Long-term follow up of patients with mesothelioma treated with dendritic cell therapy in three phase I trials.

2618 Background: Immunotherapy targeting PD-(L)1 has become indispensable in the treatment of many malignant tumors. Recently, checkpoint inhibition using anti-PD-1 in combination with anti-CTLA-4 was proved to be effective in patients with malignant pleural mesothelioma (MPM). However, the minority of patients benefit from this treatment. The lack of immunotherapy efficacy in the majority of patients with mesothelioma can be explained by the fact that mesothelioma is a tumor with an “immune-desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of dendritic cells (DCs), which were cultured, activated, and exposed to antigens ex-vivo, this “immune-desert” phenotype might be turned into an “inflamed” phenotype. Previously, we performed and published three phase I trials using activated DCs, which support this concept. Here, we report the long-term survival of the patients treated with DCs in these three phase 1 studies. Methods: We collected the survival data of the phase 1 trials using DC therapy in patients with MPM. In the first two trials, DCs loaded with autologous tumor lysate were used, while in the third allogeneic tumor lysate was used to load the DCs (Mesopher). Results: Between 2006 and 2015, in the three studies combined, 29 patients with MPM were treated with DC vaccination. At data cut-off, the median OS was 27 months (95% confidence interval (CI): 21 – 47 months). OS at 2 years was 55.2% (95% CI: 39.7%-76.6%), OS at 5 years was 20.7% (95% CI: 10.1%-42.2%). Conclusions: The long-term follow up of MPM patients treated with DC vaccination in the three separate phase 1 trials show a promising signal, with a 2-year OS of over 50% and a 5-year OS of over 20%. In addition, 2 patients are alive after 10 years of treatment. In our opinion, these findings show the potency of DC vaccination therapy in long-term activation of the immune system. DC vaccination therapy in patients with MPM is currently being investigated in a large, randomized phase II-III trial (NCT03610360) and in pancreatic cancer. Additional biomarker studies, as well as treatment combinations with for example ICI, could further improve the outcomes of DC-vaccination therapy. Clinical trial information: NCT02395679. [Table: see text]

Clinical Trial Design Features of Myelofibrosis Trials during the Last Decade: Comprehensive Review of Clinicaltrials.Gov Data 2010-2019

Introduction: FDA approval of JAK2-inhibitors for myelofibrosis (MF) has changed the landscape for treatment introducing possible increased complexity of clinical trial designs in MF. Many patients with MF will have insufficient response or intolerance to ruxolitinib, opening an opportunity for testing of novel agents alone or in combination. Novel trial designs exist for early stage (phase 1 and 2) studies. The Myeloproliferative Neoplasms Research Consortium (MPN-RC) is an NCI-funded academic group of laboratory and clinical scientists working to develop and evaluate treatments that will improve the survival of patients with MPNs focused on early stage trials in MF. This review was undertaken to understand the landscape of MF clinical trials and improve our approach to trial design. Methods: Studies with "myelofibrosis" as a condition were abstracted from clinicaltrials.gov using an application programming interface from 2010-2019 and reviewed for phase, trial design features, and endpoints. Trial design review captured such features as presence of dose escalation and approach (rule-based versus model-based/assisted) in the phase 1 setting. Observational and behavioral based studies were excluded. A total of 165 treatment interventional studies including MF patients (either MF as the primary cohort, or MF along with other MPN, myelodysplastic syndrome, or hematologic malignancies related cohorts) were reviewed. Primary and secondary endpoints were reviewed for quality of life, symptoms, or other patient-reported outcomes (PRO). Results: A median of 16.5 (range 13-20) trials were initiated per year; 92 (56%) phase 2, 54 (33%) phase 1; 17 (10%) phase 3 and 2 (1%) phase 4, with 77 (47%) industry sponsored (Figure 1). Among phase 1 trials, 41/54 (76%) included dose escalation, the majority employing a standard 3+3 design (or other rule-based design) or not specifically detailing the dose escalation schema. Less than 5 dose escalation trials were explicitly described as model-based or model-assisted. Almost half of the phase 1 trials (23/54; 43%) included combination treatment, with 17/23 (74%) using ruxolitinib or fedratinib. Among phase 2 trials, 82 (89%) were non-randomized and 10 (11%) randomized trials; 35/92 (38%) involved combination treatment and 57 (62%) single agent. Median actual/target enrollment for the phase 3 trials (n=16) was 192 patients (range 49-2233 patients); only 2 phase 3 trials were > 500 patients. Median number of total outcomes was 6.0 (range 1-28) across all studies with a median of 5.5 (range 1-28) for 2010-2014 versus 7.0 (range 1-22) for 2015-2019 (p=0.09). Overall 63/165 (38%) studies included at least one PRO endpoint; 15 (28%) phase 1, 33 (36%) phase 2 and 14 (82%) phase 3. Inclusion of PRO endpoints for years 2010-2014 was similar to studies started in years 2015-2019 [31/82 (38%) and 32/83 (39%)]. Industry sponsored studies included PRO endpoints more frequently [46/77 (60%) versus 17/88 (19%); p<0.001] than non-industry sponsored trials but this is primarily due to a higher proportion of phase 3/4 trials (n=17) being conducted by industry versus non-industry (n=2) (Figure 2). Conclusions: For phase 1 trials in MF, few dose-escalation trials included model-based or model-assisted methods. These designs are encouraged in order to maximize therapeutic benefits in MF, a rare cancer. Clinical trial designs in myelofibrosis have shifted in recent years as evidenced by an increase in number of endpoints, likely to accommodate new challenges in the post JAK2-inhibitors approval era. Use of patient-reported outcomes including quality of life and symptom assessment was high in the phase 3 setting, and continued use should be encouraged as endpoint assessments in MF clinical trial designs. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Mesa:LaJolla Pharma: Consultancy; Novartis: Consultancy; Sierra Onc: Consultancy; Abbvie: Research Funding; Celgene: Research Funding; CTI: Research Funding; Genetech: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Samus: Research Funding. Hoffman:Dompe: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy; Protagonist: Consultancy.

