ALBERT

Description: Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.

Description: Normal white blood cells and cells from patients with leukemia are able to incorporate C14-DL-leucine into proteins in vitro. Cells from individuals with chronic myelogenous leukemia were able to incorporate significantly greater amounts of the amino acid, and they were able to maintain this incorporation for a longer period of time than the control cells. Both types of cells had the same in vitro survival time of four days, following storage at 3 C. The incorporation was partially decreased in the presence of dinitrophenol, as well as in an atmosphere of nitrogen.

Description: An assay method for erythropoietin-sensitive cells has been developed based on the fact that cells of mouse fetal liver respond to erythropoietin in vitro by increased heme synthesis. To determine whether or not hemopoietic colony-forming stem cells are identical with erythropoietin-sensitive cells, C3H/Bi 13-day fetal liver cells were separated into fractions on the basis of size by unit gravity sedimentation through a 1-2 per cent bovine serum albumin gradient. The cell fractions obtained were assayed for erythropoietin-sensitive cells by the present method and for spleen colony-forming cells by the method of Till and McCulloch. It was found that the modal sedimentation velocity of erythropoietin-sensitive cells was greater than that of the spleen colony-forming cells of mouse fetal liver, showing that these two classes of cells are distinct.

Description: Background: MM inevitably relapses and becomes refractory to treatment, representing a patient (pt) population with unmet needs. Teclistamab (JNJ-64007957) is a bispecific BCMA x CD3 antibody that induces T cell-mediated cytotoxicity against BCMA-expressing MM cells. Previously presented results from an ongoing study of teclistamab in RRMM (NCT03145181) included a 67% objective response rate [ORR] for the 270 µg/kg dose administered intravenously (iv) (Usmani et al, ASCO 2020 Oral Presentation #100). Here we present updated results and newly available data for subcutaneous (sc) administration. Methods: Pts have MM that is RR to established therapies. The primary objective is to identify a recommended phase 2 dose(s) (RP2D). Multiple sc and iv doses ± step-up doses were explored. Adverse events (AEs) were graded per CTCAE v4.03 and cytokine release syndrome (CRS) per Lee et al 2014. Response was investigator-assessed using IMWG criteria; minimal residual disease (MRD) in bone marrow was assessed by next generation sequencing. Results: As of 20 Jul 2020, iv teclistamab (0.3-720 µg/kg) and sc teclistamab (20-3000 µg/kg) were received by 84 and 44 pts, respectively. Overall, median age was 64 y (24-82), median number of prior lines of therapies (LOT) was 6 (2-14), 95%/79% triple-class exposed/refractory, 70%/38% penta-drug exposed/refractory, and 91% refractory to last LOT. AEs in 〉20% of pts (both iv and sc combined) included anemia (55%), neutropenia (55%), thrombocytopenia (41%), and leukopenia (26%), as well as non-hematologic events of CRS (53%), pyrexia (28%), diarrhea (24%), cough (23%), fatigue (23%), nausea (22%), back pain (20%), and headache (20%). 39% of pts had treatment-related grade ≥3 AEs; neutropenia (23%) and anemia (9%) were most frequent. CRS occurred in 55% and 50% of pts with iv and sc dosing, respectively, tending to occur later (relative to the most recent dose) with sc administration (median time to onset of 1.0 day iv and 2.0 days sc). CRS events were all gr 1 (n=51) or 2 (n=17) and generally confined to initial doses. 5% of pts (all iv) had neurotoxicity (2% gr ≥3), and 12% had treatment-related infusion/injection related reaction (including 4 infusion reactions [all iv, 5%] and 11 injection related reactions [all sc, 25%], all gr 1/2). Gr 3 or higher infection-related AEs were reported in 15% of pts (3% treatment related). Four gr 5 AEs were reported (all iv and considered unrelated to treatment by investigator except for 1 case of pneumonia). Pharmacokinetic results showed that the half-life of teclistamab supports weekly iv dosing. Exposure increased in an approximately dose-proportional manner following weekly iv or sc treatment dosing. 1500 µg/kg sc dose had comparable Cmax to that of 270 µg/kg iv and higher trough levels than that of 720 µg/kg iv. Individual time to reach Cmax following sc dosing ranged from Day 3 - Day 8. Teclistamab treatment in both iv and sc cohorts led to pharmacodynamic changes supporting mechanism of action, including increases in T cell activation and circulating cytokine levels, such as IL-10, IL-2Ra and IL-6. 120 pts were evaluable for response, with the highest and most active dose levels of 270 µg/kg and 720 µg/kg weekly for iv and 720 µg/kg and 1500 µg/kg weekly for sc (of note, response data for 3000 µg/kg sc is not yet mature). Combining these 4 iv and sc dose levels, ORR was 30/47 (63.8%, including n=24 with very good partial response [VGPR] or better and n=9 with complete response [CR] or better). 1500 µg/kg sc was selected as a RP2D, and currently at this dose, 6 of 6 pts are in response (3 PR, 1 VGPR, 2 stringent CR) with progressive deepening of responses over time. Among 48 pts with responses across all iv and sc cohorts, median time to first response was 1 mo (range, 0.3-4.2) and median duration of response has not been reached, with 38 responding pts remaining on therapy 1.6 to 21.3+ months. Of MRD-evaluable pts who had a CR, 4/5 pts treated in the iv cohorts and 2/2 pts in the sc cohorts are MRD negative at 10-6. Conclusions: Teclistamab has a manageable safety profile, which includes low-grade CRS (with no gr ≥3 events) and low severe infection and neurotoxicity rates with both iv and sc administration. Deep and durable responses were observed with both iv and sc administration. The encouraging tolerability and efficacy of teclistamab support the planned phase 2 monotherapy (at 1500 µg/kg sc) trial and future combination studies. Disclosures Garfall: Tmunity: Consultancy, Other: Personal fees, Research Funding; Kite Pharma: Other: Personal fees; Amgen: Research Funding; Novartis: Research Funding; GSK: Consultancy; Janssen: Consultancy, Research Funding; Surface Oncology: Consultancy. Usmani:Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; SkylineDX: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Array Biopharma: Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Mateos:Adaptive: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Pharmamar: Consultancy; Janssen: Consultancy; Celgene: Consultancy; EDOMundipharma: Consultancy; AbbVie: Consultancy; Takeda: Consultancy. van de Donk:Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Ferrer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oriol Rocafiguera:Amgen: Consultancy, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chari:Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Array BioPharma: Honoraria; The Binding Site: Honoraria; Sanofi Genzyme: Consultancy; Adaptive Biotechnology: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Secura Bio: Consultancy; Glaxo Smith Kline: Consultancy; Oncopeptides: Consultancy. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Sanofi Genzyme: Consultancy; MedImmune: Other: Clinical Trial Funding to Institute. Pei:J&J: Current Employment, Current equity holder in publicly-traded company. Verona:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Girgis:Johnson & Johnson: Current Employment, Current equity holder in private company. Stephenson:Johnson & Johnson: Current Employment, Current equity holder in private company. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Banerjee:Janssen: Current Employment. Krishnan:BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Janssen: Consultancy; Takeda: Speakers Bureau; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy.

