A phase I/II study of the safety and anti-cancer activity of IV-administered belinostat (PXD101) plus carboplatin (C) or paclitaxel (P), or both in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3574-3574 ◽  
Author(s):  
R. Sinha ◽  
R. Moliffe ◽  
M. Scurr ◽  
L. Vidal ◽  
S. A. Engelholm ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Standard Dose ◽  
Sensory Neuropathy ◽  
Recurrent Ovarian Cancer ◽  
Chemotherapeutic Agents ◽  
Ca 125 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Anti Cancer ◽  
Cancer Activity

3574 Background: Belinostat (PXD101), a HDAC inhibitor of the hydroxamate class has shown anti-tumor preclinical activity in combination with other standard chemotherapeutic agents. In Ph. I and II clinical trials the MTD for belinostat has been established at 1,000 mg/m2/d. This Ph I/II study assesses safety, and anti-cancer activity of belinostat administered in combination with C and/or P. Methods: Sequential cohorts of 3–6 patients (pts) with advanced solid tumors and PS 0–2 were recruited to determine the MTD of standard dose C and/or P with escalating doses of belinostat administered as a 30-min IV infusion daily for 5 days (d) every 21 d. C and/or P were administered 2–3 hours following infusion of belinostat on d 3. Results: 23 pts have been treated with a mean of 5 cycles (range 1 - 15) at 5 dose levels: C and belinostat (600 mg/m2) (5 pts); P and belinostat (600 mg/m2) (5 pts); C and P and belinostat (600 mg/m2) (3 pts); C and P and belinostat (800 mg/m2) (4 pts); C and P and belinostat (1,000 mg/m2) (6 pts). Possibly drug-related grade 3 or 4 toxicities were thrombocytopenia (2), vomiting (1), sensory neuropathy (1), myalgia (1), and fatigue (1).No DLT was observed. One SAE (grade 1 T-wave morphology change) was graded as possibly drug-related. No QTcf greater than 500ms were reported. There are 2 confirmed PRs: 1 with heavily treated metastatic rectal cancer and 1 with gemcitabine pre-treated metastatic pancreatic cancer. An additional 11[E1] patients had SD for 2–15 cycles, with 4 being SD for >10 cycles. One pt with mixed mullerian cancer of ovarian origin with SD had an 81% reduction in CA-125 to normal levels after 6 cycles. [E1]If you include MMMT pt as SD on radio. Conclusions: Belinostat with standard dose C and/or P is well-tolerated and shows clinical activity in heavily pre-treated patients with advanced metastatic disease. Recruitment to a phase II expansion in pts with recurrent ovarian cancer is ongoing. No significant financial relationships to disclose.

A phase I dose-escalation study of volasertib (BI 6727) combined with nintedanib (BIBF 1120) in advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2556-2556 ◽  
Author(s):  
Filippo G. De Braud ◽  
Stefano Cascinu ◽  
Gianluca Spitaleri ◽  
Korinna Pilz ◽  
Laura Clementi ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Safety Profile ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Day Treatment ◽  
Single Agent ◽  
Safety Data ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

2556 Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF receptors. Both have shown clinical activity with a manageable safety profile in patients (pts) with advanced solid tumors. This study was designed to determine the maximum tolerated dose (MTD) of V combined with N in these pts. Methods: Cohorts of 3–6 pts received V (100–450 mg IV Q3W) + oral standard dose N (200 mg BID continuously, except V infusion day). Treatment continued until clinical progression. Up to 12 pts were treated at the MTD for additional safety data. Primary endpoint was the MTD; secondary endpoints were pharmacokinetics (PK), overall safety, and preliminary efficacy. Results: 30 pts were treated (median age, 56.5 yr; ECOG PS 0/1/2, 33%/60%/7%; ≥3 prior therapies, 87%). At V doses >200 mg, 7 pts experienced 13 dose-limiting toxicities (DLTs) during cycle 1: increased alanine aminotransferase [ALT] or aspartate aminotransferase [AST], neutropenia and thrombocytopenia. The MTD was V 300 mg (Table). At the MTD, the most common all grade (Gr) adverse events (AEs) were neutropenia (69%), asthenia and thrombocytopenia (62% each), increased ALT, increased AST and diarrhea (54% each). Median (range) duration on treatment was 4 (1–18) cycles. Treatment was discontinued due to progressive disease (80%), DLT (3%) and other non-AE related reasons (17%). 2 objective responses were observed (1 complete [breast cancer] and 1 partial [NSCLC]), both with the 300 mg dose. 6 pts had SD for ≥ 6 mo. PK data will be presented at the meeting. Conclusions: MTD of V + standard dose N (200 mg BID) was determined to be 300 mg Q3W (the same as the recommended phase II single agent dose of V in solid tumors). This combination had a manageable safety profile without unexpected or overlapping toxicities and showed preliminary antitumor activity. Clinical trial information: NCT01022853. [Table: see text]

scholarly journals Apatinib in treating clinical and biochemical recurrent ovarian cancer

2019 ◽  
Author(s):  
Zhongyu Wang ◽  
Yake Huang ◽  
Ling Long ◽  
Li Zhou ◽  
Yan Huang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Chemotherapeutic Agents ◽  
Ca 125 ◽  
Clinical Activity ◽  
Clinical Relapse ◽  
Biochemical Relapse

Abstract Background: Apatinib, a small molecule inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), exerts antiangiogenic effects. Taken orally, apatinib shows clinical activity in the treatment of recurrent or platinum-resistant ovarian cancer (OC) as monotherapy or in combination with other chemotherapeutic agents. We investigated the efficacy of apatinib in recurrent OC and preliminarily evaluated the clinical activity of apatinib in biochemical-only recurrent OC patients. Results: We retrospectively analyzed clinical material of 41 recurrent patients who had received apatinib monotherapy or apatinib plus chemotherapy between June 2016 and August 2018. Apatinib was administered at a 500 mg daily dose. Response was determined according to measurable disease or serum carbohydrate antigen (CA)-125 levels. Progression-free survival (PFS) was estimated by Kaplan-Meier method. All patients were evaluable, 19 (46.34%) had biochemical relapse and 22 (53.66%) had clinical relapse. The objective response rate (ORR) and disease control rate (DCR) in the overall population were 31.71% and 78.05%, respectively. The median PFS was 7 months (95% confidence interval 5.43-8.57). In patients with biochemical relapse only, the median PFS was 6 months, with ORR of 26.32% and DCR of 89.47%. Conclusions: Apatinib is a well-tolerated and effective agent in patients with recurrent OC and has the potential to delay clinical progression in patients with asymptomatic biochemical relapse.

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

Phase I Study of the Novel Epothilone Analog Ixabepilone (BMS-247550) in Patients With Advanced Solid Tumors and Lymphomas

2007 ◽  
Vol 25 (9) ◽  
pp. 1082-1088 ◽  
Author(s):  
Carol Aghajanian ◽  
Howard A. Burris ◽  
Suzanne Jones ◽  
David R. Spriggs ◽  
Marvin B. Cohen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Degradation Products ◽  
Standard Dose ◽  
Chemical Degradation ◽  
Maximum Plasma ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies

Purpose To establish the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or relapsed/refractory non-Hodgkin's lymphoma. Dosing schedules of 40 mg/m2 and 50 mg/m2 over 3 hours were also evaluated. Patients and Methods Sixty-one patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase, with doses of ixabepilone ranging from 7.4 to 65 mg/m2. The pharmacokinetics of ixabepilone and two of its chemical degradation products were evaluated. Plasma pharmacodynamics were evaluated for both 1- and 3-hour infusions using an assay that measures the amount of endogenous tubulin in peripheral-blood mononuclear cells that exists in the polymerized versus the unpolymerized state. Response evaluation was performed every 6 weeks. Results The most common DLTs were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase less than proportionally to dose. Durable objective responses were seen in eight patients, including two complete responses. Five of the responders had experienced treatment failure with a taxane. Conclusion The recommended dose of ixabepilone for the initiation of phase II studies on the basis of these results is 50 mg/m2 over 1 hour every 3 weeks. The promising efficacy and tolerability results demonstrated by ixabepilone in this study warrant its continued development.

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 Nelfinavir Overcomes Proteasome Inhibitor Resistance in Multiple Myeloma By Modulating Membrane Lipid Bilayer Composition and Fluidity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Andrej Besse ◽  
Lenka Besse ◽  
Sara C. Stolze ◽  
Amin Sobh ◽  
Esther A. Zaal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Membrane Fluidity ◽  
Active Site ◽  
Proteasome Inhibitor ◽  
Membrane Lipid ◽  
Clinical Activity ◽  
Anti Cancer ◽  
Reporter Systems ◽  
Target Activity ◽  
Cancer Activity

INTRODUCTION Nelfinavir is a highly lipophilic, first generation HIV-protease inhibitor (HIV-PI) approved for HIV treatment. It has largely been replaced by next-generation HIV-PI with increased specificity and efficacy for HIV therapy, partly reflecting the significant rate of the off-target activity of nelfinavir. Increasing preclinical and clinical evidence shows that nelfinavir has broad anti-cancer activity as a single agent and in combination, potentially related to its off-target activity in mammalian cells. Nelfinavir is particularly effective in the treatment of proteasome inhibitor-refractory multiple myeloma (MM), where the combination of nelfinavir+bortezomib+dexamethasone yielded an overall response rate (ORR, PR or better) > 65% in a Phase II clinical trial. The targets and molecular mechanism of action of nelfinavir in MM are unknown. This hampers both, a rational clinical repositioning and development of nelfinavir as antineoplastic drug, as well as the design, synthesis and testing of next generation nelfinavir-like compounds with optimized antineoplastic activity and improved specificity or pharmacologic properties. We therefore aimed to take an unbiased target-identification approach to identify molecular targets of nelfinavir in human malignant cells and link them to cell biological processes and mechanisms that mediate sensitivity or resistance to nelfinavir treatment. METHODS Proteome-wide affinity-purification of targets binding the nelfinavir active site was combined with genome-wide CRISPR/Cas9-based screening to identify protein partners interacting with nelfinavir and candidate genetic contributors affecting nelfinavir cytotoxicity. Multiple intracellular reporter systems including RUSH system, ATP/ADP constructs; FRAP microscopy, Seahorse measurements, flow cytometry, qPCR, metabolic labelling, lipidomics and viability assays were used to dissect functional alterations in pathways related to nelfinavir targets. RESULTS We identified a common set of proteins interacting specifically with the active site of nelfinavir. These proteins are embedded in intracellular, lipid-rich membranes of mitochondria (VDAC1,2,3, ANT2), endoplasmic reticulum (BCAP31, CANX, SRPRB) and nuclear envelope (PGRMC2) and are consistent across multiple cancer cell types. ADIPOR2, a key regulator gene of membrane lipid fluidity, was identified as a key nelfinavir resistance gene, while genes involved in fatty acids (FAs) and cholesterol metabolism, vesicular trafficking and mitochondria biogenesis are candidate sensitivity genes. We further show that via binding to proteins in lipid-rich membranes nelfinavir affects membrane composition and reduces membrane fluidity, leading to induction of FAs synthesis and the unfolded protein response (UPR). Via its structural interference with membrane fluidity, nelfinavir impairs the function and mobility of a diverse set of membrane-associated proteins and processes, such as glucose flux and processing, mitochondria respiration, energy supply, transmembrane vesicular transport and ABCB1-mediated drug efflux, as we show in different reporter systems in live MM cells. These functional effects are prevented by addition of metabolically inert lipids to be incorporated in membranes, supporting a direct structural activity of nelfinavir. The adaptive biology of proteasome inhibitor (PI)-resistant myeloma relies on metabolic reprogramming and changes in lipid composition, drug export and down-modulation of the UPR. Modulation of membrane fluidity and depletion of FAs/cholesterol is synergistic with proteasome inhibitors in PI-resistant MM. Thus, the mechanism of action of nelfinavir perfectly matches with the biology of PI-resistant MM, serving as a molecular rational for its significant clinical activity. CONCLUSION We here demonstrate in vitro that the activity of nelfinavir against MM cells is triggered through changes in lipid metabolism and the fluidity of lipid-rich membranes. Pharmacologic targeting of membrane fluidity is a novel, potent mechanism to achieve anti-cancer activity, in particular against PI-refractory MM. This mechanism explains the clinical activity of nelfinavir in MM treatment as well as the key side effects of nelfinavir during antiretroviral therapy. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

2020 ◽  
Author(s):  
Xiaofei Zhou ◽  
Farhad Sedarati ◽  
Douglas V. Faller ◽  
Dan Zhao ◽  
Hélène M. Faessel ◽  
...  
Keyword(s):  
Phase I ◽  
Mass Balance ◽  
Solid Tumors ◽  
Whole Blood ◽  
Enzyme Inhibitor ◽  
Systemic Exposure ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Related Material ◽  
The Mean

Summary Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366.

Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: the PACT phase Ia/Ib trial

2020 ◽  
pp. clincanres.2821.2020
Author(s):  
Amita Patnaik ◽  
Timothy A. Yap ◽  
Hyun Cheol Chung ◽  
Maria de Miguel ◽  
Yung-Jue Bang ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Clinical Activity ◽  
Advanced Solid Tumors
Sign in / Sign up

Export Citation Format

Share Document