Humanized anti-DEspR monoclonal antibody to improve overall survival in xenograft pancreatic peritoneal carcinomatosis nude rat model.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16262-e16262
Author(s):  
Christopher Gromisch ◽  
Matthew Stannard Gromisch ◽  
Mark Grinstaff ◽  
Victoria L.M. Herrera ◽  
Nelson Ruiz-Opazo
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Single Dose ◽  
Peritoneal Carcinomatosis ◽  
Rat Model ◽  
Median Overall Survival ◽  
Caspase 3 ◽  
Xenograft Tumor ◽  
Anoikis Resistance ◽  
Nude Rat

e16262 Background: Pancreatic adenocarcinoma (PDAC) with peritoneal carcinomatosis (PPC) has the worst median overall survival (mOS) among all PDAC metastasis. Novel therapeutic approaches are needed for PPC. The Dual Endothelin-1/VEGF-signal-peptide Receptor (DEspR) is a cell surface receptor which regulates PDAC tumor cell and cancer stem-like cell (CSC) anoikis resistance, tumorigenicity, and tumoral angiogenesis. To translate these findings into a novel anti-cancer therapy, we evaluated the efficacy, empirical safety, pharmacokinetics, and pharmacodynamics of a recombinant, humanized, anti-DEspR hinge-stabilized IgG4S228P monoclonal antibody, hu-6g8, in a PPC xenograft tumor nude rat model. Methods: We used a Panc1 CSC-derived xenograft tumor model of PPC developed via intraperitoneal injection of two million Panc1 CSCs functionally isolated for anoikis resistance. Isolated CSCs had variable DEspR expression, thus modeling CSC-heterogeneity. For efficacy studies, PPC-rats were randomized to receive a single intravenous injection of either 3mg/kg or 15mg/kg hu-6g8, 100mg/kg gemcitabine, or saline, given 3 weeks after CSC injection with palpable PPC tumors. Blood samples were collected to monitor for hematological adverse events (AEs) and vital organs were collected to evaluate for hu-6g8-induced apoptosis. Pharmacokinetics was assessed in a separate study cohort by sequential blood draws after rats received a single dose of 3 mg/kg or 15 mg/kg hu-6g8. In a 3rd cohort, pharmacodynamics were assessed by vital organ collection and immunohistochemistry after rats received either a single-iv injection of 3mg/kg hu-6g8 or IgG4 isotype control. Results: Single dose 15 mg/kg hu-6g8 treatment significantly improved median overall survival (189 days, n = 0.0007) with 3 mg/kg hu-6g8 being comparable to 100 mg/kg gemcitabine (92 vs 115 days, n = 0.62). No hematological AEs were observed in hu-6g8 treated rats, and there was no evidence of increased apoptosis by hu-6g8 in normal tissues by immunohistochemistry of activated Caspase-3. Hu-6g8 demonstrated an average elimination half-life of 46.1 hrs in a two-compartment model. Biodistribution of the antibody showed predominant uptake, albeit heterogenous, and induction of activated caspase 3+ apoptosis in the peritoneal tumors by 24-hours with minimal off-target binding. Conclusions: Treatment with monoclonal hu-6g8 significantly improved survival in a model of PCC with excellent tumor specificity and minimal off-target effect.

scholarly journals First Preclinical Report of the Efficacy and PD Results of KHK2823, a Non-Fucosylated Fully Human Monoclonal Antibody Against IL-3Rα

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1349-1349 ◽  
Author(s):  
Tadakazu Akiyama ◽  
Shin-ichiro Takayanagi ◽  
Yoshimi Maekawa ◽  
Kohta Miyawaki ◽  
Fumiaki Jinnouchi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Rat Model ◽  
Research Funding ◽  
Tumor Xenograft ◽  
Cynomolgus Monkeys ◽  
Nude Rat

