Legend for Supplementary Figure 1

Supplemental Figure 1. Platelet recovery after lomustine administration was not diminished by giving LY2157299 during the recovery period suggesting no bone marrow toxicity.

TPS221 Background: Despite recent advances, effective treatment for GI cancers remains a significant unmet medical need. Gremlin-1 is secreted by the peri-tumoral stroma and down-regulates bone morphogenetic proteins (BMP) -2, -4, and -7 (members of the transforming growth factor-β superfamily), thereby allowing malignant cell expansion, renewal, and a more treatment-resistant mesenchymal phenotype. Gremlin-1 mRNA is highly expressed in multiple solid tumors including >60% of colorectal, pancreatic and esophageal cancers. UCB6114 is a first-in-class, fully human IgG4P monoclonal antibody optimized for neutralizing the activity of human Gremlin-1 thereby restoring BMP signaling. Preclinical studies have demonstrated that UCB6114 binds to Gremlin-1, inhibits its pharmacological activity, and has antitumor activity in several in vivo mouse models (including several GI cancers). Methods: ONC001 (clinicaltrials.gov: NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study evaluating the safety, pharmacokinetics (PK) and antitumor activity of UCB6114 administered intravenously as monotherapy or in combination with selected standard of care (SOC) regimens. Eligible patients (pts) are: aged ≥18 years; resistant or refractory to standard therapy; ECOG performance status 0/1; and have adequate renal, hepatic and bone marrow function. In the Phase I monotherapy dose escalation and adaption part (part A and A1; modified rolling 6 design), up to 66 pts with advanced solid tumors associated with high levels of Gremlin-1 mRNA expression will be recruited. In parts B and C (modified toxicity probability interval design), up to 54 pts with locally advanced or metastatic colorectal, gastric or gastroesophageal junction adenocarcinomas will receive UCB6114 in escalating doses in combination with either mFOLFOX6 (5-fluorouracil, leucovorin and oxaliplatin) or trifluridine/tipiracil, given at SOC dosing and schedules. The overarching objective of the phase I parts of the study (Parts A‒C) is to identify the recommended phase II dose of UCB6114 either as monotherapy or in combination. The primary objective is to characterize the safety profile of UCB6114; secondary and exploratory objectives include PK, antitumor activity (RECIST v1.1), and pharmacodynamics (including circulating Gremlin-1). Enrollment in ONC001 began in July 2020; as of Sept 2021, four dose escalation levels in the monotherapy dose-escalation module (Part A) have been completed without DLT. Recruitment to parts B and C is due to commence in Q4 2021. Clinical trial information: NCT04393298.

Abstract Background Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)‐β signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF‐targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC). Methods This is a multicenter, open‐label, phase 1b study of galunisertib, an inhibitor of TGF‐β receptor 1, and ramucirumab, an anti‐VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha‐fetoprotein and TGF‐β kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1–14 of a 28‐day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks. Results Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose‐limiting toxicities were observed. Treatment‐related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment‐related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose‐proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively. Conclusion Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFβ signaling enhances efficacy of VEGF‐targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.

[This corrects the article DOI: 10.1371/journal.pone.0222259.].

Summary Purpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study ( N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX ( n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.

Leveraging historical data into the design and analysis of phase 2 randomized controlled trials can improve efficiency of drug development programs. Such approaches can reduce sample size without loss of power. Potential issues arise when the current control arm is inconsistent with historical data, which may lead to biased estimates of treatment efficacy, loss of power, or inflated type 1 error. Consideration as to how to borrow historical information is important, and in particular, adjustment for prognostic factors should be considered. This paper will illustrate two motivating case studies of oncology Bayesian augmented control (BAC) trials. In the first example, a glioblastoma study, an informative prior was used for the control arm hazard rate. Sample size savings were 15% to 20% by using a BAC design. In the second example, a pancreatic cancer study, a hierarchical model borrowing method was used, which enabled the extent of borrowing to be determined by consistency of observed study data with historical studies. Supporting Bayesian analyses also adjusted for prognostic factors. Incorporating historical data via Bayesian trial design can provide sample size savings, reduce study duration, and enable a more scientific approach to development of novel therapies by avoiding excess recruitment to a control arm. Various sensitivity analyses are necessary to interpret results. Current industry efforts for data transparency have meaningful implications for access to patient-level historical data, which, while not critical, is helpful to adjust for potential imbalances in prognostic factors.

