Dose-limiting Toxicity Evaluation Research Articles

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

BackgroundThis Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.MethodsEligible 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).ResultsMaximum 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.ConclusionsSapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.Clinical trial registrationClinicalTrials.gov, NCT01058707.

A first-in-human phase I study of CYH33, a phosphatidylinositol 3-kinase (PI3K) α selective inhibitor, in patients with advanced solid tumors.

e15645 Background: PI3Kα is the only subtype in PI3K family of which activated mutations occur frequently in tumors. CYH33 is a potent PI3Kα–selective inhibitor with anti-tumor activity in xenograft models. An open-label, Phase I dose-escalation & expansion study of CYH33 monotherapy (NCT03544905) is underway in patients (pts) with advanced solid tumors. Methods: This study evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of CYH33 administered daily orally in 28-day cycles until intolerable toxicity or disease progression (PD). Adult pts with advanced solid tumors who have progressed despite standard therapies are enrolled to this trial, and pts with or without PIK3CA mutant are eligible for dose-escalation and pts with PIK3CA mutant are eligible for dose-expansion. Results: As of the cut-off date 20 Dec 2019, 17 pts (median age 47.0 y) were enrolled in the first 6 dose levels (1mg, 5mg, 10mg, 20mg, 40mg and 60mg) of the dose-escalation cohorts, and 3 pts were enrolled in expansion cohort of 40 mg. Cohorts 1 mg to 20 mg were completed without dose-limiting toxicities (DLT), cohort 40mg was completed with 1 DLT (Grade 3 hyperglycemia) out of 6 evaluable pts, and 3 enrolled pts at 60 mg are still in the DLT evaluation. Most frequent treatment-related adverse events (TRAEs) (all grades, ≥ 20%) included hyperglycemia (17 pts, 85%), decreased appetite (5 pts, 25%), diarrhea (4 pts, 20%). Grade≥3 TRAEs were hyperglycemia (8 pts, 40%), nausea (1 pt, 5%) and decreased appetite (1 pt, 5%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. The preliminary PK profile of CYH33 showed dose proportionality across the tested dose levels, half-life (t1/2) was about 20 hours with minimum accumulation, and the maximum concentration (Cmax) achieved 2-4 hours after dosing. Over all, among 15 tumor response evaluable pts, partial response (PR) was observed in 2 pts treated with 40mg (1 colorectal cancer with unknown PIK3CA mutation status, 1 breast cancer with PIK3CA mutant), and stable disease (SD) was observed in 3 pts with unknown PIK3CA mutation status. After the cut-off date, 1 more pt (ovarian cancer with PIK3CA mutation) treated with 40mg achieved PR, so that 2 out of 3 enrolled PIK3CA mutant pts treated with 40mg achieved PR. Conclusions: The first-in-human study of the PI3Kα selective inhibitor CYH33 demonstrated a manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. CYH33 single agent and in combination with other anti-tumor agents have be planned in future studies. Clinical trial information: 03544905.

Model of a Queuing Approach for Patient Accrual in Phase 1 Oncology Studies

Phase 1 cancer studies, which guide dose selection for subsequent studies, are almost 3 times more prevalent than phase 3 studies and have a median study duration considerably longer than 2 years, which constitutes a major component of drug development time. To discern a method to reduce the duration of phase 1 studies in adult and pediatric cancer studies without violating risk limits by better accommodating the accrual and evaluation process (or queue). The process modeled, the phase 1 queue (IQ), includes patient interarrival time, screening, and dose-limiting toxicity evaluation. For this proof of principle, the rules of the 3 + 3 and rolling 6 phase 1 designs were modified to improve patient flow through the queue without exceeding the maximum risk permitted in the parent designs. The resulting designs, the IQ 3 + 3 and the IQ rolling 6, were each compared with their parent design by simulations in 12 different scenarios. (1) The time from study opening to determination of the maximum tolerated dose (MTD), (2) the number of patients treated to determine the MTD, and (3) the association of the design with the dose selected as the MTD. Based on 800 simulations, for all 12 scenarios considered, the IQ 3 + 3 and the IQ rolling 6 designs were associated with reduced expected study durations compared with the parent design. The expected IQ 3 + 3 reduction ranged from 1.6 to 10.4 months (with 3.7 months for the standard scenario), and the expected reduction associated with IQ rolling 6 ranged from 0.4 to 10.5 months (with 3.4 months for the standard scenario). The increase in the mean number of patients treated in the IQ 3 + 3 compared with the 3 + 3 ranged from 0.6 to 3.2 patients. No increase in the number of patients was associated with the IQ rolling 6 compared with the rolling 6 design. The probability of selecting a dose level as the MTD changed by less than 3% for all dose levels and scenarios in both parent designs. This study found that IQ designs were associated with reduced mean duration of phase 1 studies compared with their parent designs without changing the risk limits or MTD selection operating characteristics. These approaches have been successfully implemented in both hematology and solid tumor phase 1 studies.