Abstract Human interleukin-3 receptor alpha (IL-3Ra, CD123), which promotes the proliferation and differentiation of hematopoietic cells, is highly expressed in myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We newly generated KHK2823, a non-fucosylated fully human IgG1 monoclonal antibody against human IL-3Ra, by utilizing the POTELLIGENT® technology. Here, we describe the in vitro and in vivo preclinical efficacy and safety of KHK2823, as well as its pharmacodynamic (PD) profile. At first, we explored that KHK2823 bound to various hematological malignant cells and leukemic stem cells. The cells from AML and MDS bone marrows were found to be bound by KHK2823. A significant part of bone marrow cells derived from B-cell acute lymphoblastic leukemia (B-ALL) patients was also bound by KHK2823. KHK2823 bound to soluble human IL-3Ra protein with a sub-nanomolar dissociation constant (KD), and recognized CD34+ CD38+ (leukemic blast) and/or CD34+ CD38- (leukemic stem cell) cells in patients with AML/MDS, as well as AML cell lines, thereby obtaining a high antibody-dependent cellular cytotoxic activity without complement-dependent cytotoxicity. Interestingly, KHK2823 did not interfere with the binding of IL-3 to IL-3R. The lack of a receptor-ligand interaction may conserve the IL-3 signal, which plays an important role in normal hematopoiesis. In a tumor model xenografting the human AML cell line MOLM-13 on nude rats, KHK2823 significantly suppressed the tumor growth at doses of 0.1 and 1 mg/kg (Figure 1). The PD and toxicity profiles of KHK2823 were assessed in cynomolgus monkeys administered at doses ranging from 0.1 to 100 mg/kg by i.v. infusion, once weekly for 4 weeks. KHK2823 was generally well tolerated in monkeys, even at 100 mg/kg. The number of IL-3Ra-positive cells in the peripheral blood of cynomolgus monkeys decreased in all groups receiving KHK2823, which suggest KHK2823 could exert its depletion activity of IL-3Ra-positive cells in human (Figure 2). Currently, the safety and tolerability of KHK2823 is being investigated in patients with AML or MDS in a Phase 1 study (NCT02181699, https://clinicaltrials.gov/ct2/show/NCT02181699). This is the first non-randomized, open-label, dose escalation clinical study to investigate the safety, PK, immunogenicity and PD of repeated doses of KHK2823. In summary, KHK2823 was confirmed to bind to AML, MDS and B-ALL cells as the IL-3Ra in accordance with other publications. KHK2823 was also found to eliminate AML cells in vitro and also suppressed the AML tumor growth in the in vivo model. In addition, the number of IL-3Ra-positive cells in cynomolgus monkeys decreased following i.v. infusion of 0.1mg/kg KHK2823 with a tolerable safety profile, even at a dose of 100 mg/kg. Taken together, KHK2823 may therefore be a promising anti-IL-3Ra therapeutic drug for the treatment of AML. Figure 1. Antitumor activity of KHK2823 in a tumor xenograft nude rat model Figure 1. Antitumor activity of KHK2823 in a tumor xenograft nude rat model Figure 2. PD profile of KHK2823 in cynomolgus monkeys Figure 2. PD profile of KHK2823 in cynomolgus monkeys Disclosures Akiyama: Kyowa Hakko Kirin Co., Ltd.: Employment. Takayanagi:Kyowa Hakko Kirin Co., Ltd.: Employment. Maekawa:Kyowa Hakko Kirin Co., Ltd.: Employment. Shimabe:Kyowa Hakko Kirin Co., Ltd.: Employment. Nishikawa:Kyowa Hakko Kirin Co., Ltd.: Employment. Yamawaki:Kyowa Hakko Kirin Co., Ltd: Employment. Iijima:Kyowa Hakko Kirin Co., Ltd: Employment. Hiura:Kyowa Hakko Kirin Co., Ltd.: Employment. Takahashi:Kyowa Hakko Kirin Co., Ltd.: Employment. Akashi:Asahi Kasei: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Tawara:Kyowa Hakko Kirin Co., Ltd: Employment.

Caspase 3 Expression in Mantle Cell Lymphoma: An Immunohistochemical Study of 84 Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4676-4676
Author(s):  
Carsten Schrader ◽  
Wolfram Klapper ◽  
Paul Riis ◽  
Peter Meusers ◽  
Guenter Brittinger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Survival Time ◽  
Median Overall Survival ◽  
Caspase 3 ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Overall Survival Time ◽  
Mantle Cell ◽  
Median Overall Survival Time

Abstract Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. We investigated immunohistochemically the expression of the apoptotic marker caspase 3 in relation to the clinical course. Biopsy specimen from 84 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, Caspase3. The Caspase3 expression was analyzed in three groups: less than 1 positive cell per high power field (HPF), more than 1 positive cell per HPF and more than 2 positive cells per HPF. The expression was compared with the overall survival data analysed according to Kaplan and Meier. In 75 cases the caspase 3 staining could be analyzed. The caspase 3 expression had a range of 0.1–4.7 positive cells per HPF (median value:1.1, mean:1.3). Patients with mantle cell lymphoma that had less than 1 caspase 3 positive cell per HPF (33 cases) had a median overall survival time of 48 months compared to 27 months for patients with more than 1 positive cell per HPF (24 cases) and 15 months for more than 2 positive cells per HPF (18). The Kaplan-Meier analysis showed a significant difference in the overall survival time between these groups (p<0.0001). The immunohistochemical detection of caspase 3 in mantle cell lymphoma is a predictor for survival in MCL.