AbstractPurpose:Overactivation of TGF-β signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-β receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies.Patients and Methods:A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin ≤ 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off.Results:Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4–40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%).Conclusions:In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.

INTRODUCTION: Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

To evaluate the exposure–overall survival (OS) relationship in patients with advanced pancreatic cancer treated with galunisertib plus gemcitabine (GG) or gemcitabine plus placebo (GP). Galunisertib 300 mg/day was given orally as intermittent dosing and gemcitabine as per label. Galunisertib exposure metrics for each patient in the GG arm (n = 99) of a phase 2 study of pancreatic cancer were calculated. Parametric survival models were used to identify influential baseline and response covariates on OS. The population pharmacokinetics dataset included data from 297 patients/healthy subjects (age: 22–84 years, weight: 39–126 kg) across multiple studies, including this pancreatic cancer study. Galunisertib was rapidly absorbed with peak concentrations attained within 0.5–2 h and had an elimination half-life of 8 h. Between-subject variance on apparent clearance was estimated to be 47%. Age was the only characteristic to have a statistically significant effect on apparent clearance. A parametric Weibull survival model with treatment effect (dose) estimated a hazard ratio of 0.796, after adjusting for patient baseline factors that were significantly associated with OS. There was also a flat daily exposure–OS relationship within the observed exposure range, once all significant baseline covariates were included. Response covariates, such as reduction in CA19-9, time on treatment, and cumulative exposure over treatment cycles were also identified as significant factors for OS for patients with pancreatic cancer. This analysis suggests that 300 mg/day galunisertib administered as 150 mg twice daily for 14 days on/14 days off treatment is an appropriate dosing regimen for patients with pancreatic cancer.

Background and Aims We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-beta 1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP). Methods Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS <= 1 were enrolled into Part A (AFP >= 1.5x ULN) or Part B (AFP < 1.5x ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-beta 1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS). Results Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-beta 1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2). Conclusions Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-beta 1 levels (vs no response) correlated with longer survival. Trial Registration Number: NCT01246986 at ClinicalTrials.gov.

Galunisertib, the first small molecule transforming growth factor beta (TGFβ) receptor inhibitor, plus gemcitabine resulted in the improvement of survival in patients with unresectable pancreatic cancer, but markers to identify patients likely to respond are lacking.

Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined. This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib–gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers. Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59–1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit. Galunisertib–gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.

Recent advances in technology have enabled the digitizing of the traditional Clock Drawing Test by a video-equipped pen to record the entire test taking process followed by applying a scoring algorithm to extract hidden signals and to generate standardized reports for analysis. This has led to the development of DCTclock by Digital Cognition Technologies as a potential tool in the screening phase of Alzheimer's disease (AD) clinical trials. This study aims to evaluate DCTclock performance compared with existing cognitive screening tools and to investigate its associations with atrophy, amyloid and tau pathology. Participants were screened for inclusion into an AD clinical trial across sites in US, UK and Japan. Subjects were assessed for cognitive status as well as brain atrophy, amyloid and tau pathology, depending on progress in screening. Cognitive status was evaluated with DCTclock, MMSE, FCSRT and CDR-SB. DCTclock uses a video tracking pen and automated scoring algorithm that reports total score for both command and copy components, as well as subscores representing functional areas including drawing efficiency, information processing, motor, and spatial reasoning. Anatomical MRI scans were processed in FreeSurfer v5.3 and vertex-wise statistical maps assessing relationships between cortical thickness and DCTclock scores were generated using FreeSurfer's Query, Design, Estimate, Contrast interface. A weighted SUVR was calculated in [18F]-Flortaucipir PET images to measure global tau load. Relationships between DCTclock metrics and the other measures were assessed with Spearman correlations and linear regression analyses. High correlations between DCTclock COPY test for information processing and both cognitive tests and cortical thickness were observed. Cognitive assessments all had similar distributions by amyloid status. Information processing in the copy test also correlated with global PET Tau signal. These results suggest that DCTclock is associated with other cognitive tests and information processing scored in the copy clock test may be the most relevant DCTclock score in screening AD subjects for entry into clinical trials. As with previous studies, DCTclock shows some associations with regional atrophy as well as pathology measured with PET but larger studies are warranted to verify these findings. Future work will investigate longitudinal measurements and test/re-test validity of the results.

