Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors

Abstract Background The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. Methods The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered. Results No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. Conclusion Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registrationwww.clinicaltrials.gov; NCT: 02432846; registration date: February 22, 2016.

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Phase I trial evaluating safety and efficacy of intratumorally administered allogeneic monocyte-derived cells (ilixadencel) in advanced gastrointestinal stromal tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.15 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 15-15

Author(s):

Alex Karlsson-Parra ◽

Robin Fröbom ◽

Erik Berglund ◽

David Berglund ◽

Inga-Lena Nilsson ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Stable Disease ◽

Phase I Trial ◽

Second Line ◽

Safety And Efficacy ◽

Recist 1.1 ◽

Choi Criteria ◽

The Subject ◽

Third Line

15 Background: Ilixadencel is a cell-based, off-the-shelf product based on allogeneic monocyte-derived inflammatory cells aimed to prime an anti-cancer immune response when injected intratumorally. The present single arm Phase I trial (ClinicalTrials.gov Identifier: NCT02686944) assessed the safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Methods: Three GIST patients were progressing while on sunitinib (second-line), one on regorafenib (third-line), and two on pazopanib (fifth-line). Treatment consisted of two intratumoral injections of ilixadencel two weeks apart. If further tumor progression was observed at the 3-month follow up, the TKI was withdrawn and the subject performed an end of study visit. If stable disease or objective response was observed, the subject continued with the TKI until progression of disease. Results: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. Two patients had stable disease as best response; one of these patients (on third-line regorafenib) progressed at 12 months and the other (a patient on second-line sunitinib) showed continued stable disease at end of study (12 months) as per RECIST 1.1. These two patients also developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. No serious adverse events were found to be possibly or probably related to ilixadencel administrtion. Conclusions: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial information: 02686944.

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Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study

Haematologica ◽

10.3324/haematol.2017.171249 ◽

2018 ◽

Vol 103 (8) ◽

pp. 1298-1307 ◽

Cited By ~ 16

Author(s):

Carlo Gambacorti-Passerini ◽

Jorge E. Cortes ◽

Jeff H. Lipton ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Phase I ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Second Line ◽

Safety And Efficacy

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First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920926796 ◽

2020 ◽

Vol 12 ◽

pp. 175883592092679

Author(s):

Seung Tae Kim ◽

Jung Yong Hong ◽

Se Hoon Park ◽

Joon Oh Park ◽

Young Whan Park ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Phase I ◽

Cancer Patients ◽

Phase I Trial ◽

Maximum Tolerated Dose ◽

Safety And Efficacy ◽

Hepatocyte Growth

Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy in vitro and in vivo. This is a first-in-human trial of this antibody. Materials and Methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg). Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema ( n = 7, 18.9%) followed by pruritis and nausea ( n = 5, 13.5%, each), fatigue, anemia, and decreased appetite ( n = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders. Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned. Conclusion: ClinicalTrials.gov Identifier: NCT02499224

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Safety and Efficacy of Pre-Operative, Short Course Radiation Therapy for Prostate Cancer: Results From a Phase I Trial

Journal of Medical Imaging and Radiation Sciences ◽

10.1016/j.jmir.2019.03.141 ◽

2019 ◽

Vol 50 (2) ◽

pp. S6

Author(s):

Tara Rosewall ◽

Rachel Glicksman ◽

Padraig Warde ◽

Alejandro Berlin

Keyword(s):

Prostate Cancer ◽

Radiation Therapy ◽

Phase I ◽

Phase I Trial ◽

Safety And Efficacy ◽

Short Course

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Phase I trial of weekly irinotecan combined with UFT as second-line treatment for advanced colorectal cancer

European Journal of Cancer ◽

10.1016/s0959-8049(01)00321-5 ◽

2001 ◽

Vol 37 (18) ◽

pp. 2385-2391 ◽

Cited By ~ 13

Author(s):

V Alonso ◽

P Escudero ◽

M Zorrilla ◽

M.D Isla ◽

A Herrero ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase I ◽

Phase I Trial ◽

Advanced Colorectal Cancer ◽

Line Treatment ◽

Second Line

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A Phase I Trial of Sirolimus (Rapamycin) in Pediatric Patients with Relapsed/Refractory Leukemia.

