Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2512-2512 ◽  
Author(s):  
Amita Patnaik ◽  
Soonmo Peter Kang ◽  
Anthony W. Tolcher ◽  
Drew Warren Rasco ◽  
Kyriakos P. Papadopoulos ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Preliminary Evidence ◽  
Open Label ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
Multiple Tumor ◽  
Label Dose ◽  
Grade 3 ◽  
Tumor Types

2512 Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that may lead to suppression of antitumor immunity. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown antitumor activity in multiple tumor types. This first-in-human phase I trial explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancy refractory to standard therapy. Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following an initial dose and 28-day Cycle 1, patients were allowed to subsequently receive multiple doses given every 2 wks. Radiographic assessment was conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non–small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). To date, a total of 63 doses were administered (median 7/patient; max 12) without DLT. Drug-related adverse events (AEs) across all doses included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs ≥ Grade 3 were observed. PK data are shown in the table. Based on RECIST, 1 patient with MEL on therapy >6 mths had a partial response, and preliminary evidence of tumor size reduction (stable disease) was observed in 3 additional patients with advanced cancer. Conclusions: MK-3475 was well-tolerated without DLT across 3 tested dose levels. Evidence of antitumor activity was observed. Enrollment continues to obtain additional safety, PK, and efficacy data; updated data will be presented at the meeting. [Table: see text]

A phase I study to evaluate safety and antitumor activity of biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in patients with RCC and other advanced refractory malignancies.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 331-331 ◽  
Author(s):  
D. F. McDermott ◽  
C. G. Drake ◽  
M. Sznol ◽  
J. A. Sosman ◽  
D. C. Smith ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Median Duration ◽  
Dose Escalation ◽  
Tumor Type ◽  
Duration Of Treatment ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Dose Escalation Study ◽  
Grade 3

331 Background: Programmed death-1 (PD-1), a T-cell inhibitory receptor, may suppress antitumor immunity. BMS-936558, a fully human PD-1 blocking antibody, has shown antitumor activity and manageable toxicity after biweekly dosing (Sznol, ASCO 2010, #2506). This report provides an update on safety and antitumor activity with special emphasis on RCC. Methods: An open-label phase I dose escalation study of BMS-936558 was conducted in patients (pts) with treatment refractory metastatic clear-cell renal cell carcinoma (RCC), castrate-resistant prostate cancer (CRPC), melanoma (MEL), non-small cell lung cancer, or colorectal cancer (CRC). Dose escalation continued to 10 mg/kg when an expansion cohort for pts (16) with each tumor type was opened for additional safety and efficacy information. Tumor response (RECIST) was evaluated every 8 weeks. Clinically stable pts with early PD could continue until further PD or clinical deterioration. Results: 126 pts (18 RCC) were treated with 1, 3, or 10 mg/kg. MTD was not reached. Across all doses, the most common AEs (Any/grade 3-4) were fatigue (45.2%/6.3%) and diarrhea (30.2%/0.8%) while the most common drug-related AEs (Any/grade 3-4) were fatigue (20.6%/0.8%), rash (11.9%/0%), pruritus (11.3%/0%), and diarrhea (10.3%/0.8%). There was no apparent relationship between dose and frequency of AEs. One pt died with sepsis while being treated for drug-related grade 4 pneumonitis. The median number of prior treatment regimens in the RCC cohort was 2 (range 1-6). Of the 18 RCC pts, 16 were treated with 10 mg/kg. The median duration of treatment was 7.6+mo. ORR was 5/16 (31.2%) and SD>4mo was 6/16 (37.5%). The median duration of response was 4.0+ mo (3.7-7.4+ mo). Of the 2 RCC pts treated with 1 mg/kg, 1 obtained a CR (12+ mo) and 1 had SD (21+ mo). For evaluable CRPC pts, 1/15 pts (6.7%) obtained a PR (2+ mo) and 3/15 (20%) had SD>4mo. Conclusions: BMS-936558 administered biweekly is tolerable and has encouraging antitumor activity in a previously treated patients with RCC. Data on baseline characteristics, long-term toxicity and response duration will be updated at the meeting. [Table: see text]

