Sharma, Manish R.

2549 Background: BDC-1001 is a novel ISAC consisting of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist with a non-cleavable linker. BDC-1001 was designed to activate the innate immune system, eliciting antibody-mediated effector functions (eg, antibody-dependent cellular phagocytosis) and a durable adaptive immune response. In preclinical tumor models resistant to anti-HER2 treatments, BDC-1001 demonstrated potent and durable immune-mediated antitumor efficacy. Methods: A 4-part, phase 1/2 dose-escalation/expansion study was initiated to evaluate BDC-1001 ± PD1 inhibitor pembrolizumab in pts with HER2-expressing solid tumors who had progressive disease on standard of care (NCT04278144). Preliminary results of the monotherapy dose escalation (Part 1) are reported. Pts with advanced metastatic HER2-expressing (IHC2/3+) or amplified solid tumors received BDC-1001 IV q3w in a 3+3 design w/ 12 pts/cohort backfill allowed. Primary objectives were to evaluate safety, tolerability, dose-limiting toxicities (DLTs) and determine a phase 2 dose; secondary objectives were to assess pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity. Results: As of Jan 29, 2021, 20 pts w/ a median age of 65 (46-85) have enrolled in 4 dose levels (0.15mg/kg to 5 mg/kg). Cancer types include breast, biliary, cervical, colorectal (CRC), lung, gastroesophageal, salivary, urinary tract and endometrial. Pts had received a median of 4 (1-7) prior therapies; 65% received >1 prior anti-HER2 therapy. All pts completed the 21-day DLT period; no DLTs or drug-related serious adverse events (AEs) have been observed. AEs deemed related to BDC-1001 have been mild to moderate including infusion-related reactions. The MTD has not been reached (treatment duration 5-17+wk); enrollment is ongoing. PK evaluations showed Cmax levels consistent with predicted modeling based on non-human primates (NHP). One pt with microsatellite stable (MSS) HER2+ CRC with lung metastases had a confirmed partial response after 4 cycles and remains on study; 2 additional pts with metastatic MSS HER2+ CRC had stable disease (SD) and a pt with heavily pretreated MSS endometrial cancer with lung metastases had confirmed SD and remains on treatment 17+ wk; 3 of these pts had received 2 prior anti-HER2 therapies. Conclusions: In this first-in-human study, BDC-1001 appears to be well-tolerated up to the dose tested to date (5 mg/kg), with Cmax levels achieved as predicted by NHP modeling. Evidence of clinical activity have been observed, including in pts previously treated with anti-HER2 therapy. Dose escalation is ongoing and will be followed by combination dosing with CPI and the phase 2 component in selected tumors. Clinical trial information: NCT04278144.

AbstractChemotherapy‐induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient‐reported outcome and (2) propose a dose‐adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose‐neuropathy model was developed using dosing and patient‐reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin–bound paclitaxel or ixabepilone as first‐line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose‐adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin–bound paclitaxel, and ixabepilone, simulations with the proposed dose‐adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient‐reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

Purpose Treatment options are limited for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Tumor cells can exploit the programmed death-1 checkpoint pathway to evade immune surveillance. In the current study, we evaluated the efficacy and safety of programmed death-1 blockade by nivolumab in patients with relapsed/refractory DLBCL. Methods In this phase II, open-label study, patients with relapsed/refractory DLBCL who were ineligible for autologous hematopoietic cell transplantation (auto-HCT) or who had experienced failure with auto-HCT received nivolumab 3 mg/kg every 2 weeks. We assessed the efficacy and safety of nivolumab as well as genetic alterations of 9p24.1. Results Among 121 treated patients, patients in the auto-HCT–failed cohort (n = 87) received a median of four nivolumab doses and a median of three doses were administered to those in the auto-HCT–ineligible cohort (n = 34). At a median follow-up of 9 months in the auto-HCT–failed cohort and 6 months in the auto-HCT–ineligible cohort, independently assessed objective response rates were 10% and 3%, and median durations of response were 11 and 8 months, respectively. Median progression-free survival and overall survival were 1.9 and 12.2 months in the auto-HCT–failed cohort and 1.4 and 5.8 months in the auto-HCT–ineligible cohort respectively. All three patients with complete remission—3% of the auto-HCT–failed cohort—had durable response (11 or more, 14 or more, and 17 months). Treatment-related grade 3 and 4 adverse events were reported in 24% of patients. The most common were neutropenia (4%), thrombocytopenia (3%), and increased lipase (3%). Of all evaluable samples for 9p24.1 analysis, 16% exhibited low-level copy gain and 3% had amplification. Conclusion Nivolumab monotherapy is associated with a favorable safety profile but a low overall response rate among patients with DLBCL who are ineligible for auto-HCT or who experienced failure with auto-HCT. Genetic alterations of 9p24.1 are infrequent in DLBCL.

Purpose The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]). Methods Tumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with α = 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS. Results For FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited > 80% power with 60 to 80 patients per arm. Conclusion TTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point.