Once-daily oral afatinib (A) combined with pemetrexed (P) in patients (pts) with advanced solid tumors: A phase I dose escalation trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13011-e13011
Author(s):  
Quincy Chu ◽  
Randeep Sangha ◽  
Sebastien J. Hotte ◽  
Qiqi Deng ◽  
Steve Gyorffy ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Standard Dose ◽  
Single Agent ◽  
Egfr Mutations ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Once Daily

e13011 Background: A is an oral, irreversible, ErbB Family Blocker with single-agent activity in a variety of solid tumors. Preclinical studies have demonstrated additive antitumor effects when combining A or erlotinib with P in non-small cell lung cancer cell lines with sensitizing or resistant EGFR mutations. We hypothesized that once-daily A given with P would be safe and feasible in pts with advanced solid tumors. Methods: This Phase I trial was a standard 3+3 dose escalation design where A was administered orally at a starting dose of 30 mg/day on days 2–21 and combined with IV P (500 mg/m2) on Day 1 of a 21-day cycle. A was increased by 10 mg for each successive cohort until determination of the MTD, defined as the dose of A below which ≥2 of six pts experienced dose-limiting toxicity (DLT) in Cycle 1. MTD cohort was expanded to 18 pts and incidence and severity of AEs were graded according to CTCAE v3.0. Pts were treated to a maximum of 6 cycles with the option for A monotherapy thereafter. Results: 23 pts with advanced tumors were treated: 10 males, 13 females, ECOG 0/1/2 (30%/65%/4%), median age 58 yrs, and 57% received ≥3 prior chemotherapies. In Cycle 1, treatment-related DLTs were observed in six pts; two pts of three treated at 40 mg/day A dose and four pts of 20 treated at the MTD of 30 mg/day A dose. A and P were well tolerated, with the most frequent treatment-related AEs being diarrhea (91%; of which 86% were grade 1–2), stomatitis (65%) and rash (61%). Pts received a median of 2 cycles of treatment; five pts received >4 cycles, including one patient with serous ovarian cancer who continues on trial treatment beyond 14 months. Best response of 21 available pts included two partial responses, 14 with stable disease, and three with progressive disease. Detailed response and PK data will be further analyzed. Conclusions: In pts with relapsed or refractory advanced solid tumors, oral A at 30 mg/day combined with standard dose P (500 mg/m2) administered on Day 1 of a 21-day cycle, had an acceptable safety and tolerability profile. The study is currently evaluating an intercalated schedule of A on Days 2–6 with P based on preclinical synergy thought to arise from cell-cycle pharmacodynamic separation of A and P.

Phase I study of ispinesib in combination with carboplatin in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2027-2027 ◽  
Author(s):  
S. F. Jones ◽  
E. R. Plummer ◽  
H. A. Burris ◽  
A. R. Razak ◽  
A. A. Meluch ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Mitotic Spindle ◽  
Phase I Study ◽  
Single Agent ◽  
Tolerability Profile ◽  
Synergistic Activity ◽  
Platinum Compound ◽  
Advanced Solid Tumors ◽  
Carboplatin Auc

2027 Background: Kinesin spindle protein (KSP) is required for establishment of mitotic spindle bipolarity and cell cycle progression. Ispinesib (SB-715992), a KSP inhibitor, blocks assembly of a functional mitotic spindle leading to G2/M arrest. Carboplatin is a platinum compound that produces predominantly interstrand DNA cross-links. In vivo combination of a platinum-containing agent (cisplatin) and ispinesib resulted in synergistic activity and an increase in maximum tolerated dose (MTD) of ispinesib. In a phase I study of single agent ispinesib on a once every 21-day schedule, the MTD was 18 mg/m2 with prolonged gr 4 neutropenia and febrile neutropenia as DLTs. Methods: Patients (pts) with advanced solid tumors, PS ≤ 1, and ≤ 3 prior chemotherapy regimens were eligible for this study. Escalating doses of carboplatin (AUC 4-6) were administered over 30 minutes followed by a 1-hour infusion of escalating doses of ispinesib (9– 21 mg/m2) on a 21-day schedule. At least 3 pts were treated at each dose level. The primary objectives of this study included characterizing safety and tolerability and defining the optimally tolerated regimen (OTR). Limited pharmacokinetic (PK) samples were obtained. Clinical response assessments per RECIST criteria were performed every 2 cycles. Results: 24 pts [15 M/9 F; median age 63yrs, ECOG PS 1], were treated at 6 dose levels. The most common tumor types were prostate (7) and breast (4). A median of 3 cycles were administered (range 1–7; total 75 cycles). In 17 pts, the most common toxicities were (# pts, [grade]): nausea (10, Gr 1–2), vomiting (8, Gr 1–3), fatigue (8, Gr 1–2), neutropenia (8, Gr 2–4), anemia (7, Gr 1–3), and thrombocytopenia (7, Gr 1–4). Gr 4 thrombocytopenia was the observed DLT in 2 pts [ispinesib (mg/m2)/carboplatin (mg/ml·min) (# pts): 15/6 (1); 18/6 (1). PK assessment of ispinesib and carboplatin will be completed when the OTR has been defined. Unconfirmed minor responses have been observed in 3 pts (breast, prostate, NSCLC) starting at doses of 18/6. Conclusions: Determination of an OTR is ongoing. Ispinesib doses ≥ single agent MTD when combined with carboplatin AUC 6 have an acceptable tolerability profile and demonstrate preliminary evidence of anti-tumor activity. [Table: see text]

