efficacy, safety and quality of life. Results A total of 36 patients have been enrolled into this phase 1/2 study of which 15 patients who have undergone treatment in the phase 2 part are included in the current analysis. The median age of the patients was 68 years and the median number of prior regimens was 2 (range: 1-9). All 15 subjects have completed the screening assessment and 7 patients have completed the 3 month assessment, data from all subjects at both screening and the month 3 assessment will be presented at the annual meeting. To date 907 responses to questions have been collected including 622 questions at screening and 285 responses at 3 months post-treatment. At enrolment patients overall had a good health-related quality of life with a median baseline score of 121 and this was similar at 3 months post-treatment (median score: 132, p-value: 0.558). This maintenance of the patients quality of life was achieved while 5/7 patients (71%) showed a complete or partial response to treatment. Of the 7 patients who have so far completed the month 3 assessment, 3 had grade 3 thrombocytopenia or neutropenia (none had grade 4), the quality of life assessment of these patients (median score: 158) was similar to or higher than the 4 patients who did not have grade 3 thrombocytopenia/neutropenia (median score: 110). This indicates no negative impact on the health related quality of life when patients experienced haematological side effects associated with 177Lu-satetraxetan-lilotomab. When the 3-month assessment has been completed by all patients a subscale analysis and a correlation with ECOG performance status will be performed. Conclusion The health related quality of life as measured by the validated FACT-Lym questionnaire was maintained following treatment with Betalutin, while also achieving a durable tumour response in a significant proportion of the patients assessed. The treatment related hematological side effects experienced by patients were modest and appeared not to have a negative effect on the quality of life. Further analysis is required to confirm these findings when the 3 month assessment has been completed by all patients. Disclosures Kolstad: Nordic Nanovector: Other: Membership of Scientific Advisory Board. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership. Baylor Curtis:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment. Turner:Nordic Nanovector: Employment. Hartvig Larsen:Nordic nanovector: Equity Ownership. Holte:Amgen: Research Funding; Mundipharma: Research Funding.

Description: 177Lu-Satetraxetan-lilotomab (Betalutin®) is a novel CD37-binding IgG1 antibody labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of Non-Hodgkins lymphoma. CD37 is an internalizing transmembrane antigen highly expressed on most B-cell malignancies, and is a promising therapeutic target. The optimisation of the pre-dosing regimen prior to administration of 177Lu-Satetraxetan-lilotomab may result in an improved safety and efficacy profile. The phase 1 stage of this study is designed with 4 arms to test different pre-dosing regimens (no pre-dosing, rituximab and two doses of lilotomab) on the effect of 177Lu-Satetraxetan-lilotomab. Methods: Patients with relapsed incurable NHL of follicular grade I-IIIA, marginal zone, mantle cell, lymphoplasmacytic and small lymphocytic subtypes and with platelet counts ≥ 150 x109/l were eligible for inclusion in the study. All patients received pre-treatment with rituximab (375 mg/m2) to deplete peripheral B cells and improve biodistribution of the labelled antibody. Pre-dosing with lilotomab (cold anti-CD37 antibody) was given in arms 1 and 4 or rituximab in arm 3, within 4 hours of 177Lu-Satetraxetan-lilotomab to block binding in the non-tumour tissue. The pre-treatment and pre-dosing regimen used in each arm is summarised below: Arm 1: rituximab day1 and 8, lilotomab (40 mg) plus Betalutin day 29 Arm 2: rituximab day 1 and 8, Betalutin day 29 Arm 3: rituximab day 1, rituximab plus Betalutin day 15 Arm 4: rituximab day 1, lilotomab (100 mg/m2) plus Betalutin day 15 The starting dose for Arm 1 was10 MBq/kg and was 15 MBq/kg for arm 2, 3 and 4 and in phase 2. Response was assessed by FDG PET/CT scans at 3 and 6 months post-treatment and then by CT scan up to 5 years after treatment. The results of the protocol specified interim analysis will be presented. Results: A total of36 patients have been enrolled into study, of which 24 are currently evaluable. Patients enrolled into the study had either follicular (n=20), mantel cell (n=2) or marginal zone (n=2) lymphoma. The number of prior therapies ranged from 1 to 8. The efficacy and safety results from patients enrolled into Arms 3 and 4 and treated with two different pre-dosing regimens will be presented for the first time. The most common toxicities observed were hematologic with all dose limiting toxicities (DLTs) being reversible and manageable and related to thrombocytopenia and neutropenia. At a dose of 15 MBq/kg, pre-dosing with 40 mg of lilotomab (Arm 1 and phase 2) reduced the incidence of hematological DLTs to 14% (2/14 patients) compared with 100% (2/2 patients) with no pre-dosing in Arm 2. No DLTs have been reported at 10 MBq/kg in either Arm 1 or 2. Fourteen serious adverse events (SAEs) were reported by 8 patients: Atrial fibrillation (n=2) and platelet count decreased (n=2) were the only SAEs reported by more than one patient. There have been no deaths and no secondary malignancies or other long-term safety events. The overall tumor response rate observed in 23 patients evaluable for efficacy was 57%, comprising 7/23 complete responses, 6/23 partial responses, 5/23 stable disease and 5/23 with progressive disease. In addition, one patient had a confirmed transformed lymphoma at 3 months. One patient is still in remission more than 3 years after treatment and two further patients are still in remission more than 2 years after treatment. Conclusions: Betalutin has the potential to be a novel, safe and effective therapy for B-cell malignancies with durable responses. Betalutin, a single dose, ready-to-use formulation, has a predictable and manageable safety profile which is improved by pre-dosing. Most AEs were haematological, all transient and reversible. Disclosures Kolstad: Nordic Nanovector: Other: Membership of Scientific Advisory Board. Illidge:Nordic Nanovector: Consultancy. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership. Baylor Curtis:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment. Turner:Nordic Nanovector: Employment. Hartvig Larsen:Nordic nanovector: Equity Ownership. Holte:Mundipharma: Research Funding; Amgen: Research Funding.