Abstract P3-09-19: Preliminary safety data of intrahepatic talimogene laherparepvec and intravenous atezolizumab in patients with triple negative breast cancer

Abstract Background Talimogene laherparepvec (T-VEC) is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and to produce granulocyte-macrophage colony-stimulating factor to enhance systemic antitumor immune responses. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with the checkpoint inhibitors (CPI) pembrolizumab and ipilimumab. Additionally, T-VEC monotherapy has demonstrated tolerable safety for intrahepatic injection (Hecht GICS 2018). Atezolizumab (atezo) is a humanized monoclonal antibody that promotes antitumor immunity by targeting programmed cell death ligand-1 (PD-L1) and is approved for metastatic triple negative breast cancer (mTNBC). We hypothesize that T-VEC in combination with a CPI may be effective in mTNBC and CRC in addition to melanoma. This phase 1b, multicenter study (clinicaltrials.gov identifier: NCT03256344) evaluates the safety of intrahepatic injection of T-VEC in combination with intravenous (IV) atezo in patients (pts) with mTNBC or colorectal cancer (CRC) with liver metastases (LMs). Here we report early safety data in the TNBC cohort. Methods Key eligibility criteria included age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG PS 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable LM suitable for injection. T-VEC (≤ 4mL) was injected by image-guided intralesional injection: 106 PFU/mL day 1, 108 PFU/mL every 21 days thereafter; atezo 1,200 mg IV was given on day 1 and every 21 days thereafter. The primary objective of this study is to evaluate incidence of dose limiting toxicity (DLT) for safety of T-VEC injection into LMs in combination with IV atezo, by tumor type. The DLT analysis set included DLT-evaluable pts who were on treatment for at least 6 weeks from the initial dose of study treatment and received at least 2 doses of T-VEC and 2 doses of atezo in combination or have a DLT during the DLT evaluation period. Key secondary objectives include objective response rate, durable response rate, progression-free survival, and overall survival of the combination therapy, by tumor type. Results Thirty-two pts were enrolled in two parallel cohorts (8 TNBC, 24 CRC). Of the 8 TNBC pts, 4 were evaluable for DLT at the time of this analysis. Of the 4 pts that were not DLT-evaluable, 1 never received study drug, 1 received atezo monotherapy, and 2 received intrahepatic T-VEC and IV atezo but stopped study drugs for unconfirmed progression before the DLT evaluation period was completed. No DLTs were reported in the TNBC cohort. In the 7 TNBC pts who received at least one dose of the study drug, the most common treatment-emergent adverse events (TEAEs) in terms of the subject incidence were pyrexia (71.4%), chills (42.9%), and rash (42.9%). In the 7 TNBC pts who received at least one dose of study drug, T-VEC related AEs in more than one pt were pyrexia (n=3) and chills (n=2). Atezo related AEs in more than one pt were pyrexia (n=5), chills and rash (n=3 each), and fatigue, arthralgia, pain, and pruritus (n=2 each). Study drug-related serious adverse events (SAEs) occurred in 3 (42.9%) pts, including Grade (G) 3 hypersensitivity related to atezo, G3 orthostatic hypotension related to T-VEC and atezo, and G1 pyrexia related to T-VEC and atezo. Procedure-related SAEs occurred in 1 (14.3%) pt, of G3 hepatic hematoma and G3 abdominal infection, but these were not related to the study drugs. One confirmed partial response in the TNBC cohort has been seen thus far. Conclusion T-VEC intrahepatic injection in combination with IV atezo at standard doses has thus far been demonstrated as feasible and tolerable with no DLTs observed in the TNBC cohort to date. Citation Format: Joel Randolph Hecht, Arlene Chan, Jean-Francois Baurain, Miguel Martin, Federico Longo-Munoz, Kevin Kalinsky, Steven Raman, Chunxu Liu, Edward Cha, Emily Chan. Preliminary safety data of intrahepatic talimogene laherparepvec and intravenous atezolizumab in patients with triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-19.

Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma.

BackgroundDimethyl fumarate (DMF), an oral agent approved for the treatment of relapsing–remitting multiple sclerosis (RRMS), has promising preclinical activity against glioblastoma (GBM). This phase I study sought to determine the recommended phase 2 dose (RP2D) of DMF and evaluate its safety and toxicity when combined with standard concurrent radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ in patients with newly diagnosed GBM.MethodsUsing a standard 3 + 3 dose-escalation design with 3 dose levels, patients received daily DMF with 60 Gy RT and concurrent TMZ 75 mg/m2 daily, followed by maintenance DMF (continuously) and TMZ 150–200 mg/m2 on days 1–5 of each 28-day cycle for up to 6 cycles. The maximum tolerated dose (MTD) was determined by evaluation of dose-limiting toxicity (DLT) during the first 6 weeks of therapy.ResultsTwelve patients were treated at the 3 dose levels, and no DLTs were observed. There were no unexpected toxicities. The most common grade 3/4 treatment related adverse events (AEs) were lymphopenia (58%), decreased CD4 count (17%), and thrombocytopenia (17%). Four patients completed all planned treatment; seven patients had progression on treatment. One patient chose to withdraw from the study during maintenance. The median progression-free survival (PFS) for all patients was 8.7 months with no difference in PFS between those with stable disease or a partial response; median overall survival was 13.8 months.ConclusionsDMF may be safely combined with RT and TMZ in patients with newly diagnosed GBM. The RP2D for DMF is 240 mg three times daily.

Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

HM43239, a Novel Potent Small Molecule FLT3 Inhibitor, in Acute Myeloid Leukemia (AML) with FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1 /2 Study

Background: HM43239 is an orally active small molecule inhibitor of FLT3 that selectively inhibits not only FLT3 wild type, ITD mutants or TKD mutations, but also FLT3 ITD/TKD double mutations. HM43239 directly inhibits the kinase activity of FLT3 as a reversible Type I inhibitor and effectively modulates downstream p-STAT5 and p-ERK. HM43239 also demonstrated inhibition of SYK, JAK1/2 and TAK1, known to be involved in tumor cell proliferation and/or differentiation HM43239 monotherapy induced dose-dependent regression of tumor growth in FLT3 wild-type and FLT3 mutated leukemia cancer cell lines (Poster presented at AACR 2018; Abst.804 and also prolonged survival in a FLT3 ITD/TKD double mutated xenograft mouse model (Poster presented at AACR 2019; Abst.1293). The anti-leukemic activity of HM43239 monotherapy was evaluated in in vivo studies that suggested the ability of this agent to potentially target LSCs (Poster presented at AACR 2019; Abst.1293). Preclinical studies suggest that HM43239 may be an effective agent in patients with hematologic malignancies including AML, to target various mutant types of FLT3. Herein, we present a clinical trial design to assess the potential clinical activity and safety of HM43239 in patients with AML. This phase I/II clinical trial (NCT03850574) consists of dose escalation (Part A) and dose expansion (Part B) stages to access the overall safety and efficacy findings. Trial Design: This is an ongoing, open-label, multicenter, first in human, phase I/II trial enrolling adult patient with AML who relapsed or have refractory disease after at least one prior line of therapy. Patients were treated with HM43239 once daily (QD) in 28-day cycle except for the first 30-day cycle including a single PK sampling period. This trial comprises two parts: dose escalation and dose expansion. During dose escalation, the study follows an accelerated titration design, with around 50% dose increments and 1 patient per dose level. Accelerated titration will continue until 1 patient experiences a dose-limiting toxicity (DLT) or moderate toxicity (MT), drug-related grade 2 adverse event (except for hematologic toxicities), at any dose level, after which, a 3 + 3 dose escalation design will be used. If a patient achieves a clinical response [complete remission (CR), complete remission with low platelets (CRp), complete remission with incomplete hematologic recovery (CRi) or partial remission (PR)] at any dose level in escalation cohort, then an expansion cohort will be open at that dose level. Based on the evaluation of DLTs and composite complete remissions (CRc) from the dose escalation cohorts, additional subjects may be recruited in expansion cohorts at each dose level selected for expansion. At least 10 subjects with FLT3 mutations (ITD or activating point mutations such as D835Y, D835V, I836) will be enrolled to each dose level selected for expansion (including the subjects from the dose escalation cohort). Blood samples are collected for pharmacokinetics (PK) & pharmacodynamics (PD) evaluation and for exploratory biomarker analysis in both cohorts. A 2-parameter Bayesian logistic regression will be used to model the dose-toxicity relationship on DLT in dose escalation and expansion parts and the estimated DLT rate will be provided as supportive reference for dose escalation procedure and safety monitoring. The primary endpoint is the assessment of pharmacokinetics, safety and tolerability in order to determine the recommended phase 2 dose (RP2D). Secondary endpoints include best response rate [CRc (CRc=CR+CRp=CRi)+ PR], duration of response, event free survival, overall survival, cumulative incidence of relapse of HM43239. PK-PD relationships and PD evaluated by plasma inhibitory assay (PIA) are exploratory endpoints. At first, this trial was initiated in Jan 2019 and an enrolled patient has been evaluated since May 2019. Dose level 1 (20 mg) was completed without any DLTs; enrollment to next dose level (40 mg) was initiated in June 2019 . This new cohort is currently recruiting patients in the Republic of Korea and the USA. Clinical trial information: NCT03850574. 3,800 characters allowed 3,580 characters in abstract Disclosures Daver: Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Agios: Consultancy; Otsuka: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; Astellas: Consultancy; Incyte: Consultancy, Research Funding; Servier: Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding.

Preliminary Analysis Results of a Phase I Study of the FLT3 Inhibitor SKLB1028 in Patients with Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia

Background: Mutations of FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) are associated with poor prognosis. SKLB1028, a novel multikinase inhibitor, has shown exceptional antileukemic activity in mouse xenograft models of FLT3-driven AML. Preclinical data has demonstrated that SKLB1028 has anti-proliferation and pro-apoptosis effects on tumor cells in vitro and in vivo, and prolonged survival in SKLB1028-treated mice has been observed in a dose-dependent manner (Cao et al., Leukemia, 2012). The present study is to assess the safety, tolerability and pharmacokinetics (PK) of SKLB1028 in patients with relapsed/refractory (R/R) FLT3-mutated AML. Here we report the preliminary analysis results of the study. Methods: An open label, 3+3 cohort dose escalation, single arm, phase I study was conducted in adult patients with FLT3-mutated AML who were refractory to or relapsed after ≥ 1 cycle of induction chemotherapy and had an Eastern Cooperative Oncology Group performance status of ≤ 3. Dose cohorts of at least 3 patients received study drug following a sequential dose-escalation design with 20 mg/day as the lowest dose level. For each dose level, patients were firstly given 1 dose of SKLB1028 as an oral capsule followed by 72-hour observation in the single-dose PK period. Then the patients entered the repeated-dose period from day 1, cycle 1, and received oral SKLB1028 once per day in a 28-day cycle. Observations of dose limiting toxicities (DLTs) were recorded through cycle 1. For a specific dose level, if a DLT was observed during the first cycle in 1 patient, 3 additional patients were enrolled at that level. If a second DLT was observed within the same dose cohort, escalation was discontinued, and maximum tolerated dose (MTD) was defined as the immediately lower dose level. Patient who had completed cycle 1 and did not experience a DLT or disease progressionduring cycle 1 could continue receiving SKLB1028, at the discretion of the investigator, until disease progression or intolerable toxicity occurred. The primary endpoints were safety and tolerability. Secondary endpoints included PK and efficacy. Analyses of safety (e.g. DLT and adverse event (AE)) and efficacy parameters (e.g. complete response (CR) and partial response (PR))were performed using descriptive statistics on safety analysis set and full analysis set respectively. PK parameters were estimated using non-compartmental analysis on PK analysis set. Results: Twenty-eight patients with a median age of 50 years (range 19-70 years) were enrolled. The median number of prior regimens was 3.5 (range 1-9). Patients received a median of 2.5 cycles (range 1-15)of therapyin 8 dose cohorts: 20, 40, 80, 120, 160, 200, 250, and 310 mg/day. Three patients discontinued from the study due to AEs. For a subject to be eligible for DLT evaluation, he/she should have received 100% of the planned (28) doses of SKLB1028 in cycle 1, unless the doses were omitted for DLT defining event. Two patients did not complete the first treatment cycle, 1 because of DLT and 1 because of withdrawal of consent. Twenty-seven patients were evaluable for DLT.One patient in the 200 mg cohort experienced DLT (Grade 3 hepatic function abnormal). Among 3 additional patients at this dose level, no DLTs occurred again. The most common treatment-emergent AEs of any grade (regardless of causality) were pyrexia (67.9%), diarrhoea (64.3%), asthenia (53.6%), dizziness (50.0%). There was no death attributed to the use of SKLB1028. The MTD had not been reached. Among the 28 patients treated, only 26 patients were evaluable for efficacy. Two patients were not enlisted due to premature discontinuation of study drug in cycle 1; 1 for DLT and the other for withdrawal of consent. Of 28 patients in the full analysis set, overall response rate (ORR) was 21.4% (6/28) with 1 CR, 5 PR, 20 stable disease and no progressive disease as the best response. One patient achieved CR at the does of 250 mg/day. Of the 5 patients with PR, 1 was in the 160mg cohort, 3 in the 200 mg cohort, and 1 in the 310 mg cohort. The ORR for the 160 mg, 200 mg, 250 mg, and 310 mg cohort of 16 patients was 37.5% (6/16). Conclusions: The results of our preliminary analysis suggested that SKLB1028 is safe, well-tolerated and effective for R/R FLT3-mutated AML patients. Larger studies are needed to more comprehensively assess the safety and efficacy of SKLB1028 in this population. This trial is registered at Clinical Trials.gov, number NCT02859948. Disclosures Yao: CSPC Zhongqi: Employment. Wang:CSPC Zhongqi: Employment. Zhan:CSPC Zhongqi: Employment. Ni:CSPC Zhongqi: Employment. Qiao:CSPC Zhongqi: Employment. Hu:CSPC Zhongqi: Employment.

Safety and Preliminary Clinical Activity of REGN5458, an Anti-Bcma x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Safety and Preliminary Clinical Activity of REGN5458, an Anti-Bcma x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Abstract CT024: Early safety from an open label Phase I study to evaluate the safety and efficacy of a telomerase-specific oncolytic adenovirus (OBP-301) with pembrolizumab in patients with advanced solid tumors. (EPOC1505)

Abstract Background: PD-1 blockade showed promising efficacy for broad type of cancer patients (pts), though objective response rates are very limited. The antitumor potential of oncolytic adenoviruses has been demonstrated in preclinical and clinical studies. In addition to the specific killing of cancer cells via oncolytic adenovirus, these agents prompt the immune system to stimulate an antitumor immune response. OBP-301 is an oncolytic adenovirus in which gene is modified to be able to selectively replicate in cancer cells by introducing human telomerase reverse transcriptase (hTERT) promotor. Further antitumor effect might be expected with an active activation of two different antitumor immunity by OBP-301 in combination with pembrolizumab. Therefore, we conducted phase I study to evaluate the safety and efficacy of OBP-301 with pembrolizumab. Methods: The major eligibility criteria are pts with advanced or metastatic solid tumor not responded to or intolerant of standard chemotherapies, and with possibility of intratumoral injection. Phase Ia part was designed to determine the recommended dose in a “3+3” cohort-based dose escalation design of OBP-301 (1x1010VP on cohort 1, 1x1011VP on cohort 2 and 1x1012VP on cohort 3) with pembrolizumab (200mg/body q3w). OBP-301 is administered at day1, 15, and, 29 by intratumoral injection and pembrolizumab is administered at day 8 and thereafter every 3 weeks. Primary endpoint is dose limiting toxicity (DLT). Secondary endpoint is response rate, progression free survival, and incidence of adverse event. Phase Ib part was designated to evaluate the safety and efficacy of the recommended dose OBP-301 selected in phase Ia part in combination with pembrolizumab in 10 pts. Biomarker study was planned using paired samples of both tumor biopsy and blood. Clinical trial information: NCT03172819. Results: The first patient was enrolled on 7 Dec 2017; the last patient in phase Ia part was enrolled on 12 Oct 2018. Nine DLT-evaluable pts were enrolled and treated in phase Ia part: median age was 59; 2/9 female; 8/9 esophageal squamous cell carcinoma, 1/9 gastric adenocarcinoma. No DLT was observed during the DLT evaluation period. The most common adverse events were fever (Gr.2: 2/9, Gr.1: 2/9), hepatic disorder (Gr.3: 1/9, Gr.1: 1/9), pleural effusion (Gr.1:1/9). Preliminary efficacy assessment of phase Ia by investigators’ judgment demonstrated 2 PRs of the 9 pts. Conclusion: The combination of OBP-301 with pembrolizumab was well tolerated in tested doses. The recommended dose for phase Ib part is 1x1012VP (cohort 3), and additional 10 pts will be enrolled to obtain additional safety and efficacy data. Preliminary result of biomarker analyses using paired samples of both tumor biopsy and blood will be presented. Citation Format: Takashi Kojima, Toshiyoshi Fujiwara, Yasuhiro Shirakawa, Keisuke Hori, Hiromi Ono, Masako Nakamoto, Nami Hirano, Masashi Wakabayashi, Shogo Nomura, Yosuke Togashi, Hiroyoshi Nishikawa, Akihiro Sato, Atushi Ohtsu, Toshihiko Doi. Early safety from an open label Phase I study to evaluate the safety and efficacy of a telomerase-specific oncolytic adenovirus (OBP-301) with pembrolizumab in patients with advanced solid tumors. (EPOC1505) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT024.

