XLSX - 54K, Table S2. 261 probsets gene signature in sens and res cell lines in Excel format.

PDF - 1128K, Figure S1. Knockdown of CDK7 and CDK9 can inhibit RNAP II CTD P-Ser2 and P-Ser5. Figure S2. LY2857785 and flavopiridol inhibit MCL-1, XIAP protein expression and induce CASP-3 and cleaved PARP in AML cell MV-4-11. Table S1. LY2857785 inhibits solid tumor cell proliferation and induces apoptosis. Table S2. 261 probsets gene signature in sens and res cell lines. Table S3. LY2857785 inhibits proliferation of normal human hematopoietic cells in vitro.

PDF file - 71KB, VPC of the biomarker model in colo-205 xenograft bearing mice following a single 3.125, 6.25 or 12.5 mg/kg oral dose of LY2835219.

PDF file - 22KB, Model simulated dose response curve for the average (red line), minimum (green line) and maximum (blue line) levels of p-Rb and pHH3 over a 24 period at steady state following daily dosing.

Abstract Background: MM remains incurable and new tx options are needed, especially in heavily pre-treated R/R pts. REGN5459, a BCMAxCD3 bispecific Ab, binds to BCMA on MM cells and with low affinity to CD3 on T cells, triggering T-cell activation and plasma cell depletion with low cytokine release preclinically. This first-in-human study aimed to assess the safety, tolerability, and preliminary anti-tumor activity of REGN5459 monotherapy in pts with R/R MM. Methods: Eligible pts had received ≥3 prior lines of tx including an anti-CD38 Ab, proteasome inhibitor, and immunomodulatory drug, and had exhausted all available tx options. Pts could receive REGN5459 until progression/intolerable toxicity. Primary objectives were to assess safety, tolerability, dose limiting toxicities (DLTs), and determine the recommended Ph 2 dose (RP2D) of REGN5459 (Ph 1) and assess efficacy of REGN5459 (Ph 2) per ORR. Results: As of June 9, 2022, 43 pts were enrolled (Ph 1, 33; Ph 2, 10): median age 67 yrs (range, 26-85), 51% female, 16% high cytogenetic risk, 14% extramedullary plasmacytoma, 37% R-ISS Stage III disease, 61% triple-class refractory, and median of 5 (range, 2-9) prior lines of tx. In Ph 1, one DLT was reported in a pt receiving the highest dose (900 mg; Gr 3 hypoxia, pt later found to have primary lung cancer). RP2D was identified as 480 mg. All pts enrolled had ≥1 TEAE, 74% had Gr ≥3 TEAEs. TEAEs all-Gr in ≥30% of pts were CRS (54%), fatigue (44%), neutropenia (37%), anemia (35%), cough (30%), and diarrhea (30%). Gr ≥3 TEAEs in ≥15% of pts were neutropenia (37%), anemia (26%), lymphopenia (23%), thrombocytopenia (19%), and hypertension (16%). CRS Gr 1, 2, and 3 were reported in 47%, 2%, and 5%, respectively; there was no Gr 4 or 5 CRS. No Gr 3 CRS with RP2D. Tocilizumab was used in 19% and steroids in 9% of pts. One pt developed ICANS (2%, Gr 2). Incidence of serious TEAEs and TEAEs leading to tx discontinuation was 63% and 16%. Infections occurred in 61% (37% Gr ≥3). After data-cutoff, two deaths due to COVID pneumonia and COVID infection have been reported. ORR was 67% (58% ≥VGPR) for the entire cohort and 100% (85% ≥VGPR; 15% sCR; 39% CR) among pts receiving the RP2D (n=13). Median follow-up was 7 mos (range, 1-26) with longest response ongoing for 22+ mos. Median time to response was 0.8 mos. Median DOR was NR (95% CI, 12-NE); 12-mo DOR for RP2D was 66.7% (95% CI, 5.4-94.5). Of pts in ≥CR with available MRD results (n=8), 50% were MRD negative at the 10−5 threshold. Conclusion: These initial data show that REGN5459 has acceptable safety/tolerability in R/R MM with most CRS of low grade and low incidence of ICANS. Modulation of CD3 affinity on bispecific Abs to maximize tumor killing, and mitigate CRS and T-cell exhaustion, warrants further research. Efficacy in this heavily pre-treated cohort was encouraging, with 100% ORR with the RP2D. Updated data will be presented at the meeting. Citation Format: Attaya Suvannasankha, Prashant Kapoor, Matthew J. Pianko, Joshua Richter, Anita D'Souza, Larry D. Anderson, Andrew Magyar, Oluwaseun Aina, Anita Boyapati, Damien Cronier, Nikhil Singh, Karen Rodriguez-Lorenc, Glenn S. Kroog, Hans C. Lee. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT013.