Blood ◽

10.1182/blood.v110.11.2834.2834 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2834-2834 ◽

Cited By ~ 2

Author(s):

Susan R. Rheingold ◽

Nancy Sacks ◽

Yueh J. Chang ◽

Valerie I. Brown ◽

David T. Teachey ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Stable Disease ◽

Phase I Trial ◽

Pediatric Patients ◽

Loading Dose ◽

Mtor Inhibition ◽

Level 1 ◽

Dose Levels

Abstract Background: Downstream inhibition of the mammalian Target of Rapamycin (mTOR) pathway by sirolimus affects a variety of cellular functions including cap-dependent protein translation and cell cycle progression from the G1-to-S phase. Inhibition of mTOR also leads to dysregulation of the upstream signaling pathway that couples growth factor-receptor binding to mTOR activation through the PI-3 kinase/Akt pathway and may render PTEN-induced resistant lymphoblasts sensitive to agents that target the mTOR pathway. This hypothesis is supported by preclinical data which shows that sirolimus inhibits growth of ALL lines in vitro and has activity in a murine model of leukemia including ALL xenografts. Based upon these preclinical data we have piloted a Phase I trial of sirolimus in pediatric patients with relapsed acute leukemia. Methods: Pediatric patients with ≥ 2nd relapse of acute leukemia were enrolled in a Phase I dose escalation trial of oral daily sirolimus. We used a starting dose that is known to be well tolerated in pediatric renal transplant recipients and results in levels that inhibit ALL growth in vitro. At dose level 1, a loading dose of 9 mg/m2 was given on day 0, and 3 mg/m2 was given daily on days 1 to 21 or 28. Dose level 2 has a loading dose of 12 mg/m2 and daily dose of 4mg/m2. Sirolimus trough levels were obtained on days 3, 7, and end of cycle. Bone marrow aspirates (BM) were performed prior to therapy, and on day 7 (if no peripheral blasts) and day 21 or 28. Peripheral blood (PB) mononuclear cells and PB and/or BM lymphoblasts were obtained on days 0, 3, 7, 14, and 21/28 to evaluate the effect of sirolimus on intracellular targets, including ribosomal protein S6 (a pharmocodynamic marker of mTOR inhibition), 4e-BP1 and STAT5. Results: To date, 5 males and 3 females, ages 1–21, have been enrolled on study at the first 2 dose levels. Six patients had ALL, 1 infant had MLL(r) ALL, and 1 had AML. They had received 2–4 prior therapies. Three patients with ALL had stable disease at the end of the first cycle. One had a decrease in BM lymphoblasts from 39% to 12% by day 28 and a drop in absolute blast count (ABC) in the PB from 1134 to 290 but remained thrombocytopenic. The patient with MLL(r) infant ALL had a decrease in PB ABC from 62,415 to 0 by day 14 but had no change in BM lymphoblast % on day 21. Two of the 3 patients with stable disease progressed during their second cycle of therapy. The remaining 5 patients had progressive disease or were removed from study prior to the end of cycle 1 and were non-evaluable. At dose level 1 average trough level on day 7 was 10.9 (range 1–20.7) and at the end of the first cycle for non-progressors was 8.5 (range 5.8–12.2). There have been no DLTs attributable to sirolimus in any cycle to date. Preliminary immunoblots show hypophosphorylation of S6 in patients’ PB and BM after initiating sirolimus therapy. Conclusions: Sirolimus was well tolerated in pediatric patients due to its ease of administration and lack of toxicity. At the first and second dose levels there have been 2 patients and 1 patient with stable disease, respectively. Preliminary biologic data shows evidence of inhibition of mTOR, manifested by a decrease in phosphorylated S6, suggesting that S6 may be used as a biomarker for response to mTOR inhibition. Although sirolimus at these doses had a modest impact on the leukemia burden, it may be more effective when used in concert with other cytotoxic agents that inhibit cell growth and survival. Combined therapy is being investigated.

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A phase II trial of second-line axitinib following prior antiangiogenic therapy in advanced hepatocellular carcinoma (HCC).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.314 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 314-314

Author(s):

Mairead Geraldine McNamara ◽

Anne M Horgan ◽

Alex Aspinall ◽

Eric Xueyu Chen ◽

Kelly Burak ◽

...

Keyword(s):