Description: B cell maturation antigen (BCMA; CD269; TNFRSF17) is a surface receptor, expressed on benign and malignant plasma cells. The restricted expression of BCMA on B-cell lineage makes it an ideal target for multiple myeloma (MM) immunotherapy. BCMAxCD3 bispecific antibody (Teclistamab; JNJ-64007957) has been developed to recruit CD3+ T-cells to BCMA+ MM cells. Teclistamab demonstrated potent cytotoxicity in a murine xenograft model and against ex vivo primary MM cells. Teclistamab clinical starting dose in the first in human (FIH) study in relapsed refractory MM patients began at the minimal anticipated biological effect level (MABEL) of 0.3 µg/kg using the EC20 of the in vitro cytotoxicity assay in the purified T cells model with MM.1R cell line. Since the MABEL dose is usually low, it is important to have guidance on the expected therapeutic range in patients. The therapeutic concentrations of teclistamab were estimated from an ex vivo cytotoxicity assay in which samples from MM patients (frozen purified mononuclear cells from bone marrow) were treated with healthy human purified T cells (1:1 ratio) spiked with teclistamab and incubated for 48 hours. The mean and range of EC50 and EC90 values of the cytotoxicity endpoint were estimated. The pharmacokinetic (PK) data following the first cycle doses in the low dose cohorts in the FIH study in MM patients were modeled using 2-compartment model and simulated to predict the doses that will have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC50 and EC90). The predicted doses with average serum concentrations between the mean EC50 (372 ng/mL) and mean EC90 (2287 ng/mL) range were validated with the observed clinical data showing positive response in 2 out of 4 patients at the 38.4 µg/kg intravenous treatment dose level and their average serum teclistamab concentration overlaid within the estimated therapeutic range. This was also confirmed with the teclistamab concentrations in bone marrow samples (measured in a subset of MM patients in the study) where they were found to superimpose in the estimated therapeutic range. In addition, simulations predicted the dose that will have trough levels above the maximum EC90 (6070 ng/mL), to account for patients with high tumor burden, at which the observed clinical data have shown promising response rate and has been selected to be the recommended subcutaneous phase 2 dose of 1500 µg/kg. In conclusion, ex vivo cytotoxicity assay with MM patients bone marrow samples is an informative tool to predict the efficacious serum concentration of immuno-oncology drugs in MM patients. PK modeling and simulations of MM patients' data in FIH study coupled with the ex vivo cytotoxicity estimates provided guidance on the expected recommended phase 2 dose during the escalation phase of the FIH study. Disclosures Girgis: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Wang Lin:Johnson & Johnson: Current Employment. Pillarisetti:Johnson & Johnson: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Shetty:Johnson & Johnson: Current Employment. Stephenson:Johnson & Johnson: Current Employment, Current equity holder in private company. Hilder:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Hanna:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Smit:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Adams III:Genmab: Current Employment. Sun:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Infante:Janssen: Current Employment. Elsayed:Johnson & Johnson: Current Employment. Sharma:Johnson & Johnson: Current Employment.