Background: Subjective cognitive decline (SCD) is consistently associated with adverse affects, such as subclinical depression, anxiety, along with poor psychological well-being. However, detailed aspects of psychological stress, a potential predictor of brain alteration and cognitive decline, have rarely been studied in this group. We aimed to further characterize the affective profile of SCD by assessing rumination, stress coping, and psychological quality of life in this at-risk cohort. Methods: In total 60 individuals, 30 SCDs (70.665.4 years) and 30 healthy older adults (HO) (70.767.3), underwent cognitive evaluation and filled out self-reported questionnaires. We examined associations of global cognitive complaints (Every Day Cognition, ECog), global cognition (neuropsychological composite), cognitive response styles of rumination and distraction (Response Style Questionnaire RSQ), negative and positive stress coping (Stress Coping Questionnaire SVF-78), and quality of life (WHO Quality of Life WHoQol). Correlation and mediation analyses were conducted to highlight relationships between cognitive and affective variables. Results: In the total sample, cognitive complaints were significantly associated with higher symptom rumination, negative coping, and lower quality of life in the psychological domain (Table 1); with SCD reporting higher symptom rumination and lower quality of life when compared to HO. Mediation models corroborated a significant indirect effect of cognitive complaints on quality of life through symptom rumination (b1⁄4-5.9, CI: -13.06, -1.17) Similar relationships were not found for global cognition in the total sample. However, in the SCD group, lower global cognition was associated with negative coping strategies(r1⁄4-.40). Additionally, negative coping mediated the adverse impact of lower cognition on psychological well-being (b1⁄45.03 CI: .08, .75). Conclusions:Our findings suggest that symptom rumination and negative stress coping help form the psychological profile of SCD. In addition, these factors play a central role on how complaints and cognition compromise psychological well-being. Rumination and stress are associated with cognitive debt [1], which may increase the vulnerability of the brain and cognitive function to pathological changes. Interventions that target these specific affective factors may increase quality of life and reduce risk of future

4097 Background: TGFβ signaling is associated with HCC progression. Inhibition of TGFβ R1 potentiates activity of sorafenib in in-vitro and in-vivo models. Here we report the clinical activity of galunisertib (G) plus sorafenib (S) in pts with incurable HCC and no prior systemic therapy. Methods: Eligibility criteria included incurable HCC with measurable disease per RECIST 1.1, no prior systemic therapy, Child Pugh A, ECOG PS ≤1.G was administered as 80 mg PO BID (lead-in Cohort 1) or 150 mg PO BID (lead-in Cohort 2 and expansion cohort), as intermittent dosing of 14 days on/off (28 days = 1 cycle). S was administered continuously as a 400 mg PO BID. Primary objective was to characterize time-to-progression (TTP) and biomarker changes in pts. Secondary objectives included evaluation of OS, PK, and toxicity (CTCAE v 4.0). Results: 47 pts were enrolled (Cohort 1 = 3, Cohort 2 and expansion cohort = 44). In the 150 mg BID cohort: Male = 88.6%; median age = 64 years; PS = 0/1, 81.8%/18.2%; etiology: hepatitis C = 34.1%, hepatitis B = 18.2%, alcohol = 20.5%, multiple = 13.6%; AFP≥200 µg/L = 50%; portal vein invasion = 34.1%. Incidence of AEs was similar between G dose levels. Overall in the 150mg BID cohort, treatment related AEs ( > 15%) were hand and foot syndrome (61.4%), diarrhea (40.9%), pruritus (22.7%), anemia and weight loss (20.5%), fatigue (29.5%), alopecia (18.2%), myalgia (22.7%), decrease in platelet count and nausea (15.9%). Two pts on 150 mg BID discontinued treatment due to study drug related AEs (anemia and weight loss). PK of G at 150 mg BID (n = 12) when co-administered with S, was similar to that observed in the G monotherapy study. G was rapidly absorbed and had an elimination half-life of approximately 8h. Median TTP (RECIST) was 4.1 (2.8, 5.5) months. OS, with a high censor rate of 55% was not mature at the time of this data cutoff. Median OS was 17.9 (14.8, NE) months. Conclusions: The combination of G plus S demonstrated acceptable safety and a meaningful OS of 17.9 months in an advanced HCC population. TTP was similar to S monotherapy in contemporary clinical trials though interpretation is limited by single arm design. Clinical trial information: NCT01246986.

Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4+ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.

OBJECTIVE:Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor β (TGFβ) pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC) dry-milled (RCD) and RC slurry-milled (RCS) processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG) process. The secondary objective was to report the safety profile after a single dose of the three formulations.METHODS:Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK) parameters, including area under curve (AUC) and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests.RESULTS:Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast), AUC(0-48 h), and AUC(0-∞) for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation.CONCLUSIONS:In this relative bioavailability study comparing galunisertib formulations after a single dose, RCD and RCS formulations had similar exposure and safety profile compared with the HSWG formulation.

Abstract Background: Galunisertib, a selective transforming growth factor-β receptor1 inhibitor, is being investigated in clinical trials for hepatocellular carcinoma (HCC). MicroRNAs (miRs) are small (∼22 nucleotide) non-coding RNAs that regulate expression of targeted genes, and are secreted by cells into blood. miRs are differentially expressed during HCC progression, differentiation, and response to therapy. We hypothesize that circulating miRs may be useful to identify patients who benefit from galunisertib treatment. Patients and Methods: Plasma samples from HCC patients (n = 105) treated with galunisertib were analyzed for miR expression. Patients were enrolled in part A, of a multi-part single-arm study in 2nd-line HCC (phase II trial NCT01246986/JBAK). All patients had elevated alpha-fetoprotein (AFP) levels at baseline (AFP ≥1.5 x ULN). The median OS of this cohort of patients was 7.2 mo. Eighty percent of patients received prior sorafenib treatment. Plasma samples were collected during patient screening, cycle 1 day 1 (pretreatment), and cycle 2 day 14. The Exiqon RT microRNA PCR Human panel I+II was used to measure 752 miRs. Expression levels of detectable miRs and their association with overall survival (OS) were investigated. Results: Low plasma levels of miR-665 (HR = 0.50, p = 0.001, q = 0.13), miR-320d (HR = 0.44, p = 0.001, q = 0.13), miR-320a (HR = 0.47, p = 0.001, q = 0.13), and miR-130b-3p (HR = 0.44, p = 0.002, q = 0.13) are associated with better survival. Whereas, low plasma levels of miR-451a (HR = 2.0, p = 0.002, q = 0.13), miR-let7g-5p (HR = 2.3, p = 0.002, q = 0.13), and miR-18a-3p (HR = 2.0, p = 0.002, q = 0.13) are associated with poor survival. To assess within patient baseline biological variation of miR expression, a comparison of the expression of 369 miRs in patients (n = 42) with 2 pre-treatment samples was performed. The proportion of miRs attaining statistical significance was smaller than what we would expect by chance. Conclusions: Circulating miRs may serve as easily accessible markers to identify HCC patients who may benefit from galunisertib treatment, which requires confirmation in randomized controlled study. Given the low intra-patient variability measured at baseline for most of the miRs, circulating miRs may represent reliable molecular markers with prognostic and/or predictive utility. Citation Format: Shawn T. Estrem, Michael Man, Xuekui Zhang, Duytrac Nguyen, Danni Yu, Michael M. Lahn, Ann Cleverly, Durisala Desaiah, Sandrine Faivre, Gianluigi Gianneli, Karim A. Benhadji. Plasma microRNAs associated with overall survival in patients with hepatocellular carcinoma treated with galunisertib (LY2157299 monohydrate), an inhibitor of transforming growth factor-β receptor1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1076.

The combination of galunisertib, a transforming growth factor (TGF)-beta receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma.Galunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity.One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of similar to 8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR < 1) = 26%]. Median progression-free survival of similar to 2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS.Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms.NCT01582269, ClinicalTrials.gov.