A phase I multiple-dose escalation study to assess the safety, tolerability, and pharmacokinetics of VEGF-receptor inhibitor telatinib (EOC315) in Chinese patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
Hongming Pan ◽  
Tianshu Liu ◽  
Jason Tsai ◽  
Yapeng Zhao
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Left Ventricular Systolic Dysfunction ◽  
Single Agent ◽  
Left Ventricular ◽  
Chinese Patients ◽  
Vegf Receptor ◽  
Advanced Solid Tumors

3061 Background: Telatinib (EOC315) is a highly selective inhibitor of VEGFR/PDGFR (VEGFR 1-3, PDGFR-β, and c-Kit tyrosine kinases). This phase I study was to assess the safety, tolerability, and pharmacokinetics (PK) of Telatinib in Chinese patients with advanced solid tumors. Methods: Telatinib was administered to Chinese patients with advanced refractory solid tumors as a single agent in 3+3 dose escalation design, starting from 600mg and escalated to 900mg and 1200mg, given orally twice daily. The PK profile, safety, and tolerability were evaluated per protocol. Efficacy was evaluated with RECIST 1.1 criteria every 6 weeks. Results: A total of 15 subjects (6 colorectal cancer, 4 lung cancer, 1 head and neck cancer, 1 melanoma, 1 thymic carcinoma, 1 esophageal carcinoma,1 peritoneal carcinoma) were enrolled per protocol between July 2017 and August 2018, and 13 subjects received at least second line therapies before enrollment. Telatinib was well tolerated in the three dose arms. No dose limiting toxicities (DLTs) occurred during the dose escalation phase. CTC grade 3 AEs observed include hypertension (46.7%, 7/15), fatigue (6.7%, 1/15), transaminase elevation (6.7%, 1/15), hand-foot syndrome (6.7%, 1/15), oral mucositis (6.7%, 1/15), neutropenia (6.7%, 1/15), urobilinogen elevation (6.7%, 1/15), left ventricular systolic dysfunction/decreased ejection fraction (6.7%, 1/15). No CTC grade 4 AE were observed. There were 2 drug related SAEs (hospitalization due to high blood pressure. The PK profile of Telatinib (EOC315) at 600, 900, 1200 mg in Chinese patient cohorts is summarized in Table. For 12 evaluable patients, DCR was 58.3%. For all patients, mPFS was 15 weeks (3.3-34.3w). Conclusions: This study demonstrated the safety and tolerability of Telatinib (EOC315) in a multiple dose escalation design at 600, 900, and 1200 mg PO bid in Chinese patients with advanced refractory solid tumor. Telatinib AUC increased dose-proportionally from 600 mg to 900 mg bid, where 900 mg Telatinib bid is the maximum feasible and recommended dose for future studies in Chinese patients with advanced tumors. Clinical trial information: NCT03175497. [Table: see text]

A phase I dose-escalation and expansion study of JPI-547, a dual inhibitor of PARP/tankyrase in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3113-3113
Author(s):  
Seock-Ah Im ◽  
SeungHwan Lee ◽  
Keun Wook Lee ◽  
Youngjoo Lee ◽  
Joohyuk Sohn ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Dose Range ◽  
Single Agent ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Dual Inhibitor ◽  
Expansion Phase