scholarly journals Humanized anti-DEspR IgG4S228P antibody increases overall survival in a pancreatic cancer stem cell-xenograft peritoneal carcinomatosis ratnu/nu model

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Christopher M. Gromisch ◽  
Glaiza L. A. Tan ◽  
Khristine Amber Pasion ◽  
Ann-Marie Moran ◽  
Matthew S. Gromisch ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peritoneal Carcinomatosis ◽  
Protein Function ◽  
Apoptotic Cell ◽  
Metastatic Cancer ◽  
Apoptosis Resistance ◽  
Anoikis Resistance ◽  
Nuclear Shuttling ◽  
Cell Changes

Abstract Background Pancreatic peritoneal carcinomatosis (PPC), with the worst median overall-survival (mOS), epitomizes the incurability of metastatic cancer. Cancer stem cells (CSCs) underpin this incurability. However, inhibitors of CSC-stemness fail to increase mOS in cancer patients despite preclinical tumor-reduction. This shortfall reinforces that preclinical efficacy should be defined by increased mOS in the presence of cancer comorbidities, CSC-heterogeneity and plasticity. The primary objectives of this study are: to test the dual endothelin-1/signal peptide receptor, DEspR, as a nodal therapeutic target in PPC, given DEspR induction in anoikis-resistant pancreatic CSCs, and to validate humanized anti-DEspR antibody, hu-6g8, as a potential therapeutic for PPC. Methods We used heterogeneous pools of CSCs selected for anoikis resistance from reprogrammed Panc1 and MiaPaCa2 tumor cells (TCs), and adherent TCs reprogrammed from CSCs (cscTCs). We used multiple anti-DEspR blocking antibodies (mAbs) with different epitopes, and a humanized anti-DEspR recombinant mAb cross-reactive in rodents and humans, to test DEspR inhibition effects. We measured DEspR-inhibition efficacy on multiple prometastatic CSC-functions in vitro, and on tumorigenesis and overall survival in a CSC-derived xenograft (CDX) nude rat model of PPC with comorbidities. Results Here we show that DEspR, a stress-survival receptor, is present on subsets of PDAC Panc1-TCs, TC-derived CSCs, and CSC-differentiated TCs (cscTCs), and that DESpR-inhibition decreases apoptosis-resistance and pro-metastatic mesenchymal functions of CSCs and cscTCs in vitro. We resolve the DNA-sequence/protein-function discordance by confirming ADAR1-RNA editing-dependent DEspR-protein expression in Panc1 and MiaPaCa2 TCs. To advance DEspR-inhibition as a nodal therapeutic approach for PPC, we developed and show improved functionality of a recombinant, humanized anti-DEspR IgG4S228P antibody, hu-6g8, over murine precursor anti-DEspR mabs. Hu-6g8 internalizes and translocates to the nucleus colocalized with cyto-nuclear shuttling galectins-1/3, and induces apoptotic cell changes. DEspR-inhibition blocks transperitoneal dissemination and progression to peritoneal carcinomatosis of heterogeneous DEspR±/CD133 ± Panc1-derived CSCs in xenografted nude rats, improving mOS without chemotherapy-like adverse effects. Lastly, we show DEspR expression in Stage II-IV primary and invasive TCs in the stroma in PDAC-patient tumor arrays. Conclusion Collectively, the data support humanized anti-DEspR hu-6g8 as a potential targeted antibody-therapeutic with promising efficacy, safety and prevalence profiles for PPC patients.

scholarly journals FOLFIRINOX in patients with peritoneal carcinomatosis from pancreatic adenocarcinoma: a retrospective study

2019 ◽  
Vol 26 (4) ◽  
Author(s):  
E. Bonnet ◽  
C. Mastier ◽  
A. Lardy-Cléaud ◽  
P. Rochefort ◽  
M. Sarabi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peritoneal Carcinomatosis ◽  
Median Overall Survival ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Poor Prognostic Factor ◽  
Group 2 ◽  
Ecog Ps ◽  
Group 1

