ALBERT

Description: Cytogenetics has proven an essential tool not only for confirming a diagnosis/classification, but for providing prognostic value as well in myelodysplastic syndromes (MDS). However, approximately 50% of primary MDS do not show discernible chromosome changes. In recent years, the fluorescence in situ hybridization (FISH) technique using gene or chromosome locus/region specific probes has emerged as a promising test in various hematopoietic and lymphoid neoplasms. To evaluate the application of FISH panels and cytogenetic studies in MDS, we retrospectively analyzed 1,885 consecutive bone marrow results from patients with suspected MDS due to cytopenia(s). In particular, we assessed the additional information a FISH reflex testing might have given in cytogenetically normal cases. The probes used in the panel included the EGR1 at 5q31, the D7S522 at 7q31, the D8Z2 for the centromere of chromosome 8, the MLL at 11q23 and the D20S108 at 20q12 (Vysis, Inc.). Among all patients, 190 (10%) had clonal chromosome abnormalities, mostly as reported in the literatures, eg, -5/5q- accounted for 34.7% of abnormalities, trisomy 8 29.5%, -7/7q- 14.2%, 20q- 13.7%. Of 345 cases with a FISH reflex test ordered and performed, only 3 (0.87%) showed positive results: a deletion of 7q31, a deletion of 20q12 and a deletion of 5q31 in 9.6%, 8.2% and 71.5% of interphase cells respectively. For the case with 5q- detected by FISH, only 12 metaphases were available for cytogenetic analysis. From our data and experience, at present, interphase FISH panel testing seems not to be an efficient and cost-effective method used as a screening test for cytopenia(s) in the diagnosis of MDS, different from its applications in B-cell chronic lymphoid leukemias, non-Hodgkin lymphomas and plasma cell neoplasms where neoplastic cells inherited not to divide easily in culture for metaphase analysis. Rather, it should be used for suspected MDS cases as a technique of choice for problematic specimens compromised for cytogenetic analysis such as cellular insufficiency, extended transit time and extremely low mitotic index or poor chromosome morphology. Until more genetic defect targeted probes become available with a better understanding of the stem cell biology and pathogenesis in MDS, cytogenetics is still the best and a “must” technique for detecting genomic aberrations in MDS and nearly all other myeloid hematopoietic neoplastic disorders.

Description: Oral mucositis (OM) is a common complication in cancer patients receiving chemotherapy (CT). OM is characterized by damage to the epithelium of the oral-pharyngeal cavity. CG53135-05, a recombinant human fibroblastic growth factor 20 (rhFGF-20) protein, has demonstrated epithelial and mesenchymal cell proliferation stimulating activity in vitro and reduces OM using single doses in a hamster mucositis model. The goal of this dose-escalating tolerance study was to assess the safety, tolerability and pharmacokinetics of CG53135-05 in cohorts of four patients (pts) at 0.03, 0.1, 0.33, and 1mg/kg (concentrations are determined by the UV method which are equivalent to 0.1, 0.3, 1.0, and 3.0 mg/kg by the Bradford method previously used). Dose escalation was stopped due to tolerability information at 0.33 mg/kg delivered in 15 min (reported in another Phase I study) and the protocol was amended to add a 0.2 mg/kg dose. The World Health Organization (WHO) OM and OMAS scoring systems were used to measure the incidence and severity of OM. The interim results are reported: Ten pts received CG53135-05 at 0.03 mg/kg (n=4) or 0.1 mg/kg (n=6) as a single 100-ml intravenous infusion administered 3 days after completion of the CT. After infusion, CG53135-05 reached maximum plasma concentration within 1h. The mean terminal exponential half-life was 49 min (range: 16.2–87 min, n=5). No pts discontinued the trial due to adverse experiences. Adverse events (number pts) that may be related to the study drug include: nausea (2); chills (2); fever (2); vomiting (1); dizziness (1); vision - “lights flashing” (1) and astigmatism (1); neuropathy (1); tachycardia (1); headache (1); and premature atrial complex (1). All reported incidences were mild to moderate. No grade 3 or 4 laboratory toxicity associated with the study drug was noted. Three serious adverse events deemed unrelated to study drug were noted from two pts including cancer progression, catheter infection, and small intestinal obstruction. Among the treated pts, no grade 3 or 4 OM was observed. Three pts developed Grade 2 mucositis that lasted between 1–5 days. No pts required total parenteral nutrition. Approximately 72–84% of pts receiving CPT-11 experience diarrhea. Of the six pts who received CPT-11 as part of CT in this trial, two pts (both receiving 0.03mg/kg of CG53135-05) experienced mild to moderate diarrhea. Conclusions: CG53135-05 is well tolerated with single dose administration at 0.03 and 0.1 mg/kg. Dosing at 0.2 mg/kg is ongoing. The full results of this study will be presented.

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.