Phase Ii ◽

Kinase Inhibitor ◽

Phase Ii Trial ◽

Antiangiogenic Therapy ◽

Dynamic Imaging ◽

Advanced Hepatocellular Carcinoma ◽

Second Line ◽

Recist 1.1 ◽

Choi Criteria ◽

Modified Recist

314 Background: Second-line options in treatment of HCC are limited. Axitinib is a multi-targeted tyrosine kinase inhibitor (TKI) of VEGFRs 1, 2, and 3, PDGFR and c-KIT that warrants exploration in HCC. Methods: This is an open-label, single-arm, two-stage phase II trial of axitinib in advanced HCC. Eligible patients (pts) are Child-Pugh A/B7, with measurable progressive disease after TKIs/antiangiogenic drugs. Axitinib starts at 5 mg bid orally, titrated to 10 mg bid as tolerated. Treatment continues to progression (PD) or intolerable toxicity. Primary endpoint is response defined by reduction in size by RECIST 1.1 on CT scan at 16 wks, secondary endpoints to compare response by RECIST 1.1 to Choi criteria and modified RECIST, explore dynamic imaging models, feasibility, safety, PFS and overall survival. Results: We present results of 15 (of 29) pts enrolled from 01/11 - 09/12. Median age; 62y (range 18-78) with ECOG PS 0 (5 pts), 1 (10 pts) with prior therapy of Temsirolimus/Bevacizumab (2 pts), sorafenib (13 pts). A planned safety/futility interim analysis was passed. Most common axitinib-related AEs were hypertension (HTN) (60%), hand-foot skin reaction (HFSR) (60%), diarrhea (60%), fatigue (50%). Most common axitinib-related grade 3 (G3) AEs were HTN (20%) and diarrhea (20%). There were no G3 HFSR. There was 1 G4 hyperbilirubinaemia. 60% of pts had dose interruptions due to AEs; most common reasons included fatigue (20%), HTN (10%), and HFSR (10%). 20% required dose reductions, 14% of pts tolerated dose escalation above 5 mg bid. As of 09/12, 8 pts remain on study, 7 pts discontinued (4pts: PD, 3pts: AEs). Med duration of treatment; 4.0 mo (range 6 d - 15.5 mo). Out of 9 evaluable for response, there was 1 confirmed PR per RECIST 1.1; 3 other pts had tumor reduction; 10%, 22%, 23%, 2 PR by Choi criteria and none by modified RECIST. Early on-treatment perfusion changes were noted on functional imaging. Of the 9 pts with evaluable AFP response, 3 (33%) had >50% decrease from baseline. 11 pts are still alive, 4 pts are deceased secondary to PD. Conclusions: Axitinib is tolerated and has shown preliminary efficacy in this VEGF pretreated HCC pt population.This is early analysis and updated data will be presented. Clinical trial information: NCT01334112.

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Association of UGT1A1 gene polymorphism with the safety and efficacy of irinotecan monotherapy for advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.16 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 16-16 ◽

Cited By ~ 1

Author(s):

Toshifumi Yamaguchi ◽

Satoru Iwasa ◽

Hirokazu Shoji ◽

Yoshitaka Honma ◽

Atsuo Takashima ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Initial Dose ◽

Uridine Diphosphate ◽

Second Line ◽

Safety And Efficacy ◽

Line Therapy ◽

Third Line ◽

Grade 3 ◽

Ugt1a1 Genotype

16 Background: The uridine diphosphate glucuronosyltransferase (UGT) 1A1, which transforms SN-38 into SN-38 glucuronide, is a key enzyme involved in the metabolism of irinotecan. Previous studies showed that UGT1A1 genotype is related to the toxicity of irinotecan-based chemotherapy in metastatic colorectal cancer. The purpose of this study was to investigate the relationship between UGT1A1genotype and safety and efficacy of irinotecan monotherapy in patients with advanced gastric cancer. Methods: We reviewed the data of 208 patients who were tested for UGT1A1 genotype and treated with irinotecan-based chemotherapy for advanced gastric cancer from 2009 to 2014. We evaluated the efficacy and safety of irinotecan monotherapy in the three groups with wild-type (WT), single heterozygosity (SH), and homozygosity/double heterozygosity (Homo-DH) classified by the genotypes for UGT1A1*28 or UGT1A1*6. Results: A total of 117 patients received irinotecan monotherapy: 40 patients in second-line, 74 in third-line, and 3 in forth-line therapy. The UGT1A1genotype was WT in 62 patients (53.0%), SH in 41 (35.0%), and Homo-DH in 14 (12.0%). Patients’ characteristics were similar among the three groups. The initial dose of irinotecan was reduced in 10 patients (16%) with the WT genotype, in 11 (27%) with SH, and in 10 (71%) with Homo-DH. Grade 3-4 neutropenia, diarrhea, and febrile neutropenia occurred in 13/22/64%, 6/5/21%, and 2/7/50% of WT/SH/Homo-DH patients. Median time to treatment failure of second-line and third-line therapies were 2.4/2.8/3.3 months and 2.4/2.3/1.3 months in WT/SH/Homo-DH patients. Median overall survival of second-line and third-line therapy were 7.9/9.9/4.6 months and 6.9/6.3/2.8 months in WT/SH/Homo-DH patients. Conclusions: Patients with UGT1A1 Homo-DH displayed high frequency of grade 3-4 toxicities, although the initial dose of irinotecan was reduced in some patients. UGT1A1 polymorphism may be related to the efficacy of irinotecan monotherapy in second- and third-line treatments for advanced gastric cancer.

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