Ixabepilone given weekly in patients with advanced malignancies: Final efficacy and safety results of a phase I trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2040-2040 ◽  
Author(s):  
N. Dickson ◽  
R. Peck ◽  
C. Wu ◽  
H. Burris
Keyword(s):  
Phase I ◽  
Sensory Neuropathy ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Weekly Infusion ◽  
Neck Tumors ◽  
Grade 3 ◽  
Tumor Types ◽  
Experienced Grade

2040 Background: Ixabepilone is a potent tubulin-targeting agent. The first epothilone analog, ixabepilone, has been developed to optimize the characteristics of the naturally occurring epothilone B. Methods: This open-label, single-arm Phase I dose escalation study was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and a recommended dose of ixabepilone when administered as a weekly infusion to patients (pts) with solid tumors who had failed standard therapy. Eligible pts were aged ≥18 years and had histologically/cytologically confirmed solid tumor disease and an ECOG status of 0–2. Ixabepilone was administered weekly as a 30-minute infusion on a 21-day schedule. Due to neurotoxicity, infusion time was increased to 1 hour with a 1-week break allowed. Dosing ranged from 1–30 mg/m2. Tumor evaluations were performed every 6 or 8 weeks (21-day or 28-day schedule, respectively). Toxicity was evaluated continuously. Results: 34 pts were treated on the 21-day schedule (median age 55, range 30–73) and 52 on the 28-day schedule (median age 55, range 33–79). 88% of pts had received prior chemotherapy. Grade 3 fatigue was the DLT in 2 of the 4 pts treated with 30 mg/m2 ixabepilone. No DLTs were seen at doses ≤25 mg/m2 on the 21-day schedule, or at doses of 15, 20 or 25 mg/m2 on the 28-day schedule. The MTD was 25 mg/m2 for the 21-day schedule. Of 12 pts who received this dose and schedule, 7 (58%) experienced Grade 1/2 neuropathy, 1 (8%) developed Grade 3 sensory neuropathy and 3 (25%) experienced Grade 3 fatigue. Of 52 pts who received 20 mg/m2 on the 28-day schedule, 2 (13%) had Grade 3 neutropenia, 1 (7%) had Grade 3/4 sensory neuropathy and 4 (27%) had Grade 3 fatigue. Five pts (two pts [21-day schedule], three pts [28-day schedule]) with breast, colon, ovary, head and neck tumors achieved objective partial responses. Conclusions: The recommended doses of ixabepilone from this study are 25 mg/m2 (30-minute weekly infusion, 21-day schedule) and 20 mg/m2 (1-hour weekly infusion, 28-day schedule). Ixabepilone demonstrated efficacy and an acceptable safety profile in pts with a broad range of tumor types, several of whom had failed a taxane. [Table: see text]

Phase I study of daily administration of MGCD265 to patients with advanced malignancies (Study 265–101)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14525-e14525 ◽  
Author(s):  
C. K. Kollmannsberger ◽  
H. Hurwitz ◽  
G. Vlahovic ◽  
C. Maroun ◽  
J. Dumouchel ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Tumor Development ◽  
Daily Administration ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Grade 3

e14525 Background: MGCD265 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor that targets the mesenchymal epithelial transition (c-Met) and the vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3). Additional RTK targets include Tie-2, and Ron. Those kinases are known to be involved in tumor development and angiogenesis. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of daily administration of MGCD265 in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered as a continuous 21-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Ten patients with advanced solid tumors have been treated. Characteristics: age range 25–75; gender: 8 M/2F; ECOG: 0 (1 patient); 1 (9 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs during cycle 1 have been reported. Eight patients received treatment for 2 cycles or more. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax with an approximate mean half-life of 23 hours (see Table below). At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Daily oral administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Further dose escalation is underway. [Table: see text] [Table: see text]