Reexamining Ophthalmic Drugs, Safety and Tolerability in Phase 1 Clinical Trials

Background: The purpose of this study was to evaluate the safety and tolerability profile of drugs used for treating common eye disorders when applied to normal healthy volunteers (NHV) as explored in phase 1 trials. Methods: A total of 166 NHV were identified in six phase 1 trials. These included the exposure to lubricant (n=88), hypotensive (n=48) or antibiotic (n=30) ophthalmic drugs, examined in a retrospective analysis. The primary endpoints were visual comfort, assessed by the ocular comfort index (OCI); and safety, evaluated through laboratory evaluations, vital signs, visual acuity (VA), intraocular pressure (IOP), lissamine green and fluorescein staining, conjunctival hyperemia, chemosis, and the incidence of adverse events (AE). Other measured parameters included discomfort (assessed by burning, itching and foreign body sensation) and conjunctival impression cytology. Results: Compared to baseline, 72.3%, 39.6% and 66.7% of participants (for lubricant, hypotensive and antibiotic treatments, respectively), improved their OCI score by their final visit (p=0.001). As expected for NHV, laboratory evaluations and vital signs were within normal ranges in 88% of NHV, with no significant differences observed between treatments. Similar results were found for VA, corneal and conjunctival staining and chemosis. IOP decreased significantly in the hypotensive agents group (p=0.001), trace to mild hyperemia was reported in 20.7%, 26% and 5.2% of NHV in each group (p=0.006). Additionally, lubricant and hypotensive investigational drugs (ID) had a lower risk of incidence of AE than approved drugs (AD) of these groups (OR 0.856, 95% CI [0.365, 1.999], and OR 0.636, 95% CI [0.096, 4.195], respectively). Meanwhile, on antibiotic drugs the risk for ID related AE was higher (OR 1.313, 95% CI [0.309, 5.583]). Conclusions: Phase 1 trials are important in order to ensure the safety and tolerability of ophthalmic medications. This study demonstrates that NHV do not face a significant risk of harm in these studies, since 98% of the reported AE were mild, and all AE were resolved by the end of the study in which they appeared. Furthermore, it was also demonstrated that the instillation of ID is as safe and tolerable as that of AD in NHV.Trial registration: The studies were registered at clinicaltrials.gov as follows: NCT04081610, NCT03524157, NCT03520348, NCT03966365, NCT03965052 and, NCT03519516.