3113 Background: JPI-547 is an oral inhibitor of PARP 1/2 and Tankyrase 1/2. JPI-547 demonstrated anti-tumor activity in BRCA-deficient xenograft models as a single-agent and in combination with chemotherapy and immune checkpoint inhibitors. Methods: This is the first in human (FIH) phase I study of JPI-547 in patients (pts) with advanced solid tumors. For the dose escalation phase, a 3+3 design was used with 4 doses from 50 to 200 mg QD on 21-day cycles. Primary objectives were to assess safety and tolerability to determine RP2D, and secondary objectives included pharmacokinetics and preliminary antitumor activities. DLT monitoring period was 21 days. Pharmacodynamics and information of HRR mutation were also explored. For the dose expansion phase, pts with documented pathogenic germline or somatic BRCA/HRR mutations were enrolled to assess the preliminary efficacy and safety. Tumor response (RECIST 1.1) was evaluated every 6 weeks. Centralized germline BRCA testing was conducted to confirm pathogenic gBRCA mutations. Results available at the cut-off date of 31-Dec-2020 are presented. Results: For dose escalation phase, 22 pts were enrolled. JPI-547 was well absorbed with Tmax of 0.25-8 h post-dose and apparent half-life of 18-31 h. Mean Cmax and AUC increased proportionally (within the dose range of 50-200 mg). PAR level measured from PBMC was 53% inhibited at Cmax. One DLTs was observed at 100 mg (elevated ALT, G3) and 200 mg (elevated ALT/AST, G3) respectively. MTD was determined as 200 mg after considering DLTs and myelosuppression observed from cycle 2. RP2D was determined to be 150 mg based on the pharmacokinetic data and safety. Thirteen pts (59.1%) had at least one grade 3/4 TRAE and 12 had dose interruption/reduction due to TRAE. The most common ( > 20%) TRAE were anemia, thrombocytopenia and neutropenia. In dose expansion phase, 40 pts were enrolled, and response was evaluable in 39 pts. The best overall responses were 11 confirmed PR (cPR) and 15 SD with ORR of 28.2% (11/39) and DCR of 64.1 % (25/39). The mPFS was 3.5 mos and mDoR was 3.4 mos. At the time of data cut-off, three pts were ongoing as following response and cancer types: cPR (breast, ATMm, 9.0 mos), cPR (NSCLC, gBRCA2m, 3.8 mos) and SD (breast, gBRCAm, 9.3 mos). Five pts (2 ovarian, 3 breast) previously treated with olaparib and discontinued due to progressive disease were enrolled in this JPI-547 trial and one ovarian cancer pt showed cPR with 37% tumor shrinkage. Conclusions: These results demonstrate that JPI-547 is adequately absorbed with acceptable safety profile. Preliminary efficacy results suggest that JPI-547 monotherapy is effective in pts with BRCA/HRR mutation. Further investigation is warranted in pts with solid tumor including PARP inhibitor resistant cases. Clinical trial information: NCT04335604.

scholarly journals A Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors

2012 ◽  
Vol 31 (2) ◽  
pp. 409-416 ◽  
Author(s):  
Michael S. Gordon ◽  
David S. Mendelson ◽  
Mitchell Gross ◽  
Martina Uttenreuther-Fischer ◽  
Mahmoud Ould-Kaci ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Oral Treatment ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Label Dose

Phase I safety and tolerability of once daily oral afatinib (A) in combination with docetaxel (D) in patients (pts) with relapsed or refractory advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13010-e13010
Author(s):  
Helene Senellart ◽  
Jaafar Bennouna ◽  
Nicolas Isambert ◽  
Helene De-Montserrat ◽  
Patrick J. Squiban ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Dose Range ◽  
Safety Data ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Once Daily ◽  
Expansion Cohort ◽  
Initial Starting

e13010 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability, and PK of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part B are presented here. Methods: Eligible pts (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once daily, oral dosing of A in combination with D, given iv on Day 1 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3+3 design. Initial starting dose level was A 30 mg/day and D 60 mg /m², escalating up to A 50 mg/day and D 75 mg/m² until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 21 pts have been treated with A (30–50 mg/day) and D (60–75 mg/m2), with baseline characteristics: mean age (55.4 years), women (42.9%) and number of prior chemotherapies (≤2: 57%; >2: 43%). Fourteen pts received 2–4 cycles of treatment and five patients received 4 or more cycles. In Cycle 1, DLT was experienced by one out of six pts receiving 30 mg afatinib + 60 mg/m² docetaxel (Grade 3 diarrhea). No DLT was observed during the subsequent dose levels up to A 50 mg/day and D 75 mg/m². AEs observed in most pts were diarrhea (76.2%) and asthenia (66.7%). Conclusions: In pts with relapsed or refractory advanced solid tumors, the combination of A and D is well tolerated. AEs were manageable and the MTD was not reached in the tested dose range up to A 50 mg/day and D 75 mg/m². Considering the potential for diarrhea and rash during later cycles, the recommended dose for the expansion cohort was A 40 mg/day in combination with D 75 mg/m². Enrollment is ongoing (nine pts to date) and additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation.