Background Peritoneal carcinomatosis (PCM) in metastatic pancreatic ductal adenocarcinomas (mPDAC) is frequently encountered in day-to-day practice, but rarely addressed in the literature. The objective of the present study was to describe the management and outcome of patients diagnosed with PCM.Methods Data for all consecutive patients with mpdac treated in our centre between 1 January 2014 and 31 August 2015 were analyzed retrospectively. Computed tomography imaging was centrally reviewed by a dedicated radiologist to determine the date of pcm diagnosis.Results The analysis included 48 patients. Median age in the group was 61 years, and 41 patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. All patients presented with pcm either synchronously (group 1) or metachronously (group 2). Those groups differed significantly by baseline ecog ps and neutrophil-tolymphocyte ratio (nlr), with ecog ps being poorer and nlr being higher in group 1. In addition to PCM, the main sites of metastasis were liver (62.5%) and lungs (31.3%). First-line chemotherapy in 36 patients (75%) was FOLFIRINOX (fluorouracil–irinotecan–leucovorin–oxaliplatin). The median overall survival for the entire population was 10.81 months [95% confidence interval (ci): 7.16 months to 14.16 months]; it was 13.17 months (95% ci: 5.9 months to 15.4 months) for patients treated with folfirinox. Median overall survival was 7.13 months (95% ci: 4.24 months to 10.41 months) for patients in group 1 and 14.34 months (95% ci: 9.79 months to 19.91 months) for patients in group 2, p = 0.1296.Conclusions Compared with other metastatic sites, synchronous pcm seems to be a poor prognostic factor. It could be more frequently associated with a poor ECOG PS and a NLR greater than 5 in this group of patients. In patients with mPDAC and PCM, either synchronous or metachronous, FOLFIRINOX remains an efficient regimen.

scholarly journals Efficacy of Surgical Treatment of Peritoneal Carcinomatosis in Patients with Colorectal Cancer

2016 ◽  
Vol 23 (3) ◽  
Author(s):  
T G Fetsych ◽  
A P Revura
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Peritoneal Carcinomatosis ◽  
Cytoreductive Surgery ◽  
Median Overall Survival ◽  
Palliative Chemotherapy ◽  
Symptomatic Treatment ◽  
Group Iii ◽  
Group I ◽  
Significant Difference

Colorectal cancer is one of the most common types of cancer in Ukraine. Prognosis for patients with peritoneal carcinomatosis is unfavorable, and life expectancy is typically less than 6 months. Cytoreductive surgery was introduced as a new method of treating these patients to prolong their survival time.The objective of the research was to evaluate and compare the efficacy of cytoreductive surgery, chemotherapy and symptomatic treatment of patients with colorectal cancer and peritoneal carcinomatosis.Materials and methods. The research included 93 patients with colorectal cancer and peritoneal carcinomatosis. All patients were divided into 3 groups depending on the method of treatment being used after the detection of peritoneal carcinomatosis: Group I - cytoreductive surgery, Group II - palliative chemotherapy, Group III - symptomatic treatment. Cumulative overall survival in three groups was analyzed using the Kaplan-Meier method.Results. Statistically significant difference in overall survival was observed between patients treated with different methods. The median overall survival of patients of Group I (n=44) was 15.5 months; the median overall survival of patients of Group II (n=27) was 5.9 months; in patients of Group III (n=22) it was 3.1 months (p <0.0001). The analysis of patients’ survival in Group I depending on the application of palliative chemotherapy after cytoreductive surgery showed no significant difference in overall survival: 16.5 months with chemotherapy versus 14.2 months without chemotherapy (p = 0.12).Conclusions. Overall survival of patients with colorectal cancer and peritoneal carcinomatosis was higher when treated with cytoreductive surgery compared to palliative chemotherapy and symptomatic treatment. Palliative chemotherapy had no effect on survival after cytoreductive surgery for peritoneal carcinomatosis. 

scholarly journals The Role of Total Parenteral Nutrition in Patients with Peritoneal Carcinomatosis: A Systematic Review and Meta-Analysis

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4156
Author(s):  
Xing-Yi Sarah Ong ◽  
Rehena Sultana ◽  
Joey Wee-Shan Tan ◽  
Qiu Xuan Tan ◽  
Jolene Si Min Wong ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Parenteral Nutrition ◽  
Peritoneal Carcinomatosis ◽  
Total Parenteral Nutrition ◽  
Median Overall Survival ◽  
Meta Analysis ◽  
Significant Survival Advantage ◽  
Significant Survival

Peritoneal carcinomatosis (PC) is often associated with malnutrition and an inability to tolerate enteral feeding. Although total parenteral nutrition (TPN) can be lifesaving for patients with no other means of nutritional support, its use in the management of PC patients remains controversial. Therefore, a systematic review and meta-analysis was performed to evaluate the benefit of TPN on the overall survival of PC patients, in accordance with PRISMA guidelines. A total of 187 articles were screened; 10 were included in this review and eight were included in the meta-analysis. The pooled median overall survival of patients who received TPN was significantly higher than patients who did not receive TPN (p = 0.040). When only high-quality studies were included, a significant survival advantage was observed in PC patients receiving TPN (p < 0.001). Subgroup analysis of patients receiving chemotherapy demonstrated a significant survival benefit (p = 0.008) associated with the use of TPN. In conclusion, TPN may improve survival outcomes in PC patients. However, further studies are needed to conclude more definitively on the effect of TPN.

Induction of chronic renal allograft injury by injection of a monoclonal antibody against a donor MHC Ib molecule in a nude rat model

2008 ◽  
Vol 19 (3-4) ◽  
pp. 187-191 ◽  
Author(s):  
Martina Koch ◽  
Verena Broecker ◽  
Annice Heratizadeh ◽  
Corinna Doege ◽  
Juergen Strehlau ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Rat Model ◽  
Renal Allograft ◽  
Nude Rat

scholarly journals Significance of indeterminate pulmonary nodules in resectable pancreatic adenocarcinoma—a review

2021 ◽  
Author(s):  
Li Lian Kuan ◽  
Ashley R. Dennison ◽  
Giuseppe Garcea
Keyword(s):  
Overall Survival ◽  
Pancreatic Adenocarcinoma ◽  
Median Overall Survival ◽  
Current Knowledge ◽  
Pulmonary Nodules ◽  
Preoperative Imaging ◽  
Significant Finding ◽  
Comprehensive Overview ◽  
Significant Difference ◽  
Clinical Dilemma

Abstract Background The clinical significance of indeterminate pulmonary nodules (IPN) in patients with resectable pancreatic adenocarcinoma (PDAC) is unknown. The rate of detection on IPN has risen due to enhanced staging investigations to determine resectability. IPNs detected on preoperative imaging represent a clinical dilemma and complicate decision-making. Currently, there are no recommendations on the management of IPN. This review provides a comprehensive overview of the current knowledge on the natural history of IPN detected among patients with resectable PDAC. Methods A systematic review based on a search in Medline and Embase databases was performed. All clinical studies evaluating the significance of IPN in patients with resectable PDAC were included. PRISMA guidelines were followed. Results Five studies met the inclusion criteria. The total patient population was 761. The prevalence of IPN reported ranged from 18 to 71%. The median follow-up duration was 17 months. The median overall survival was 19 months. Patients with pre-operative IPN which subsequently progressed to clinically recognizable pulmonary metastases, ranged from 1.5 to 16%. Four studies found that there was no significant difference in median overall survival in patients with or without IPNs. Conclusion This is a first review on the significance of IPN in patients with resectable PDAC. The preoperative presence of IPN does not demonstrate an association with overall survival after surgery. The identification of IPN is a significant finding however it should not preclude patients with resectable PDAC from undergoing curative resection.

Applicability of PD-L1 tests to tailor triple-negative breast cancer treatment in Brazil

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Kátia Ramos Moreira Leite ◽  
Carlos Henrique Barrios ◽  
Antônio Carlos Buzaid ◽  
Débora Gagliato ◽  
Helenice Gobbi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Triple Negative Breast Cancer ◽  
Median Overall Survival ◽  
Triple Negative ◽  
Breast Cancer Treatment ◽  
Main Text ◽  
Critical Questions ◽  
Online Panel ◽  
Active Interest

Abstract Background Triple-negative breast cancer (TNBC) is a heterogeneous disease that represents 10–20% of breast cancer cases. The prognosis for advanced TNBC is usually poor, with a median overall survival of approximately 18 months or less. Main text New targeted therapies such as anti-PD-L1 agents are emerging as an option to treat advanced TNBC. A panel of 6 national experts with an active interest in breast cancer convened online. Panel members had either clinical or pathology experience in breast cancer. The experts pre-defined critical questions in the management of PD-L1 in TNBC, and a literature review was performed for selected topics before the online meeting. Conclusion The experts led active discussions involving a multidisciplinary team comprising pathologists and clinical oncologists. The meeting served to discuss the most relevant issues. A total of 10 critical questions for PD-L1+ TNBC were debated and are presented in this review. This article discusses the current landscape for PD-L1 tests in TNBC in Brazil.

287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Solmaz Sahebjam ◽  
Jameel Muzaffar ◽  
Timothy Yap ◽  
David Hong ◽  
Olivier Rixe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Adverse Events ◽  
Solid Tumors ◽  
Ex Vivo ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

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