Phase I study of MGCD265 administered intermittently to patients with advanced malignancies (Study 265–102)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14516-e14516
Author(s):  
D. Hong ◽  
P. LoRusso ◽  
R. Kurzrock ◽  
C. Maroun ◽  
M. Mehran ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Open Label ◽  
Dose Escalation Study ◽  
Nonhematologic Toxicity ◽  
Advanced Malignancies ◽  
Label Dose ◽  
Grade 3 ◽  
Age Range

e14516 Background: MGCD265 is an orally-available small molecule designed to inhibit c-Met, VEGFR-1, -2, -3, Tie-2 and Ron kinases. These targets are potentially relevant for the treatment of a variety of cancers. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of MGCD265 using an intermittent schedule of administration in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered on days 1–7 and 15–21 (1 week on, 1 week off schedule) of each 28-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Eleven patients with advanced solid tumors have been treated. Characteristics: age range 40–72; gender: 3 M/8F; ECOG: 1 (7 patients); 2 (4 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs have been reported during cycle 1. Six patients received treatment for 2 or more cycles. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax (Table below) with an approximate mean half-life of 30 hours and an approximate mean Tmax of 7 hours. At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Intermittent administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Treatment of patients at 192 mg/m2 is underway. [Table: see text] [Table: see text]

Epacadostat plus pembrolizumab in patients with SCCHN: Preliminary phase I/II results from ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6010-6010 ◽  
Author(s):  
Omid Hamid ◽  
Todd Michael Bauer ◽  
Alexander I. Spira ◽  
Anthony J. Olszanski ◽  
Sandip Pravin Patel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Iii ◽  
Open Label ◽  
Multiple Tumor ◽  
Prior Chemotherapy Regimen ◽  
Hpv Status ◽  
Open Label Phase ◽  
Checkpoint Inhibitor Therapy ◽  
Grade 3 ◽  
Tumor Types

6010 Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. IDO1 overexpression has been associated with poor survival in SCCHN. Epacadostat (E) is a potent, selective oral IDO1 inhibitor. ECHO-202/KEYNOTE-037 is an open-label, phase I/II (P1/2) study evaluating E plus PD-1 inhibitor pembrolizumab (P) in multiple tumor types. We report preliminary P1/2 efficacy, safety, and tolerability findings in the SCCHN cohort as of a 29OCT2016 data cutoff. Methods: Eligible adult patients (pts) had metastatic SCCHN and received ≥1 prior chemotherapy regimen that included a platinum agent. Prior checkpoint inhibitor therapy (tx) was not permitted, and pts with carcinoma of the nasopharynx or salivary gland were excluded. In P1 dose escalation (3+3+3), pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for P2 cohort expansion. Response was assessed in RECIST 1.1 evaluable pts. Results: A total of38 pts (P1, n = 2; P2, n = 36) were evaluated. Median age was 63 years, 87% of pts were men, 95% were white, and 66% received prior cetuximab. Of 36 efficacy-evaluable pts, 81% (n = 29) received 1–2 prior lines of tx and 19% (n = 7) received ≥3 prior lines of tx. ORR (CR+PR) and DCR (CR+PR+SD) for pts with 1–2 prior tx were 34% (2 CR, 8 PR) and 62% (8 SD), respectively; for pts with ≥3 prior tx, ORR and DCR were 14% (1 PR) and 43% (2 SD). Response was observed regardless of HPV status. At data cutoff, 9/11 responses were ongoing (range, 1+ to 563+ days). PFS and biomarker analyses are ongoing. The most common TRAEs in all 38 pts were fatigue (24%), nausea (11%), and decreased weight (11%). Grade ≥3 TRAEs occurred in 11% of pts; only increased amylase and lipase (both asymptomatic) were grade ≥3 TRAEs that occurred in > 1 pt. TRAEs led to discontinuation in 1 pt (increased amylase and lipase). Conclusions: In pts with advanced SCCHN, E + P was generally well tolerated and associated with encouraging response rates, particularly in pts with 1–2 prior lines of tx. A phase III SCCHN study is planned. Clinical trial information: NCT02178722.

Early safety and efficacy from a phase I open-label clinical trial of CD137(4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
Siqing Fu ◽  
Wael A. Harb ◽  
Sapna Pradyuman Patel ◽  
Charles Lu ◽  
Daniel M. Halperin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Safety Profile ◽  
Single Agent ◽  
Human Study ◽  
Hepatic Metastases ◽  
Preliminary Evidence ◽  
Open Label ◽  
Grade 3 ◽  
Favorable Safety

2521 Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by >10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.

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