Phase I safety and tolerability of once daily oral afatinib (A) in combination with gemcitabine (G) in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13009-e13009 ◽  
Author(s):  
Sylvie Zanetta ◽  
Jaafar Bennouna ◽  
Nicolas Isambert ◽  
Helene De-Montserrat ◽  
Patrick J. Squiban ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Primary Objective ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Once Daily ◽  
Initial Starting

e13009 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics of A in two parallel dose cohort expansion parts, in combination with either G (Part A) or docetaxel (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part A are presented here. Methods: Eligible patients (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once-daily, oral dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 patients using a 3+3 design. Initial starting dose level was A 30 mg/day and G 1000mg /m², escalating up to A 50 mg/day and G 1250 mg/m², until the MTD was reached, and followed by a PK expansion cohort of 12 patients at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 19 patients have been treated on study with the following baseline characteristics: mean age (53.7 years), women (63.2%) and number of prior chemotherapies (≤2: 26%, >2: 74%). Twelve patients received 2–4 cycles of treatment and five patients received 4 or more cycles. AEs observed in most patients were diarrhea (89.5%) and rash (63.2%). In Cycle 1, DLTs were experienced by one patient out of six receiving A 30 mg and G 1250 mg/m². MTD was exceeded at a dose level of at least A 40 mg/day and G 1250 mg/m². An intermediate dose level of A 40 mg/day and G 1000 mg/m² is currently under evaluation. Conclusions: In patients with relapsed or refractory advanced solid tumors, the combination of A with G is well tolerated, with manageable AEs. Dose finding is ongoing and MTD, safety profile and preliminary evidence of activity are anticipated to be reported at time of presentation.

Phase I and IIa studies of simtuzumab alone and in combination with FOLFIRI in patients with advanced solid tumors.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 554-554 ◽  
Author(s):  
Patricia LoRusso ◽  
J. Randolph Hecht ◽  
Dung Luong Thai ◽  
Michael J. Hawkins ◽  
Hua Dong ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Lysyl Oxidase ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Tumor Growth And Metastasis ◽  
Line Setting

554 Background: Simtuzumab (SIM) is a monoclonal antibody that inhibits lysyl oxidase like molecule 2 (LOXL2), an extracellular matrix enzyme involved in tumor growth and metastasis. Methods: A phase I dose escalation study evaluated the safety and pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Dose escalation occurred at doses up to 20 mg/kg of SIM every 2 weeks by IV infusion followed by a dose expansion of 20 pts at 10 mg/kg of SIM every 2 weeks. PK was evaluated following the first and fourth doses. In a separate Phase IIa study, 11 pts with KRAS mutant colorectal cancer (CRC) were given SIM at 700 mg IV combined with FOLFIRI every 2 weeks in the 2nd line setting. All pts continued until disease progression or unacceptable toxicity. CT or MRI was performed every 8 weeks. Results: In the phase I study, 12 pts (3 per cohort) received SIM at doses of 1, 3, 10 and 20 mg/kg. Tumor types included CRC (5), pancreatic neuroendocrine (PNE, 1), and other tumors (1 each). In the dose expansion, 20 CRC pts (11 KRAS mutant and 9 KRAS wild-type) received SIM at 10 mg/kg. Treatment-emergent AEs (TEAEs) included fatigue and constipation. No DLTs or drug-related SAEs were observed. The mean terminal T1/2 was ~20 days, and exposure was dose proportional between 1 and 20 mg/kg. Decreased tumor size (-56% for PNE and -17%, -8%, -5%, -5%, and -4% for CRC) as measured by the sum of the linear diameter of the target lesions was observed in 6 pts following treatment with SIM alone. In the Phase IIa trial of SIM/FOLFIRI, the most common TEAEs were diarrhea, fatigue, and nausea. Median PFS was 7.8 months. Conclusions: SIM was well tolerated as a single agent and when combined with FOLFIRI and showed promising efficacy in pts with CRC. A randomized, double-blind, placebo controlled phase II study in KRAS mutant CRC pts is ongoing. Clinical trial information: NCT01323933.

Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3640-3640
Author(s):  
Filip Janku ◽  
Elena Elez ◽  
Gopa Iyer ◽  
Noboru Yamamoto ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Mapk Pathway ◽  
Single Agent ◽  
Human Study ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Grade 3

3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .

scholarly journals Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000453 ◽  
Author(s):  
Jayesh Desai ◽  
Sanjeev Deva ◽  
Jong Seok Lee ◽  
Chia-Chi Lin ◽  
Chia-Jui Yen ◽  
...  
Keyword(s):  
Cell Death ◽  
Antitumor Activity ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Single Agent ◽  
Objective Response ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Phase Ib

BackgroundThe programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.MethodsPatients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.ResultsBetween May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.ConclusionsTislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.Trial registration numberNCT02407990.

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