Description: Introduction: Most indolent NHL patients (pts) have advanced stage disease at diagnosis, and no curative therapy exists. The mainstay of both first- and second-line (2L) therapy is anti-CD20 chemo-immunotherapy, and although initially effective, most pts relapse, with median PFS decreasing markedly after 2L and 3rd-line therapies. In addition, many pts eventually develop resistance to rituximab (RTX)/RTX-containing regimens, thus therapeutic targets other than CD20 are important. Those who develop resistance to RTX, especially the elderly, need new treatment approaches. With a median age at diagnosis of 67 (seer.gov), NHL is a disease of the elderly, who are at risk of developing cumulative myelosuppression, cardiac toxicity, and severe infections with currently available therapies. CD37 is highly expressed (〉90%) in B-cell NHL, providing an alternative target to CD20. Lutetium (177Lu) lilotomab satetraxetan (Betalutin®) is a beta-emitting anti-CD37 ARC in a ready-to-use formulation. LYMRIT 37-01 is a phase I/II open-label, multicenter, dose-escalation study to determine the safety, pharmacokinetics (PK), and preliminary efficacy of a single dose of Betalutin in pts with relapsed iNHL, and to establish a recommended phase II dose (RP2D). We present updated efficacy and safety data for the phase I/IIa part of the study (Part A) as of 22 June 2018; all pts have ≥ 6 months (m) of follow-up, except for 3 (will be completed in August). Methods: Pts with histologically confirmed iNHL relapsing after ≥1 prior therapy with 150 x 109/L, no prior SCT/RIT, and a life expectancy of ≥3 months were enrolled into 1 of 4 dose-escalation arms (Part A) to determine the optimal lilotomab pre-dose and Betalutin dose for further evaluation in an expanded phase II cohort. A fifth arm collected additional PK data. All pts received pre-treatment with RTX. Responses were assessed using Cheson IWG response criteria (including CT and FDG PET/CT scans) beginning at week 12. Results: 74 pts [57 follicular (FL), 7 mantle cell (MCL), 9 marginal zone (MZL), 1 small lymphocytic (SLL)] were enrolled at 13 sites from Dec 2012 to Feb 2018. Median age was 68 (range 38-87; 55% ≥ 65); the median no. of prior therapies was 3 (range 1-9); 48 pts (65%) had received ≥2 prior therapies. Two RP2Ds emerged: a lilotomab pre-dose of 40 mg + 15 MBq/kg Betalutin ("40/15"; Arm 1) and a lilotomab pre-dose of 100 mg/m2 + 20 MBq/kg Betalutin ("100/20"; Arm 4). For all pts, the overall response rate (ORR) was 61%, with 26% complete responses (CR). By subtype, the ORR was 65% (CR 24%) for FL, and 78% (CR 44%) for MZL. FL with ≥2 prior therapies (n=37) had an ORR of 70% (CR 27%). With a median follow-up of 9.1 m (range 4.9-49.5 m), the median duration of response for all pts is 13.3 m (20.5 m for those with a CR); 26 pts (35%) have remained free of disease progression for 〉12 m [CR(15)/PR(5)/SD(6)]. For the 36 pts receiving the "40/15" regimen, the ORR was 58% (CR 28%), and 64% (CR 28%) for FL (n=25). The ORR was 63% (CR 21%) for 19 pts receiving the "100/20" regimen, and 69% (CR 19%) for FL (n=16). Betalutinwas well-tolerated. The most common grade (G) 3/4 AEs were neutropenia (53%) and thrombocytopenia (48%); 5 pts (7%) had G3/4 infections (pneumonia, UTI, pharyngitis (G3), 2 G4 sepsis). No febrile neutropenia was reported. Four pts had plt transfusions [low plt count (2), epistaxis (1), hematuria (1)]; 3 received G-CSF. Two pts had infusion reactions; both were related to RTX. SAEs occurred in 14 pts (19%); SAEs in ≥2 pts were atrial fibrillation, thrombocytopenia, lymphoma progression and sepsis (all n=2). Five pts developed transient anti-drug antibodies. One case of CMML occurred 24 m after Betalutin (18 m after subsequent bendamustine-RTX therapy). There were no study drug-related deaths in the treatment period. G3/4 neutropenia and thrombocytopenia occurred in 56%/56% (40/15 regimen) and 47%/42% (100/20 regimen). Conclusions: Betalutin is well tolerated and has promising antitumor activity in recurrent iNHL, especially in FL and MZL. Use of a higher lilotomab pre-dose resulted in a lower incidence of G3/4 hematologic AEs. With a single administration, Betalutin has the potential to be a novel, safe, and effective therapy for pts with B-cell malignancies. The 2 RP2Ds from Part A of the study are now being compared in a randomized phase 2b cohort (Part B: "PARADIGME") in relapsed, RTX/anti-CD20 refractory FL pts who have received ≥2 prior therapies. Disclosures Kolstad: Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Research Funding. Illidge:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Jurczak:European Medicines Agency: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy; Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Afimed: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding. Rojkjaer:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment.