Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora A kinase (AAK) inhibitor MLN8054 in patients (pts) with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2578-2578
Author(s):  
T. Macarulla ◽  
E. Rodríguez-Braun ◽  
J. Tabernero ◽  
S. Roselló ◽  
J. Baselga ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Half Life ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Aurora A Kinase ◽  
Chromosome Alignment ◽  
Tumor Biopsies ◽  
Higher Doses

2578 Background: MLN8054, a first-generation, selective AAK inhibitor, induces chromosome alignment and segregation defects during mitosis, leading to cell death (Hoar et al, MolCellBio 2007;27:4513). This phase I trial examined the safety, PK, and PD of MLN8054 administered orally to adult pts with advanced solid tumors. Methods: Pts received increasing oral doses of MLN8054 until dose-limiting toxicity (DLT) in the first cycle was seen in ≥2 of 3–6 pts in a cohort. Two cohorts received 10 and 20 mg once daily (QD) on d1–5 and d8–12 of 28d cycles. Benzodiazepine-like adverse effects (somnolence) associated with chemical structure and presumably unrelated to AAK inhibition were observed with QD dosing in another Phase 1 study (Dees et al, EJC Suppl 2008;6[12]:91), so subsequent cohorts in this trial were treated with 25, 35, 45, 55, 60, 70, and 80 mg/d in four divided doses (QID) on d1–14, with the largest dose at night. To manage somnolence, methylphenidate 5–15 mg was permitted with daytime doses in the 45–80 mg cohorts. Results: 43 pts received MLN8054 (median 1 cycle [range 1–10]). Dose escalation stopped at 80 mg/d due to DLTs including G3 somnolence (n=1) and G3 transaminitis (n=1). G2 oral mucositis (n=1), which may signal target-related toxicity, was observed first at 80 mg/d, a dose considered to be above the MTD. In PK analyses, MLN8054 was absorbed rapidly (Tmax = 1–2h) and terminal half-life was 30–40h, presenting a linear exposure-dose profile. In PD analyses, MLN8054 at higher doses increased mitotic count in skin and tumor biopsies and reduced chromosome alignment and spindle bipolarity in the mitotic cells in tumor biopsies, outcomes consistent with AAK inhibition. Stable disease (range 4–9 cycles) was observed in 3 pts (colorectal, non-small cell lung, and melanoma). Conclusions: MLN8054 was absorbed rapidly with a long half-life; PD findings supported MLN8054 inhibition of AAK at higher doses. Dosing for 14d of a 28-d cycle was feasible, but off-target DLTs limited dose escalation before mechanism-based toxicity was seen. MLN8237, a second-generation AAK inhibitor designed with greater mechanistic potency and to minimize benzodiazepine effects, is now in clinical trials. [Table: see text]

Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MLN8237, a novel selective aurora A kinase (AAK) inhibitor, in patients (pts) with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2565-2565
Author(s):  
A. Cervantes-Ruiperez ◽  
M. E. Elez ◽  
S. Roselló ◽  
T. Macarulla ◽  
E. Rodríguez-Braun ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Mitotic Index ◽  
Phase 1 ◽  
Recovery Period ◽  
Advanced Solid Tumors ◽  
Aurora A ◽  
Tumor Biopsies ◽  
Mitotic Cells

2565 Background: MLN8237 is a second-generation, selective AAK inhibitor, designed to avoid benzodiazepine-like effects (somnolence) observed with another agent, MLN8054. This phase I trial examines the safety, PK, and PD of MLN8237 administered orally (PO) in pts with advanced solid tumors. Methods: Pts received MLN8237 PO once daily (QD) or twice daily (BID) for 7 days (d) followed by a 14d recovery period. Tumor and skin biopsies were done serially to evaluate bioactivity measured by mitotic index and chromosome and spindle abnormalities in mitotic cells. Doses were increased in cohorts of 3–6 pts until dose-limiting toxicity (DLT) evaluated in the first cycle was seen in ≥2 pts in a cohort. Results: As of 12-Dec-08, 27 pts received MLN8237 (median 2 cycles, range 1–10+); median age was 57 yr (range 31–78). The first cohort received 5mg QD. Higher QD doses were safe in another Phase 1 study (Infante et al, EJC Suppl 2008;6[12]:90), so subsequent cohorts in this study started at 80mg QD (Table). DLTs at 60–100mg PO BID included neutropenia, pancytopenia, stomatitis, and somnolence. Somnolence (of any grade) was seen with QD dosing, but was reduced with divided doses each <100 mg. Antitumor activity was seen in a pt in cohort 4 with a large treatment-resistant pleomorphic liposarcoma. Preliminary PK analyses showed dose-dependent increases in AUC0–24 and Cmax. Consistent with Aurora A inhibition, increased mitotic index in skin and tumor biopsies after MLN8237 dosing was coupled with decreased bipolar spindles and aligned chromosomes in mitotic cells from tumor biopsies. Conclusions: At the doses and schedule evaluated, MLN8237 is tolerable with BID dosing x7d and exhibits favorable PK, PD, and clinical antitumor activity. Additional planned cohorts include extended dosing for 14–21d in 28–35d cycles. The results support future phase 2 development. [Table: see text] [Table: see text]

BDB001, an intravenously administered toll-like receptor 7 and 8 (TLR7/8) agonist, in combination with pembrolizumab in advanced solid tumors: Phase 1 safety and efficacy results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2512-2512
Author(s):  
Manish R. Patel ◽  
Anthony W. Tolcher ◽  
Drew W. Rasco ◽  
Melissa Lynne Johnson ◽  
Angela Tatiana Alistar ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Immune Activation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Safety And Efficacy ◽  
Systemic Immune Activation ◽  
Clinical Responses ◽  
Level 3

2512 Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we report on the safety and efficacy of BDB001 in combination with pembrolizumab in a phase I dose escalation trial in advanced solid tumors (NCT03486301). Methods: BDB001-101 is a phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with pembrolizumab (IV, Q3W) in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results: Twenty-three subjects with 13 different tumor types were enrolled across 4 dose levels. Sixty one percent were female, median age was 63 years (range, 33-86), median number of prior therapies was 3 (range, 1-8), and 48% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with pembrolizumab was well tolerated and dose-limiting toxicities were not observed. The most common treatment related adverse events (TRAEs) were fever (39.1%), fatigue (39.1%), chills/rigor (34.8%), pruritus/rash (21.7%), and nausea (13.0%). Most of these TRAEs were grade 1 or 2 and transient. Only 3 (13.0%) subjects experienced grade 3 TRAEs of fatigue, rash, stomatitis, and alkaline phosphatase elevation. There were no grade 4 or 5 TRAEs. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 3 and 4. Preliminary efficacy evaluation of the 14 subjects treated at Dose Level 3 and 4 showed durable and deep clinical responses in 4 (29%) subjects with anti-PD-(L)1 mAb refractory melanoma, hepatocellular carcinoma, cholangiocarcinoma, and platinum-resistant ovarian carcinoma. The responses were observed by the initial efficacy assessment at 9-weeks, with some seen as early as 4-weeks. In addition, 4 (29%) subjects had stable disease for a disease control rate of 57%. To date, median time on treatment is 14.4 weeks (range, 6.0 – 42.1+) with 3 subjects still active on treatment. Conclusions: Intravenously administered BDB001 in combination with pembrolizumab is well tolerated. Rapid and deep clinical responses were observed, supported by robust systemic immune activation. BDB001 in combination with pembrolizumab is a promising novel therapeutic option for patients with advanced solid tumors and is being evaluated in an ongoing dose expansion trial. Clinical trial information: NCT03486301.

A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors

2016 ◽  
Vol 34 (3) ◽  
pp. 329-337 ◽  
Author(s):  
B. Milojkovic Kerklaan ◽  
S. Slater ◽  
M. Flynn ◽  
A. Greystoke ◽  
P. O. Witteveen ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Food Effect ◽  
Effect Study ◽  
Advanced Solid Tumors ◽  
Integrin Inhibitor

A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors

2009 ◽  
Vol 66 (3) ◽  
pp. 441-448 ◽  
Author(s):  
E. Gabriela Chiorean ◽  
Srikar Malireddy ◽  
Anne E. Younger ◽  
David R. Jones ◽  
Mary-Jane Waddell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Dose Escalation ◽  
Advanced Solid Tumors

Phase Ib study of the anti-TGF-β monoclonal antibody (mAb) NIS793 combined with spartalizumab (PDR001), a PD-1 inhibitor, in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2509-2509
Author(s):  
Todd Michael Bauer ◽  
Chia-Chi Lin ◽  
Richard Greil ◽  
Maria-Elisabeth Goebeler ◽  
Marie Luise Huetter-Kroenke ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Target Genes ◽  
Preliminary Evidence ◽  
Advanced Solid Tumors ◽  
Target Engagement ◽  
Cell Renal Cell Carcinoma ◽  
Grade 3 ◽  
Immune Exclusion ◽  
Tumor Biopsies

2509 Background: TGF-β plays a key role in regulating the tumor microenvironment. Emerging evidence suggests TGF-β is a key activator of cancer-associated fibroblasts, leading to fibrotic network development and immune exclusion. Preclinical data in murine models showed that TGF-β blockade alleviates intratumoral fibrosis, augmenting the efficacy of PD-1 immunotherapy. NIS793 is a human IgG2 mAb that binds to TGF-β. This study investigates NIS793 + spartalizumab in pts with advanced solid tumors. Methods: Pts initially received NIS793 (0.3–1 mg/kg Q3W) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 + spartalizumab (NIS793 0.3–30 mg/kg Q3W + spartalizumab 300 mg Q3W; or NIS793 20–30 mg/kg Q2W + spartalizumab 400 mg Q4W) in pts with/without prior anti-PD-(L)1 therapy. In dose expansion, pts with non-small cell lung cancer (NSCLC) resistant to prior anti-PD-(L)1 or pts with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). Paired tumor biopsies were required from all pts. The primary objectives were to characterize safety and tolerability of the combination and determine the RDE. Results: By December 1, 2020, 60 pts were treated in the dose-escalation phase, mainly with NIS793 + spartalizumab (n = 49), and 60 pts were treated in dose expansion (MSS-CRC: n = 40; NSCLC: n = 20). Two pts were still receiving treatment. No dose-limiting toxicities were observed, and the RDE was established as 30 mg/kg (2100 mg) NIS793 + 300 mg spartalizumab Q3W. Overall 50% pts experienced ≥1 treatment-related AE (TRAE). The most common were rash (n = 15/120), pruritus (n = 10/120), fatigue (n = 9/120), and nausea (n = 8/120). Grade 3/4 TRAEs occurred in 11% pts, with rash (3%) being the most common. Treatment-related serious AEs were reported in 8 pts; 6 were grade 3/4 in severity. No deaths occurred due to AEs; 3 (2.5%) pts discontinued due to AEs. PK for NIS793 was linearly dose proportional with no obvious correlation between exposure and response. Two pts achieved a partial response (PR; one confirmed in clear cell renal cell carcinoma and one unconfirmed in NSCLC) during dose escalation of the combination. Two confirmed PRs were achieved in the MSS-CRC dose-expansion group. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression and protein analyses in tumor biopsies displayed decreased TGF-β target genes, decreased TGF-β signatures and increased immune signatures suggesting modulation of the TGF-β pathway and preliminary evidence of biological activity. Conclusions: Data showing target engagement and TGF-β pathway inhibition supported the proof of mechanism of NIS793. The RDE of the combination was established and well tolerated in pts with advanced solid tumors. Clinical trial information: NCT02947165.

scholarly journals Safety and tolerability of quizartinib, a FLT3 inhibitor, in advanced solid tumors: a phase 1 dose-escalation trial

BMC Cancer ◽  
2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Eytan Ben-Ami ◽  
Amita Patnaik ◽  
Denise Trone ◽  
Jianke Li ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Flt3 Inhibitor

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2631-2631
Author(s):  
Sekwon Jang ◽  
John D. Powderly ◽  
Alexander I. Spira ◽  
Ouiam Bakkacha ◽  
Deryk Loo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Multiple Tumor ◽  
Melanoma Patients ◽  
Tumor Types

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.

Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2580-2580
Author(s):  
Jermaine Coward ◽  
Afaf Abed ◽  
Adnan Nagrial ◽  
Ben Markman
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Febrile Episodes ◽  
Antigen Presenting

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

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