This phase I multicenter trial provides novel insights into the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3200882 as monotherapy and with standard therapies as combination therapy across cancer types. The results indicate that LY3200882, a novel, potent and selective, next-generation, small molecule inhibitor of transforming growth factor-beta receptor 1, is safe and well tolerated, has a robust pharmacokineticpharmacodynamic profile, and is associated with early signals of monotherapy antitumor activity in grade 4 glioma. Interestingly, LY3200882 demonstrated promising antitumor activity when given with gemcitabine and nab-paclitaxel chemotherapy in treatment-naïve patients with advanced pancreatic cancer. This study provides supporting clinical evidence to further investigate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer, an area of urgent clinical need.
Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.
2630 Background: AK117 is a novel humanized IgG4 monoclonal antibody (mAb) targeting CD47, a macrophage immune checkpoint that allows tumor cells to evade immune destruction by phagocytic cells. CD47 is a target expressed in many cancers. However, the initial dose of anti-CD47 therapy may be limited by severe anemia due to ubiquitous CD47 expression on senescent red blood cells (RBCs). Here, we present encouraging preliminary AK117 safety and receptor occupancy (RO) data from an ongoing dose-escalation study in patients (pts) with advanced or metastatic solid tumors. Methods: This is a first-in-human, phase 1a/1b, multicenter, open label, single arm, dose escalation and dose expansion study of AK117 administered intravenously to adult pts with resistant/refractory advanced or metastatic solid tumors or lymphomas. In the dose escalation phase (phase 1a), an accelerated titration followed by a 3+3+3 design was used to assess the safety and tolerability of AK117 monotherapy (dose range 0.3 mg/kg to 45 mg/kg); and determine the maximum tolerated dose (MTD). AK117 was administered QW on a 28-day treatment cycle and dose limiting toxicity (DLT) observation period. Tumor assessments per RECIST v1.1 were performed once every 8 weeks (2 cycles). Results: As of 15 Feb 2021, 15 pts were enrolled in phase 1a with DLT evaluation of the 30 mg/kg cohort currently in progress. There were no DLTs up to 20 mg/kg QW AK117, inclusive. Five treatment-related adverse events (TRAEs) occurred in 4 subjects as shown in the table below. All pts with TRAEs continue to receive AK117, except the pt on 1 mg/kg AK117 who discontinued due to disease progression. G2 anemia and G1 thrombocytopenia occurred after Cycle 1 in a pt (liposarcoma, 10 mg/kg cohort), who had a medical history of anemia (hemoglobin 119 g/L at screening). No hematological TRAEs were seen in other pts, including those who received 20 mg/kg AK117 QW. There were no infusion-related reactions (IRRs) or grade ≥ 3 TRAEs. Target engagement in the periphery was confirmed by measuring CD47 RO of AK117 on RBCs and T lymphocytes. 100% RO on RBCs and T lymphocytes was achieved after the first dose and continued to Day 8 (prior to second dose) in the 10 mg/kg and 20 mg/kg cohorts. Conclusions: AK117 is safe and well-tolerated up to 20 mg/kg QW, inclusive, with no IRRs or severe TRAEs observed. There were no hematological TRAEs, except in a pt with baseline G1 anemia receiving 10 mg/kg AK117. Unlike other anti-CD47 therapies, AK117 does not require a lower ‘priming’ dose to prevent anemia. Safety evaluation of the 30 mg/kg dose level is in progress. Full and durable RO in the periphery was seen at 10 mg/kg and above. Further evaluation of AK117 in combination with AK104, an anti-PD-1/CTLA-4 bispecific antibody, shall commence imminently. Clinical trial information: NCT04349969. [Table: see text]
Marginal communities, such as culturally and linguistically diverse (CALD) patients, have significantly lower rates of recruitment, accrual, and retention in cancer clinical trials. A combination of language and cultural barriers means that trial participation from CALD communities remains at suboptimal levels, which in turn favors research findings that are biased towards therapeutic effects or toxicities within the context of non-CALD populations. Here we outline some key challenges and implications for CALD patient participation in glioma research in countries such as Australia, where English is the language of governance and health services implementation. We highlight multistakeholder interventions to improve both investigator recruitment and participation of CALD communities in future glioma research, particularly in this era when global migration has come of age. Enhancing research participation of CALD communities ensures not only wider understanding of genetic heterogeneity to improve glioma outcomes but also equity in access to care.Keywords: culturally and linguistically diverse (CALD), glioma, research participation. Culturally and Linguistically Diverse Patient Participation in Glioma ResearchImproving patient participation in clinical research remains a priority across all fields of medicine. Research demonstrates that fewer than 5% of all adult cancer patients, on an international basis, enter clinical trials annually, and this rate has not improved in more than 2 decades.1,2 Within this context, marginal communities, such as culturally and linguistically diverse (CALD) patients, have significantly lower rates of recruitment, accrual, and retention in cancer clinical trials.3 Lower participation of CALD patients negatively impacts the interpretation, validity, and generalized applicability of next-generation trial results. Thus, enhancing CALD patient participation remains an important but underresearched issue.Over the past decade, neuro-oncology research has witnessed a steady shift towards personalized medicine with a clear focus on stratifying trials in an attempt to identify phenotypes and genotypes that might gain maximum benefit from emerging novel treatments. 4,5 Although there has been a stronger research emphasis on personalized care and tumor evolution, there has been limited emphasis on widening the diversity of trial participants from diverse populations such as CALD communities. Moreover, in contemporary glioma research, healthrelated quality of life (HRQoL) has emerged as a key endpoint. 6,7HRQoL research and measurement require not only sensitivity to the cultural traditions, beliefs, or practices of CALD communities, but HRQoL metrics may even need to be specific to CALD patient nuances across nonstandardized cultural divides. 8 A combination of language and cultural barriers means that trial participation from diverse CALD communities remains at suboptimal levels, which in turn favors research findings that are biased towards the therapeutic effects within the context of non-CAL...
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