PDF file - 247KB, Model simulations of the plasma concentration, the biomarker levels of p-Rb, TopoIIalpha and pHH3, and the effect parameters driving tumor growth inhibition for a 21 day daily dosing regimen of 25 (red line), 50 (blue line) and 100 mg/kg (green line) LY2835219 using the mean parameter estimates.

Pharmacokinetic parameters of tabalumab in multiple myeloma patients

Bortezomib pharmacokinetic parameters following a single intravenous 1.3 mg/m2 bolus dose in the presence or absence of tabalumab and dexamethasone

PDF file - 122KB, Supplementary Table 1. Summary of available PK and biomarker data. Supplementary Table 2. Definitions of PK, biomarker and tumor model parameters.

PDF file - 350KB, Model simulations of tumor size dynamics for 17 days of growth followed by a 21-day daily dosing regimen of 25, 50 and 100 mg/kg of LY2835219 for the full model (green line) or for the model incorporating tumor growth inhibition by cell cycle arrest alone (blue line), compared to control tumor growth (red line).

Bortezomib pharmacokinetic parameters following a single intravenous 1.3 mg/m2 bolus dose and varying single intravenous doses of tabalumab

Percentage Change from Baseline (PCB) for B-cells (CD19+) and Immunoglobulins (Ig)at 20-day time intervals post-baseline.

PDF file - 349KB, External validation of the PK model by VPC in colo-205 xenograft bearing mice receiving a single 6.25, 12.5, 25 and 50 mg/kg oral dose of LY2835219, or with oral doses of 50 and 100 mg/kg administered daily for 21 days.

Supplementary Table 1. Summary of 33 Patients Treated with Abemaciclib in Dose Escalation. Supplementary Table 2. Baseline patient and disease characteristics. Supplementary Table 3. Possibly related treatment-emergent adverse events (>10% all grades) for hormone receptorpositive breast cancer cohort (n=19) receiving combination therapy with abemaciclib plus fulvestrant. Supplementary Table 4. Summary of abemaciclib pharmacokinetic parameters following a single oral administration. Supplementary Table 5. Summary of abemaciclib pharmacokinetic parameters following repeated once-daily (Q24H) or twice-daily (Q12H) oral administration. Supplementary Table 6. Efficacy for NSCLC cohort, overall and by KRAS status. Supplementary Table 7. Efficacy for other tumor-specific cohorts.

REGN5458 shows early, deep, and durable responses with a manageable safety profile in triple or greater-refractory patients with RRMM. This study is funded by Regeneron.

SummaryBackground. Ataxia telangiectasia mutated (ATM) kinase orchestrates DNA double strand break (DSB) repair; ATM inhibitors may therefore enhance the therapeutic effect of DSB-inducing treatments such as radiotherapy (RT). M3541 is an orally administered selective inhibitor of ATM. Methods. This phase I dose-escalation study evaluated the maximum-tolerated dose (MTD), recommended phase II dose(s) (RP2D), safety, pharmacokinetics (PK) and antitumor activity of M3541 in combination with fractionated palliative RT in patients with solid tumors. Fifteen patients received palliative RT (30 Gy in 10 fractions) and escalating doses of M3541 (50–300 mg administered on RT fraction days) guided by a Bayesian 2-parameter logistic regression model with overdose control. Results. Doses of M3541 up to 300 mg/fraction day were well tolerated. One patient (200 mg group) experienced two dose-limiting toxicities (urinary tract infection, febrile neutropenia) that resolved with antibiotics. All patients reported ≥ 1 treatment-emergent adverse event (TEAE) but none led to treatment discontinuation. No grade ≥ 4 TEAEs were reported and there was no indication of a dose effect for any TEAE. Three patients (20.0%; 95% confidence interval 4.3–48.1) had confirmed complete or partial response. M3541 total plasma levels did not increase with dose following single or repeated dosing. No relationship was observed between dose and changes in the ratio of phosphorylated to total ATM or in immune cell counts. Conclusions. The MTD and RP2D could not be established as the study closed early due to the absence of a dose–response relationship and non-optimal PK profile. No further clinical development of M3541 was pursued. (Trial registration number ClinicalTrials.gov NCT03225105. Registration date July 21, 2017).