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]

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]

scholarly journals 412 First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A437-A437
Author(s):  
Elena Garralda ◽  
Ravit Geva ◽  
Eytan Ben-Ami ◽  
Corinne Maurice-Dror ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Dose Levels

BackgroundAgonistic 4-1BB monoclonal antibodies were preclinically validated as promising cancer immunotherapies, both as monotherapy and as potentiators of the activity of PD-(L)1–blocking agents. However, toxicity and a narrow therapeutic window have hampered their clinical development. DuoBody-PD­-L1×4-1BB, a first-in-class, bispecific, next-generation checkpoint immunotherapy, was designed to overcome these limitations by activating T cells through conditional 4-1BB costimulation, while simultaneously blocking the PD-L1 axis. We present preliminary data from the ongoing, first-in-human, open-label, phase I/IIa trial of DuoBody-PD-L1×4-1BB in advanced solid tumors (NCT03917381).MethodsDuring dose escalation, patients with metastatic or unresectable solid tumors not eligible for standard therapy received flat-dose DuoBody-PD-L1×4-1BB (25–1200 mg) intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included pharmacokinetic parameters and antitumor activity (RECIST 1.1). Pharmacodynamic biomarkers and antitumor activity (iRECIST) were assessed as exploratory endpoints.ResultsAs of June 22, 2020, 61 patients were enrolled (median age: 59 years). The most common cancer types were colorectal (19.7%), ovarian (14.8%), pancreatic (9.8%), and NSCLC (9.8%). Patients had previously received a median (range) of 3 (1–11) treatments; 44.2% had prior anti-PD-(L)1 immunotherapy. Patients received a median (range) of 4 (1–15) treatment cycles; Cmax was observed shortly after the end of infusion (mean T½: 2.3–10.3 days). Maximum tolerated dose was not reached; 6 patients experienced DLTs. The most common (=10%) treatment-related AEs (all grades; grades 3–4) were transaminase elevation (24.6%; 9.8%), hypothyroidism (16.4%; 1.6%), and fatigue (13.1%; 1.6%). Treatment-related grade-3 transaminase elevations decreased upon corticosteroid administration; no treatment-related bilirubin increases or grade-4 transaminase elevations occurred. Disease control, including stable disease at first assessment and partial responses in triple-negative breast cancer, ovarian cancer, and immune checkpoint inhibitor (ICI)–pretreated NSCLC, occurred in 40/61 patients (65.6%). Pharmacologic activity, as measured by modulation of adaptive immunity mediators, was observed across a broad range of dose levels. Peripheral proliferating (Ki67+) CD8+ effector memory T cells and serum interferon-gamma levels showed maximum induction relative to baseline (p=0.01) 8 days following treatment.ConclusionsDuoBody-PD-L1×4-1BB demonstrated biologic activity and a manageable safety profile. Encouraging early clinical activity across different dose levels was observed in a heavily pretreated population with advanced solid tumors, including those resistant to prior immunotherapy or typically less sensitive to ICIs. Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.AcknowledgementsThe authors thank Manish Gupta, Lei Pang, and Thomas Breuer at Genmab A/S; Alice Bexon, Alexander Muik, and Friederike Gieseke at BioNTech SE; and Zuzana Jirakova (formerly at BioNTech SE) for their valuable contributions. This trial was funded by Genmab A/S and BioNTech SE.Trial RegistrationClinicalTrials. gov; trial number: NCT03917381Ethics ApprovalThis trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board.ConsentWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

scholarly journals Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study

2020 ◽  
Vol 8 (1) ◽  
pp. e000437
Author(s):  
Lin Shen ◽  
Jun Guo ◽  
Qingyuan Zhang ◽  
Hongming Pan ◽  
Ying Yuan ◽  
...  
Keyword(s):  
Cell Death ◽  
Antitumor Activity ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Phase 1 ◽  
Chinese Patients ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Verification ◽  
Open Label

BackgroundTislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.MethodsThe purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.ResultsAs of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.ConclusionsTislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.Trial registration numberCTR20160872.

scholarly journals A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000530 ◽  
Author(s):  
Aung Naing ◽  
Justin F Gainor ◽  
Hans Gelderblom ◽  
Patrick M Forde ◽  
Marcus O Butler ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Wide Range ◽  
Tumor Types ◽  
Tumor Biopsies

BackgroundSpartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.MethodsIn the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).ResultsPatients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.ConclusionsSpartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.Trial registration numberNCT02404441.

A phase I study of MK-5108, an oral aurora A kinase inhibitor, in both monotherapy and in combination with docetaxel in patients with advanced solid tumors.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. e13026-e13026 ◽  
Author(s):  
S. E. Minton ◽  
P. LoRusso ◽  
A. C. Lockhart ◽  
M. Saif ◽  
S. S. Krishnamurthi ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Advanced Solid Tumors ◽  
Aurora A Kinase ◽  
Aurora A

A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13599-e13599 ◽  
Author(s):  
Khurum Hayat Khan ◽  
Li Yan ◽  
Janusz Mezynski ◽  
Amita Patnaik ◽  
Victor Moreno ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Akt Inhibitor ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Simultaneous Inhibition ◽  
Investigational Agents ◽  
Dose Levels

e13599 Background: Simultaneous inhibition of both the PI3K-Akt and RAF/MEK/ERK pathways may yield greater benefits than inhibiting either pathway alone. This phase I study (NCT01021748) examined the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximal tolerated dose (MTD), and preliminary antitumor activity of the combination of a MEKi (selumetinib) and AKTi (MK-2206). Methods: Eligible patients (pts) with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered either once daily (QD) or twice daily (BID). Results: 51 pts with advanced solid tumors (15 colon, 8 NSCLC, 6 ovarian, 5 pancreatic, 3 breast and 14 others) were treated across 9 dose levels. There were 2 confirmed partial response (PR) (1 NSCLC, ongoing > 52 wks; 1 ovarian, on treatment for 47 weeks; both KRAS mutation positive), 1 unconfirmed PR (pancreatic, on treatment 20 wks), and 24 pts with stable disease (ranged from 6 to 47 wks). Preliminary assessment of PK data suggested no apparent drug-drug interactions with unaltered PK profiles of each drug when administered in combination. Conclusions: In combination the maximum tolerated doses of MK-2206 and selumetinib are 135 mg QW and 100 mg QD, respectively. This combination of investigational agents demonstrated preliminary antitumor activity in pts with advanced cancer. [Table: see text]

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