PS1344 PHASE 1/2 STUDY OF DSP‐7888 IN PATIENTS WITH HIGHER‐RISK (HR) MYELODYSPLASTIC SYNDROMES (MDS) AFTER FAILURE OF AZACITIDINE (AZA) THERAPY

Background:Although azacitidine (AZA) is the standard frontline therapy for higher‐risk (HR) myelodysplastic syndromes (MDS), approximately 40% of patients fail to respond and almost all responders eventually relapse. The prognosis for patients after AZA failure is poor with no approved therapeutic options and a median overall survival (OS) of approximately 6 months from treatment failure (Prebet T, et al. J Clin Oncol. 2011;29:3322–7.). Wilms’ tumor 1 (WT1) is constantly expressed in the leukemic cells of acute leukemia and MDS, and it is considered a prominent therapeutic target for MDS. DSP‐7888 is a WT1‐based cancer vaccine containing peptides that induce WT1‐reactive cytotoxic T lymphocytes and helper T cells. A partial peptide of DSP‐7888, WT4869 showed preliminary clinical activity in HR‐MDS (Ueda Y, et al. Cancer Sci. 2017;108:2445–53.). We hypothesized that DSP‐7888 could have significant clinical activity in HR‐MDS.Aims:This uncontrolled, open‐label, multicenter Phase 1/2 clinical trial was designed to determine the recommended dose (RD) of DSP‐7888 and evaluate its safety and clinical activity, including OS, in patients with HR‐MDS after AZA treatment failure (NCT02436252).Methods:The RD of DSP‐7888 was determined in Phase 1 using a 3+3 design that included two dose levels (3.5 and 10.5 mg/body). Eligible patients had HR‐ or lower‐risk MDS but not chronic myelomonocytic leukemia or refractory anemia with excess blasts in transformation. To evaluate clinical activity, the Phase 2 trial included 42 patients with MDS who showed no response to AZA treatment (including eligible patients from Phase 1). Patients were administered DSP‐7888 in solution intradermally with the RD—100 μL at six sites for 10.5 mg. Study drug was given every 2 weeks for 6 months and then every 2 to 4 weeks until no clinical benefit was seen. The primary endpoint was OS. Written informed consent was obtained from all patients.Results:Overall 47 patients received DSP‐7888 in Phase 1 (n = 12) and Phase 2 (n = 35). No dose‐limiting toxicities (DLT) were observed for 3.5 mg or 10.5 mg in the DLT evaluation period (first 2 cycles of DSP‐7888 in Phase 1). RD was determined to be 10.5 mg.The safety population included all patients who received the study drug (N = 47). The most common adverse events (AEs) were injection site reactions (ISR) in 91.5% (n = 43) of all patients; 27.9% were grade 1, 37.2% grade 2, 34.9% grade 3, and no grade 4. Other than ISR, AEs related to study drug seen in >5% included pyrexia (10.6%) and febrile neutropenia (8.5%).The Phase 2 clinical activity analysis was performed on patients with HR‐MDS (N = 42) and included those from Phase 1 who met the criteria (n = 7); 76.2% were male and median age was 74.0 years (range: 63–93). The median OS was 8.5 months (90% CI: 6.8–11.1). The disease control rate was 19.5% with a median duration of response of 2.7 months. (The disease control rate included patients who had achieved a complete response [CR], partial response, marrow CR, or stable disease.) Hematologic improvement was seen in 9.8% of patients. The median time to transformation to acute myeloid leukemia or death was 5.7 months (90% CI: 3.6–7.1).Of the 42 patients, 37 were evaluable for WT1 reactive immune response and the results are shown in the Table.Summary/Conclusion:DSP‐7888 was tolerable and showed signs of clinical activity in patients with HR‐MDS; those who had a positive immune response showed a significantly longer OS than those who were negative. Identifying the optimal population for treatment with DSP‐7888 is important for further investigations.image

A phase I study of [225Ac]-FPI-1434 radioimmunotherapy in patients with IGF-1R expressing solid tumors.

TPS3152 Background: Type I insulin-like growth factor receptor (IGF-1R) is a transmembrane protein which is overexpressed in solid tumors including non–small cell lung, prostate, and breast cancers. [225Ac]-FPI-1434 is a radioimmunoconjugate consisting of a humanized monoclonal antibody that binds to the external domain of IGF-1R, a proprietary bifunctional chelate, and an alpha-emitting radionuclide actinium-225 (Ac-225), which binds to the external domain of IGF-1R. Internalization of the conjugate and decay of Ac-225 causes tumor cell death primarily through double stranded DNA breaks. The indium-111 analog, [111In]-FPI-1547, with the identical antibody and bifunctional chelate is used for patient selection, in-vivo imaging, and quantification of IGF-1R targets prior to therapy. Based on anti-tumor activity of [225Ac]-FPI-1434 in preclinical models, favorable toxicology studies in cynomolgus monkeys, and prior human experience with the unconjugated antibody, the first in human clinical evaluation was initiated. Methods: This open-label multi-center phase I study (NCT03746431) follows a modified 3+3 dose-escalation design to characterize the safety profile, determine a maximum tolerated dose (MTD), evaluate dose-limiting toxicities (DLT), describe pharmacokinetics, derive radiation dose estimates to normal organs, and evaluate the objective response rate of [225Ac]-FPI-1434 therapy in patients with IGF-1R expressing solid tumors. Eligibility requirements for therapy include: presence of at least one measurable lesion as determined by sufficient tumor uptake using SPECT/CT of an imaging analog [111In]-FPI-1547; radiation dose estimates of the planned therapeutic activity within prespecified limits; and adequate bone marrow reserves, hepatic, and renal function. Dose cohorts begin with 10 kBq [225Ac]-FPI-1434 per kilogram (kg) patient weight and successively increase to 20, 40, 80, and 120 kBq/kg as a single intravenous injection per patient followed by an 8-week DLT evaluation period. This trial is currently enrolling patients. Clinical trial information: NCT03746431.

3488 A comparison between the Rolling 6 and 3+3 dose escalation study designs for phase 1 clinical trials

OBJECTIVES/SPECIFIC AIMS: The development of new anti-cancer agents for children requires an inherently longer timeline than in adults. The 3+3 study design for Phase 1 dose escalation trials is commonly used to estimate the maximum tolerated dose and assess safety. The Rolling 6 study design was developed to shorten the study conduct timeline. METHODS/STUDY POPULATION: This study compares twenty Phase 1 COG Pilot and Phase 1 Consortium trials that employed the Rolling 6 design with hypothetical results under the assumption that a 3+3 design had been executed. The number of evaluable patients required to complete the study, number of DLTs, number of inevaluable patients, overall study duration, time suspended to enrollment (i.e., waiting for DLT evaluation), and DLT risk are compared between study designs using Wilcoxon’s signed rank test. RESULTS/ANTICIPATED RESULTS: The Rolling 6 study design required less time to complete the studies compared with 3+3 design (median 273 vs. 297 days, P = 0.01). In general, the Rolling 6 study design required more patients, had more inevaluable patients, and there were more dose limiting toxicity (DLT) events. However, there was no significant difference in DLT risk (median 0.15 vs. 0.17, P = 0.72). DISCUSSION/SIGNIFICANCE OF IMPACT: The Rolling 6 study design effectively shortens the study conduct timeline compared with the traditional 3+3 design for Phase 1 COG Pilot and Phase 1 Consortium trials without increasing the risk of toxicity.

Evaluation of safety and tolerability of durvalumab (D) and tremelimumab (T) in combination with first-line chemotherapy in patients (pts) with esophageal squamous-cell carcinoma (ESCC).

146 Background: Platinum-doublet chemotherapy in first-line (1L) ESCC pts has reached a therapeutic plateau, and new therapeutic strategies are needed. Adding D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) to 1L platinum-based chemotherapy may improve outcome in pts with advanced/metastatic ESCC. Methods: In Part A of this Phase 1b study (NCT02658214), dose-limiting toxicities (DLTs) for D+T (D 1.5 g + T 75 mg on d1, q4w) plus 5-FU+cisplatin (5-FU 800 mg/m2 + cisplatin 80 mg/m2 d1-5, q4w) were evaluated for the first 4 cycles in pts with advanced/metastatic ESCC who were eligible for 1L chemotherapy. The primary objective was safety and tolerability and exploratory objectives included antitumor activity and biomarker analysis. Results: Pts (N = 6) were enrolled to receive D+T + 5-FU+cisplatin between November 13, 2017, and February 14, 2018. Median age was 56 years, 83% were male, and all were ECOG PS 1. Four pts had recurrent disease and 2 were newly diagnosed with advanced/metastatic disease. All 6 pts had ≥1 treatment-related adverse event (trAE), 3 pts had grade ≥3 trAEs. All pts experienced 5-FU+cisplatin-related AEs. All grade ≥3 trAEs were neutropenia and considered due to 5-FU+cisplatin treatment; 2 were grade 3 and 1 was grade 4, which was the only serious trAE reported. Two pts had D- and/or T-related trAEs. Immune-mediated AEs were grade 1 or 2 and included diarrhea (n = 1), pruritus (n = 1), rash (n = 1), and increased AST (n = 1). There were no trAEs that led to discontinuation or death. Two of the 6 pts had a confirmed partial response that was ongoing at data cutoff (June 29, 2018). Conclusions: For patients in the ESCC DLT evaluation cohort, D+T + 5-FU+cisplatin was tolerable, and no unexpected toxicities occurred. No DLTs were observed for this regimen. The majority of trAEs and all trAEs grade ≥3 were attributed to 5-FU+cisplatin, and all were manageable. AEs related to D and/or T were all grade 1 or 2. No treatment discontinuation or death was attributed to trAEs. The study has been expanded to further evaluate this regimen in additional patients for efficacy, safety, and biomarkers. Clinical trial information: NCT02658214.

Phase 1 Results from a Phase 1/2 Study to Assess the Safety, Tolerability and Recommended Phase 2 Dose (RP2D) of Brentuximab Vedotin Plus Doxorubicin, Vinblastine and Dacarbazine (A+AVD) in Pediatric Patients (Pts) with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma (cHL)

