Featured Clinical Trial: Targeted Combination Therapy for Advanced Solid Tumors

2005 ◽  
Author(s):  
Keyword(s):  
Clinical Trial ◽  
Combination Therapy ◽  
Solid Tumors ◽  
Advanced Solid Tumors

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.

Phase II clinical trial of uncaria tomentosa (cat´s claw) in patients with advanced solid tumors.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 9557-9557
Author(s):  
Larissa Carvalho Lopes De Paula ◽  
Fernando Fonseca ◽  
Fábio Ferreira Perazzo ◽  
Felipe Melo Cruz ◽  
Daniel de Iracema Gomes Cubero ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase Ii ◽  
Phase Ii Clinical Trial ◽  
Advanced Solid Tumors ◽  
Uncaria Tomentosa

Phase I clinical trial of temozolomide and methoxyamine (TRC-102) in patients with advanced solid tumors.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 2558-2558 ◽  
Author(s):  
Jennifer Rachel Eads ◽  
Smitha S. Krishnamurthi ◽  
Joel N. Saltzman ◽  
Neal J. Meropol ◽  
Joseph A. Bokar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Clinical Trial ◽  
Advanced Solid Tumors

A phase 1, multicenter, dose-escalation study of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors, followed by expansion cohorts in patients with FGFR genetic alterations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2616-TPS2616 ◽  
Author(s):  
Sarina Anne Piha-Paul ◽  
Cinta Hierro ◽  
Valentina Boni ◽  
Victor Moreno ◽  
Noah M. Hahn ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Elevated Serum ◽  
Genetic Alterations ◽  
Serum Phosphorus ◽  
Advanced Solid Tumors ◽  
Phosphate Binding ◽  
Pharmacodynamic Biomarkers ◽  
Fgfr Inhibition

TPS2616 Background: FGFR inhibition is a promising and clinically proven therapeutic approach in a number of solid tumors where genetic alterations of FGFR drive oncogenesis. PRN1371 is a highly selective oral, irreversible inhibitor of FGFR1-4 that exhibits high potency in cancer cell lines harboring FGFR alterations, including mutations and fusions. Methods: Part A of this phase 1 clinical trial explores ascending doses of PRN1371 in adult patients with advanced solid tumors in a "3 + 3" design, where cohorts of three patients are studied at each level until additional patients need to be added to better assess safety, establish the maximum tolerated dose and define the recommended phase 2 dose (RP2D). PRN1371 is dosed once or twice daily in continuous, 28-day cycles until disease progression. Part B studies include two or three expansion cohorts of different tumor types, 10 patients each with FGFR1-4 gene mutations, fusions, or amplification at the RP2D. The on-target effect of serum phosphorus and FGF23 increases are measured as potential pharmacodynamic biomarkers. Elevated serum phosphorus is managed with oral phosphate binding medications and a low phosphate diet, with dose interruptions and use of acetazolamide if certain thresholds are exceeded. Circulating tumor DNA from patients at baseline and during follow up is analyzed for FGFR genetic alterations. Pre and on-treatment tumor biopsies in Part B will be tested for a panel of pharmacodynamic biomarkers of FGFR inhibition. Clinical trial information: NCT02608125.

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