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First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors.

ABSTRACT: Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tumor activity in preclinical models. This first-in-human trial was performed to establish the safety and maximum tolerated dose (MTD), as well as preliminary pharmacokinetics (PK) and clinical activity. Methods Forty-seven patients were enrolled in three parts. The primary objective of Parts A and B was safety, whereas Part C evaluated the effect of proton-pump inhibitors on MK-8033 absorption. Dose escalation used an accelerated continual reassessment method, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade???3 toxicity (except alopecia or inadequately treated nausea/vomiting/diarrhea), grade 4 hematologic toxicity (except grade 3 neutropenic fever and thrombocytopenia), or toxicity where treatment is held >3 weeks. Results Forty-six patients were treated across nine dose levels, and the MTD was 750 mg twice daily. DLTs were fatigue, nausea, vomiting, transaminitis, and hypokalemia. Most frequent toxicities were fatigue (28.3%), nausea (21.7%), and alopecia (19.6%), predominately grade???2. One patient with endometriod adenocarcinoma achieved a partial response and eight had stable disease. Median progression-free survival (PFS) was 57 days. Strikingly, the PFS for the one responder was 846 days. PK results showed that proton-pump inhibitors have no effect on MK-8033 absorption. Conclusion MK-8033 was well tolerated with no significant toxicity issues, albeit with limited clinical activity. Unfortunately, the company decided to discontinue further clinical development of MK-8033.

SUBMITTER: Keedy VL

PROVIDER: S-EPMC7507839 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors.

Keedy Vicki L VL Lenz Heinz-Josef HJ Saltz Leonard L Whisenant Jennifer G JG Berlin Jordan D JD Camacho Luis H LH

Investigational new drugs 20180129 5

Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tumor activity in preclinical models. This first-in-human trial was performed to establish the safety and maximum tolerated dose (MTD), as well as preliminary pharmacokinetics (PK) and ...[more]

PMID: 29376210

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Project description:BackgroundANV419 is a stable antibody-cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor but has selective affinity for the receptor βγ subunits. Thus, ANV419 preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells.MethodsANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24-364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023).ResultsForty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR).ConclusionsANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors.Trial registration numberNCT04855929.

Project description:Lessons learnedPharmacokinetic results underscore that the vorolanib (X-82) study design was successful without the need for further dose escalation beyond 400 mg once daily (q.d.).Therefore, the recommended dose of X-82 as a single agent in patients with advanced cancer is 400 mg q.d.BackgroundVorolanib (X-82) is a novel, oral, multikinase vascular endothelial growth factor (VEGF) receptor/platelet-derived growth factor (PDGF) receptor inhibitor that was developed on the same chemical scaffold as sunitinib, but designed to improve upon the safety profile while maintaining the efficacy of sunitinib. By targeting the VEGF and PDGF receptors, X-82 was expected to disrupt tumor angiogenesis and be active in a broad spectrum of solid tumors. Therefore, we determined the maximum tolerated dose (MTD) and characterized the preliminary pharmacokinetics and clinical tumor response of X-82 as a single agent in patients with advanced solid tumors.MethodsAdult patients with advanced solid tumors received X-82 as tablets or capsules (once daily [q.d.] or b.i.d.) every 4 weeks. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity.ResultsFifty-two patients received study treatment in 17 cohorts. X-82 capsule dosing was as follows: cohorts 1-6 (20-400 mg q.d.) and cohorts 7-8 (140-200 mg b.i.d.). Patients in cohorts 9-17 received 50-800 mg q.d. tablet dosing. The median time on treatment was 58 days. X-82 blood pharmacokinetics appeared dose-independent with a t 1/2 of 5.13 hours and 6.48 hours for capsule and tablet formulations, respectively. No apparent accumulation was observed after 21 days of daily dosing.ConclusionX-82 had a safety profile consistent with its mechanism of action. It has a short half-life and was well tolerated by most patients. Study enrollment ended prior to the determination of the MTD because of the apparent saturation of absorption at 400-800 mg. The recommended dose of X-82 as a single agent in patients with advanced cancer is 400 mg q.d.

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First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors.

Publications

First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors.

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