Background:Pediatric pts with cHL have better responses to therapy compared with adult pts; however, the combination regimens and radiotherapy used in treatment can result in significant morbidity. Including brentuximab vedotin as a component of multi-agent chemotherapy for pediatric pts with newly diagnosed HL may provide clinical benefit by decreasing the need for radiotherapy following chemotherapy, and reducing the risks of late effects associated with radiotherapy, including secondary malignancies, cardiac toxicity and thyroid dysfunction. The phase 1 portion of the study assessed the safety, tolerability, and RP2D of brentuximab vedotin when combined with doxorubicin, vinblastine, and dacarbazine (AVD) for frontline treatment of advanced stage cHL in pediatric pts.Methods:Eligible pts were aged 5 to <18 years, with treatment-naïve stage III/IV cHL, a Lansky Play/Karnofsky Performance Status of ≥50, and bidimensional measurable disease by radiography. Pts received up to six 28-day cycles of 48 mg/m2 brentuximab vedotin with AVD on days 1 and 15 of each cycle. RP2D was confirmed according to a modified 3+3 design; at least three pts were monitored for dose limiting toxicities (DLTs) during the evaluation period (cycle 1+28 days; from the first dose through study day 56), if 0/1 DLTs were observed, at least 3 additional pts were enrolled and monitored for DLTs. Toxicity was evaluated according to the NCI CTCAE, v4.03. The primary endpoints were to determine the RP2D of brentuximab vedotin in combination with AVD, and to assess treatment-emergent adverse events (AEs) and serious AEs (SAEs) from the first dose of treatment through 30 days after the last dose; pharmacokinetics (PK) was a secondary endpoint. G-CSF use was not permitted in the DLT-evaluation period.Results:Eight pts were enrolled (50% male), age range 6-17 years, with advanced stage cHL (stage III, n=5; IV, n=3) one of whom had bone marrow involvement. Four pts (50%) had two extra-nodal sites of involvement and four pts (50%) had no extranodal involvement. Two pts were not DLT-evaluable due to the administration of G-CSF under the original protocol. Of the six DLT-evaluable pts, all completed the 56-day DLT evaluation period with no DLTs reported. The RP2D of brentuximab vedotin was confirmed as 48 mg/m2. All pts reported at least one treatment-emergent, treatment-related AE during the DLT-evaluation period. During the DLT-evaluation period, 10 grade 4 AEs were reported, all treatment-related: neutrophil count decrease or neutropenia (n=7) and white blood cell (WBC) count decrease (n=3). One pt reported a treatment-related SAE of grade 3 febrile neutropenia for a duration of 2 days. Fifteen additional grade 3 AEs included: vomiting (n=3), WBC decreased (n=4), neutrophil count decreased or neutropenia (n=7), mucositis (n=1), and headache (n=1, not treatment related). Treatment-related AEs in pts who were not DLT-evaluable included: grade 4 neutropenia (n=3), grade 3 neutrophil count decrease (n=4), and grade 3 WBC decreased (n=1); non treatment-related AEs (1 each; grade 3) were leukopenia, anemia, and aspartate aminotransferase increase. Dose delays during the DLT-evaluation period were due to neutrophil count decrease/neutropenia (n=6) and mucositis (n=1). Currently, 5 of the Phase 1 patients continue on treatment while 3 patients have completed all 6 cycles. Full Phase 1 AE data will be provided. PK concentrations were within target range and consistent with two prior brentuximab vedotin studies: Phase 3 ECHELON-1 study (C25003; NCT01712490) and C25002 pediatric study (NCT01492088).Conclusions:The safety, tolerability, and PK profile of brentuximab vedotin were consistent with its expected profile, and a dose of 48mg/m2 was confirmed as the RP2D. Phase 2 is currently open for enrollment in the USA, Italy, Singapore, Taiwan, Hong Kong, Japan, and Brazil. Clinicaltrials.gov NCT02979522. DisclosuresZecca:Chimerix: Honoraria. Song:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suri:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Leonard:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Takeda Pharmaceutical Company Limited: Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

Preliminary Clinical Results of a Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ B-Cell Lymphoma

Preliminary Clinical Results of a Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ B-Cell Lymphoma

Intensified Dosing of Gemtuzumab Ozogamicin Can be Safely Combined with Induction Chemotherapy in Children with Acute Myeloid Leukaemia (AML) and High Risk Myelodysplasia (MDS)

BACKGROUNDAlthough the overall survival for children with AML has serially improved due to better supportive care, intelligent use of transplant in 1st complete remission (CR1), and better salvage in CR2, the relapse rate (RR) in CR1 remains unacceptably high at 30-35%. Increasing the intensity of induction chemotherapy may improve outcome. Intensifying anthracycline dosage in induction has been reported to improve outcome in adult AML1, but this remains unproven in children in whom anthracycline-related cardiotoxicity is a major concern. Gemtuzumab ozogamicin (GO), the anti-CD33-calicheamicin conjugated antibody is the most promising new drug being explored in AML treatment presently. Cardiac myocytes do not express CD33 and therefore GO may enable intensification of induction chemotherapy without increasing cardiotoxicity. In children, GO is given as a single 3 mg/m2 dose, however the optimum dose, schedule and timing when combined with chemotherapy remains uncertain.METHODSA dose finding study (DFS) to establish the optimum tolerated number of 3 mg/m2 GO doses that can be combined with induction treatment: cytarabine plus mitoxantrone or liposomal daunorubicin (LD) was embedded within MyeChild 01; an international randomised phase III study for children with AML and high risk MDS.This major DFS recruited pts aged ≥12 months and <18 years. A minor DFS recruiting pts aged ≥12 weeks and <12 months is ongoing. The dose schedule for GO 3 mg/m2 was studied in course 1 only: cohort 1: GO d4, cohort 2; GO d4 and 7 and cohort 3; GO d4, 7 and 10.High-risk patients (defined by poor risk cytogenetics and/or a failure to achieve remission) received fludarabine, cytarabine and idarubicin for course 2. All other patients received a second course of the randomised therapy.Progression to next cohort was determined by an independent data monitoring committee (DMC) taking into account known toxicities of the induction chemotherapy. Dose limiting toxicities (DLTs) were defined as neutrophils ≤1.0 x109/l by d45 post course 1 or 2, non-transfusion dependent platelets ≤80 x109/l by d45 post course 1 or 2 due to documented bone marrow aplasia/hypoplasia and non-haematological events: death from any cause other than AML, veno-occlusive disease (VOD) and any grade ≥3 non-haematological toxicity persisting for >48 hours without resolution to grade ≤2 with specific protocol defined exceptions.RESULTSAt data cut-off (27 July 2018), 55 pts were recruited, of which 51 were AML, 1 MDS, 2 myeloid sarcoma and 1 APL (not dosed as ineligible) (Table 1). The chemotherapy randomisation was not balanced in cohort 3 due to suspension of the randomisation when LD became unavailable due to a manufacturing failure; 39 pts received cytarabine with mitoxantrone and 15 cytarabine with LD. Post-course 1, 22 (40%) were stratified as high risk.54 patients were dosed with GO. In cohort 1; 15 pts received GO 3 mg/m2 on d4; 5 were added as an expansion cohort on the recommendation of the DMC due to 2 patients having unevaluable haematological toxicities. Cohort 2; 20 pts received GO 3 mg/m2 on d 4 and 7. Both cohorts have completed the DLT evaluation period. In cohort 3; 19 pts received GO 3 mg/m2 on days 4, 7 and 10. The DLT evaluation period is near completion for all cohort 3 pts and the data will be presented.Table 2 presents grade ≥3 AEs at data cut off. 29 DLTs were reported, 6 in cohort 1 and 14 in cohort 2. In cohort 3, 9 DLTs are reported but 13 pts are still in the DLT evaluation period. The commonest DLTs were failure to recover either neutrophil or platelet count by d45 post course 1 or 2. DMC review confirmed the reported DLTs for cohorts 1 and 2 were consistent with expected toxicity from the combined chemotherapy alone. Six cases of VOD were reported, all outside the DLT evaluation period, none were fatal.CONCLUSIONSThe preliminary findings indicate that 2 doses of 3 mg/m2 GO combined with induction chemotherapy is well tolerated in this patient population, consistent with data from adult AML studies. The DMC concluded for cohorts 1 and 2 that the reported toxicities, including myelosuppression and non-haematological toxicities did not exceed the expected events associated with intensive induction chemotherapy in the absence of GO and there was a notable absence of significant DLTs. There was no apparent difference in AEs between mitoxantrone or LD arms. Cohort 3 DLT reporting is ongoing and the data will be presented.Lowenberg, NEJM 2009; Ohtake, Blood 2011. [Display omitted] DisclosuresGibson:Pfizer: Research Funding; Galen: Research Funding. Houlton:Pfizer: Research Funding. Baruchel:Novartis: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Celgene: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Servier: Consultancy; Roche: Consultancy. Wheatley:Pfizer: Research Funding. Kearns:Galen: Research Funding; Pfizer: Consultancy, Research Funding.

Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

196P - HGCSG1403: Phase I trial of oxaliplatin/irinotecan/S-1 (OX-IRIS) as first-line chemotherapy for unresectable pancreatic cancer

Background: In recent years, FOLFIRINOX has become one of the primary standard treatment for unresectable pancreatic cancer (PC) with distant metastasis. OX-IRIS is the combination therapy of oxaliplatin (L-OHP), irinotecan (IRI) and S-1. It is the useful treatment to dispense with a continuous infusion of 5FU by administering S-1 orally. For establishing OX-IRIS therapy as a new standard treatment, we planned this study. Methods: Chemotherapy-naïve patients with unresectable PC were included. L-OHP and IRI were administered on day 1 and 15, and S-1 was taken twice a day in day 1-14, and 14 days were rest for 1 cycle. This study used a standard 3 plus 3 design, and we evaluated safety and tolerability in 3 to 6 cases of each levels. It was assumed until 1 cycle completion for the evaluation period of dose limiting toxicity (DLT). Maximum tolerated dose (MTD) was defined as the highest dose beyond a more of one-third within DLT evaluation period. The primary endpoint was the frequency of DLT and MTD. Secondary endpoints were the frequency of adverse events, response rate, progression-free survival (PFS) and overall survival (OS). Results: Between January 2016 and August 2017, 13 cases were enrolled. The patients’ backgrounds were median age 62 years old, man/woman; 9/4, the primary tumor sites head/body and tail; 8/5, ECOG PS 0/1; 7/6, UR-LA/UR-M; 4/9. Two of five patients enrolled in level 0 (L-OHP: 85 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2) had DLT. In two of eight patients enrolled in level -1 (L-OHP: 65 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2), DLT was impossible to evaluate because the treatment of 1 cycle was not accomplished. And one of remaining six cases had DLT. At level 0, 100% of cases had anemia and fatigue, 80% had anorexia, diarrhea, peripheral sensory neuropathy, 60% had platelet count decrease. At level -1, 100% of cases had anemia, 75% had nausea and fatigue, 63% had anorexia. Response rate was 10% and disease control rate was 70% in ten cases with the evaluable lesion. Median PFS was 4.1 months. Conclusions: In this study, MTD was estimated to be level 0, and determined that recommended dose (RD) was level -1 in the planned future study. We are going to evaluate efficacy and the safety in a phase II study. Clinical trial identification: UMIN000017002 - 2015/04/01. Legal entity responsible for the study: Non-profit Organization: Hokkaido Gastrointestinal Cancer Study Group. Funding: Non-profit Organization: Hokkaido Gastrointestinal Cancer Study Group. Disclosure: S. Yuki: Honoraria: Yakult Honsha, Taiho Pharmaceutical. Y. Komatsu: Honoraria: Taiho Pharmaceutical; Donation: Taiho Pharmaceutical, Yakult Honsha; Research fund: Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma

SummaryBackground Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days. The dose-limiting toxicity evaluation was 28 days after the first dose. Safety measures, pharmacokinetics, and antitumor activity were assessed. Results Fourteen patients, 7 at each galunisertib dose, were enrolled and treated. Three dose-limiting toxicities were reported for 2 patients. The most common treatment-emergent adverse events (TEAEs) were hypophosphatemia (14 patients [100%]), palmar-plantar erythrodysesthesia syndrome (12 patients [85.7%]), and decreased platelet count (10 patients [71.4%]). The most common grade ≥ 3 TEAEs were hypophosphatemia (10 patients [71.4%]) and palmar-plantar erythrodysesthesia syndrome (7 patients [50.0%]). No grade 5 TEAEs were reported. The pharmacokinetic profile of galunisertib in combination with sorafenib was similar to that previously reported for galunisertib. Eleven patients had a best overall response of stable disease, and 1 patient achieved a partial response by hepatocellular carcinoma-specific modified RECIST. Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150 mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma.