A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies

Summary LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

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Abstract C216: Phase 1, first‐in‐human, dose‐escalation study of EZN‐2208, a novel anticancer agent, in patients (pts) with advanced malignancies

10.1158/1535-7163.targ-09-c216 ◽

2009 ◽

Cited By ~ 5

Author(s):

Razelle Kurzrock ◽

Jennifer Wheler ◽

David S. Hong ◽

Zhong Guo ◽

Mary F. Mulcahy ◽

...

Keyword(s):

Dose Escalation ◽

Anticancer Agent ◽

Phase 1 ◽

Dose Escalation Study ◽

Human Dose ◽

Advanced Malignancies

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A dose escalation, pharmacokinetic, and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.3533 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 3533-3533 ◽

Cited By ~ 3

Author(s):

D. Mahadevan ◽

R. Plummer ◽

M. S. Squires ◽

D. Rensvold ◽

T. Dragovich ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Kinase Inhibitor ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

Pharmacodynamic Study

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Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients harboring BRAF, KRAS, or NRAS mutations: Phase I study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3000 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3000-3000 ◽

Cited By ~ 3

Author(s):

Tae Won Kim ◽

Jeeyun Lee ◽

Sang Joon Shin ◽

Jin-Soo Kim ◽

Yu Jung Kim ◽

...

Keyword(s):

Dose Escalation ◽

Kinase Inhibitor ◽

Phase 1 ◽

Mek Inhibitor ◽

Primary Objective ◽

Pharmacokinetic Data ◽

Two Phase ◽

Dose Escalation Study ◽

Anti Tumor Activity ◽

Braf Mutant

3000 Background: Belvarafenib (HM95573/GDC-5573) is an oral type II pan-RAF kinase inhibitor which demonstrates selective anti-tumor activity in several non-clinical cancer models and in cancer patients with RAS- or RAF- mutation. Here we present overall safety and efficacy findings of two phase 1 studies, consisting of dose escalation and dose expansion stages. Methods: Patients with advanced solid cancers harboring documented RAS- or RAF- mutation were enrolled. In the dose escalation study, patients were treated with Belvarafenib at a starting dose of 50 mg once daily (QD) to 800 mg BID to assess safety and tolerability and identify the recommended dose (RD). Dose escalation was guided based on pharmacokinetic data and used a traditional 3+3 design. The dose expansion study was comprised of 6 cohorts (according to the type of tumor and RAS- or RAF gene mutation) and patients received the RD of Belvarafenib. The primary objective was to explore anti-tumor activity (per RECIST 1.1) and pharmacodynamic effects. Results: The dose escalation study included 72 patients in 9 dose cohorts (cut-off date of 18 Jan 2017). Dose dependent increase in exposures observed up to 650 mg BID. The most common treatment-emergent adverse events that occurred in more than 20% of patients were rash, dermatitis acneiform and pyrexia. A total of 4 DLTs (different kinds of rashes) were reported and included 2 DLTs at the 800 mg BID level. Therefore, 650 mg BID was considered the MTD and 450 mg BID was identified as the RD for Belvarafenib. There were 7 partial responses (3 confirmed PRs) from 200 mg QD to 800 mg BID in NRAS-mutant melanoma, BRAF-mutant melanoma, KRAS-mutant sarcoma, and BRAF-mutant GIST. Four of nine patients with NRAS-mutant melanoma had a PR (ORR 44%). The dose expansion study included 63 patients in 5 indication-specific and basket cohorts administered with 450 mg BID Belvarafenib (cut-off date of 6 Oct 2018). No new safety signal was detected. There were two PRs each in patients with NRAS-mutant melanoma (2/9), BRAF-mutant melanoma (2/6) and BRAF-mutant CRC (2/7), respectively. Conclusions: Belvarafenib was well tolerated and exhibited anti-tumor activity in patients with advanced solid tumors harboring RAS or RAF mutations. Belvarafenib is being further investigated in combination with the MEK inhibitor cobimetinib. Clinical trial information: NCT02405065, NCT03118817.

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Erratum to: A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors

Investigational New Drugs ◽

10.1007/s10637-015-0287-6 ◽

2015 ◽

Vol 33 (6) ◽

pp. 1292-1292 ◽

Cited By ~ 1

Author(s):

Geoffrey I. Shapiro ◽

Stewart McCallum ◽

Laurel M. Adams ◽

Laurie Sherman ◽

Steve Weller ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Kinase Inhibitor ◽

Phase 1 ◽

Dose Escalation Study ◽

Once Daily

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A phase I dose-escalation study of the safety and pharmacokinetics (PK) of XL184, a VEGFR and MET kinase inhibitor, administered orally to patients (pts) with advanced malignancies

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14031 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14031-14031 ◽

Cited By ~ 17

Author(s):

R. Salgia ◽

D. S. Hong ◽

L. H. Camacho ◽

C. S. Ng ◽

L. Janisch ◽

...

Keyword(s):

Dose Escalation ◽

Half Life ◽

Kinase Inhibitor ◽

Cell Cancer ◽

Dose Escalation Study ◽

Medullary Thyroid ◽

Molecule Inhibitor ◽

Advanced Malignancies ◽

Terminal Half Life ◽

Dose Levels

14031 Background: XL184 is a potent orally available small molecule inhibitor of MET and VEGFR2/KDR, and also inhibits KIT, RET, FLT3, and Tie-2. Methods: This is a ph 1 cohort dose escalation study. Pts with advanced malignancies are treated with 2 cycles of XL184 orally daily for 5 consecutive days every 2 weeks. Response is assessed every 8 wks by RECIST criteria and pts with SD or better receive maintenance therapy. Plasma markers of angiogenesis VEGF-A, sVEGFR2 and Ang2 are being analyzed. Results: A total of 25 pts with advanced malignancies have been treated across 7 dose levels: 0.08 to 5.12 mg/kg. A total of 10 pts have had SD lasting > 3 months. Three pts with medullary thyroid carcinoma (one of whom had a documented RET mutation) had substantial reductions in plasma calcitonin. Three pts have had stable disease for over 6 months, including 1 pt with carcinoid (20% decrease in liver metastases) and 1 pt with T- cell lymphoma (on treatment for >12 mos). One pt with papillary renal cell cancer, a disease that sometimes bears activating MET mutations, demonstrated 9% tumor reduction at first restaging. There have been no DLTs to date. Preliminary PK analysis (0.08–1.28 mg/kg) suggests linear PK with average Cmax values 34.2, 70, 198, 322 and 603 ng/mL following the fifth dose at 0.08, 0.16, 0.32, 0.64 and 1.28 mg/kg, respectively. The terminal half-life is 80–90 hrs, resulting in concentrations exceeding 200 ng/mL for 96 hours following the fifth dose at 1.28 mg/kg. Conclusions: XL184 appears generally well tolerated at doses tested to date. XL184 has a long terminal half-life. Early signs of antitumor activity have been observed, at doses not associated with toxicity, in patients with various cancers, including but not limited to those that may have RET (medullary thyroid) or MET (papillary renal) mutations. No significant financial relationships to disclose.

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