Spleen tyrosine kinase/FMS-like tyrosine kinase-3 inhibition in relapsed/refractory B-cell lymphoma, including diffuse large B-cell lymphoma: updated data with mivavotinib (TAK-659/CB-659)

Non-Hodgkin’s lymphoma; SYK inhibitor; Relapsed/refractoryLinfoma no Hodgkin; Inhibidor de SYK; Recidivante/refractarioLimfoma no Hodgkin; Inhibidor de SYK; Recaiguda/refractàriaWe report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report). Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60–120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity. A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%). These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL.This study was funded by Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer

Background: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer

A first-in-human study of AO-176, a highly differentiated anti-CD47 antibody, in patients with advanced solid tumors.

Research Funding: Arch Oncology Background:AO-176 is a humanized IgG2 antibody that specifically targets CD47. Expressed by multiple tumor types, CD47 binds to signal regulatory protein a (SIRPa) on phagocytes, including macrophages and dendritic cells. The CD47-SIRPa complex results in a “don’t eat me” signal that allows the tumor to escape removal by the innate immune system, disabling the generation of an adaptive immune response. The differentiated mechanisms of action of AO-176 include promotion of phagocytosis, direct tumor cell killing through programmed cell death type III and induction of damage associated molecular patterns/immunogenic cell death, preferentially binding to tumor cells vs. normal cells, and enhanced binding at an acidic pH as found in tumor microenvironments. AO-176 has negligible binding to RBCs.Methods:In a phase 1/2 first-in-human study (NCT03834948) of AO-176, pts with advanced solid tumors associated with high CD47 expression and an ECOG PS of 0-1 were enrolled into escalating dose cohorts of AO-176 given IV every 7 days. Objectives included evaluation of safety, dose-limiting toxicity (DLT) and recommended phase 2 dose (RP2D), antitumor activity, pharmacokinetic (PK) parameters and exploratory biomarkers.Results:As of 4 Jan 2021, 27 pts were enrolled (median age 64 years; 67% female; 67% ECOG PS 1; median [range] of 4 [1-7] prior therapies for metastatic disease). Dose levels of 1, 3, 10, 20 and 20 (using step-up dosing) mg/kg were evaluated in \u3e250 infusions. Most common (\u3e10%) treatment-related adverse events (TRAEs) of any grade were thrombocytopenia and infusion-related reaction (IRR) (33% each), anemia (22%) with no evidence of hemolysis, nausea (19%), and fatigue (15%). The only G3+ TRAE occurring in \u3e10% of pts was asymptomatic, brief thrombocytopenia (22%). No platelet transfusions were given. DLTs included IRRs in 2 pts dosed at 20 mg/kg, and asymptomatic thrombocytopenia and a cerebrovascular accident in 1 pt each in the 20 mg/kg step-up cohort. The RP2D was 10 mg/kg. Implementation of additional pre-medication and a 6-hr infusion duration in cycle 1 eliminated subsequent IRRs. Dexamethasone tapering and shortening of the infusion duration to 2 hrs was successful in all pts after cycle 1. Interim PK analysis of AO-176 demonstrated consistent exposure with linear PK. The T1/2 was ̃5 days. One pt with endometrial carcinoma who had not responded to any of 4 prior systemic regimens had a confirmed PR and remains on study for \u3e1 year. 7 pts had SD as a best response, with 2 pts (endometrial carcinoma, gastric cancer) on study for \u3e6 mos.Conclusions:AO-176 is a well-tolerated, differentiated anti-CD47 therapeutic. Durable anti-tumor activity was observed. Evaluations of AO-176 in combination with paclitaxel in pts with select solid tumors (NCT03834948) and as a single-agent in pts with multiple myeloma (NCT04445701) are ongoing. Clinical trial information: NCT0383494

Phase II Trial of FOLFOX6, Bevacizumab, and Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer

is unclear whether cetuximab contributed to FOLFOX/bevacizumab efficacy, although the response rate, PFS, and overall survival were high. The regimen was generally well-tolerated, with expected skin effects; thromboembolic rates should be assessed in larger analyses. Cetuximab's role in first-line mCRC treatment is likely best guided by K-RAS testing in future clinical trials

Vorasidenib (VOR; AG-881), an inhibitor of mutant IDH1 and IDH2, in patients (pts) with recurrent/progressive glioma: Updated results from the phase I non-enhancing glioma population

2504 Background: Isocitrate dehydrogenase 1 and 2 mutations (m IDH1/2) occur in approximately 70% and 4% of low-grade gliomas (LGGs), respectively, promoting oncogenesis via increased production of D-2-hydroxyglutarate. In this ongoing phase 1 trial, VOR, a potent, oral, reversible, brain-penetrant, first-in-class dual inhibitor of mIDH1/2, is being evaluated in advanced m IDH1/2 solid tumors, including gliomas. Safety and preliminary results were presented previously (Mellinghoff et al., J Clin Oncol 2018). Here, we report updated data for the non-enhancing glioma pt population. Methods: Pts with recurrent/progressive m IDH1/2 glioma received VOR daily (continuous 28-day cycles). Key eligibility criteria included: ≥18 years; histologically or cytologically confirmed glioma with documented m IDH1/2; ECOG 0-2; and evaluable disease by RANO-LGG criteria. Dose escalation cohorts enrolled using a Bayesian logistic regression model (BLRM) escalation guided by the overdose control (EWOC). Tumor response was evaluated by MRI every 8 weeks using RANO-LGG criteria by local assessment. Results: As of 28 Nov 2019, 22 pts with non-enhancing glioma had received VOR and 8 (36%) remain on treatment. M/F, 8/14; grade 2/3, 17/5; median age, 47 years; m IDH1/2, 20/1; 1p19q intact, 9/22; median (range) number of prior systemic therapies, 2 (1–4). Common (≥5 pts) treatment-emergent adverse events (AEs) of any grade and regardless of causality included increased ALT/AST (63.6%/59.1%), headache (45.5%), nausea (40.9%), neutropenia (31.8%), fatigue and hyperglycemia (27.3% each), and seizures and decreased white blood cell count (22.7% each). Transaminase elevations were grade 1 in severity at dose levels < 100mg and were less frequent (5 [38.5%] of 13 pts). Three subjects had related grade ≥3 AEs; 2 discontinued due to AEs. Objective response rate was 13.6% (1 partial response, 2 minor responses), and 17 (77.3%) pts achieved stable disease. 60.5% of pts were progression free and alive at 24 months. Conclusions: In this previously treated population with non-enhancing glioma, VOR was associated with a favorable safety profile. The study results also show encouraging preliminary activity within that population, with PFS duration extending to 24 months or longer in 60% of participants. A global randomized phase 3 study of VOR in grade 2 non-enhancing glioma pts who have had surgery only is currently enrolling (NCT04164901). Clinical trial information: NCT02481154