A phase I QTc study of tivozanib in patients with advanced solid tumors.

445 Background: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Preclinical and retrospective electrocardiogram (ECG) analyses suggest no effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the effect of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20-30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessing clinical laboratory tests, physical examinations, vital signs, and recording of adverse events. Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received ≥ 1 dose of tivozanib were evaluable. Preliminary data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented. Conclusions: Preliminary data suggest that tivozanib 1.5 mg/d over a 21-day period does not cause clinically significant QT/QTc prolongation over baseline, suggesting that its safety and PK profile is similar to that observed in previous studies, including ECG evaluation in a monkey telemetry study.

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Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.7278 ◽

2010 ◽

Vol 28 (25) ◽

pp. 3965-3972 ◽

Cited By ~ 245

Author(s):

Timothy A. Yap ◽

Laura Vidal ◽

Jan Adam ◽

Peter Stephens ◽

James Spicer ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Kinase Inhibitor ◽

Small Cell Lung Carcinoma ◽

Maximum Tolerated Dose ◽

Phase Iii ◽

Advanced Solid Tumors ◽

Irreversible Inhibitor ◽

Cell Lung Carcinoma ◽

Bibw 2992

Purpose Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy. Patients and Methods Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state. Results Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non–small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting ≥ 6 months. Conclusion Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.

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Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-11-2378 ◽

2011 ◽

Vol 18 (4) ◽

pp. 1092-1100 ◽

Cited By ~ 50

Author(s):

Adil I. Daud ◽

Smitha S. Krishnamurthi ◽

Mansoor N. Saleh ◽

Barbara J. Gitlitz ◽

Mitesh J. Borad ◽

...

Keyword(s):

Tyrosine Kinase ◽

Phase I ◽

Tyrosine Kinase Inhibitor ◽

Solid Tumors ◽

Phase I Study ◽

Kinase Inhibitor ◽

Advanced Solid Tumors ◽

Abl Tyrosine Kinase ◽

Abl Tyrosine Kinase Inhibitor

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A Phase I and pharmacokinetic study of HMN-214, a novel oral polo-like kinase inhibitor, in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.3034 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 3034-3034 ◽

Cited By ~ 8

Author(s):

D. D. Von Hoff ◽

C. Taylor ◽

S. Rubin ◽

J. Cohen ◽

L. Garland

Keyword(s):

Phase I ◽

Solid Tumors ◽

Pharmacokinetic Study ◽

Kinase Inhibitor ◽

Advanced Solid Tumors

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A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3592 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3592-3592 ◽

Cited By ~ 6

Author(s):

C. Sweeney ◽

C. Verschraegen ◽

G. Chiorean ◽

F. Lee ◽

S. Jones ◽

...

Keyword(s):

Breast Cancer ◽

Phase I ◽

Solid Tumors ◽

Kinase Inhibitor ◽

Antiangiogenic Therapy ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Curative Therapy ◽

Grade 3

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.

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