Peter Stopfer

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

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 > or = 6 months. CONCLUSION Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.

Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors.

Purpose: BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120. Patients and Methods: Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients. Results: Most frequent BIBF 1120–related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (tmax = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients. Conclusions: BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies. Clin Cancer Res; 16(1); 311–9

Phase I Open-Label Study of Continuous Treatment with BIBF 1120, a Triple Angiokinase Inhibitor, and Pemetrexed in Pretreated Non–Small Cell Lung Cancer Patients

Introduction: BIBF 1120 (planned brand name Vargatef) is a novel, oral, triple angiokinase inhibitor targeting three receptor classes involved in blood vessel formation. The objectives of this phase I, open-label dose-escalation study were to determine the safety, tolerability, and maximum tolerated dose (MTD) of BIBF 1120 with pemetrexed in patients with recurrent advanced-stage non–small cell lung carcinoma. Patients and Methods: Patients harboring a tumor of any non–small cell lung carcinoma histology, previously treated with one first-line platinum-based chemotherapy regimen, received a BIBF 1120 starting dose of 100 mg bid (days 2-21) with pemetrexed 500 mg/m2 (day 1) over a 21-day cycle. Previous pemetrexed treatment was not permitted. BIBF 1120 dose was escalated until the MTD was determined. Results: Twenty-six patients were treated. During treatment cycle (TC) 1, dose-limiting toxicities were experienced by one patient receiving 100 mg bid, one patient receiving 150 mg bid, one patient receiving 200 mg bid, and two patients receiving 250 mg bid BIBF 1120. Two additional dose-limiting toxicities were observed in TC 1 in an expanded patient cohort receiving 200 mg bid. Gastrointestinal disorders (84.6%), general disorders, and administration site conditions (76.9%) were the most frequent drug-related adverse events. One patient had a complete response 44 days after initiating trial medication; 50% had stable disease as the best overall response. No clinically relevant pharmacokinetic interactions between BIBF 1120 and pemetrexed were observed. Conclusion: The MTD of BIBF 1120 in combination with standard-dose pemetrexed was 200 mg bid. Continuous daily treatment with BIBF 1120 in this combination was tolerable, with promising signs of efficacy. Clin Cancer Res; 16(10); 2881–9. ©2010 AACR.

Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers

The pharmacokinetics and metabolism of BIBF 1120, an oral triple angiokinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), were studied in healthy male volunteers (n = 8) who had received a single oral dose of 100 mg [14C]-radiolabelled BIBF 1120 administered as solution. BIBF 1120 was well-tolerated and rapidly absorbed; median time to reach maximum plasma concentrations was 1.3 h and gMean terminal half-life was 13.7 h. A relatively high apparent total body clearance and volume of distribution possibly indicated a high tissue distribution. Plasma concentrations of BIBF 1120 plus carboxylate metabolite BIBF 1202 were lower than the total [14C]-radioactivity in plasma, indicating presence of additional metabolites. Total recovery in excreta was 94.7% 1 week post-dose; mass balance was considered complete after 96 h. BIBF 1120 and metabolites were mainly excreted via faeces. The major metabolic pathway for BIBF 1120 was methyl ester cleavage to BIBF 1202. Subsequently, the free carboxyl group of BIBF 1202 was glucuronidated to 1-O-acylglucuronide. Pathways of minor importance were oxidative N-demethylation to yield BIBF 1053, and oxidation of the piperazine moiety and conjugation. Glucuronidation of the parent drug and formylation of the secondary aliphatic amine of the piperazine ring played a minor role.

Pharmacokinetic Evaluation of a Drug Transporter Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin

This article reports the clinical investigation of a probe drug cocktail containing substrates of key drug transporters. Single oral doses of 0.25 mg digoxin (P‐gp), 5 mg furosemide (OAT1 and OAT3), 500 mg metformin (OCT2, MATE1, and MATE2‐K), and 10 mg rosuvastatin (OATP1B1, OATP1B3, and BCRP) were administered separately or as a cocktail in a randomized six‐period crossover trial in 24 healthy male volunteers. As a cocktail, relative bioavailabilities of digoxin and metformin and furosemide AUC0‐tz were similar to separate dosing. However, when administered as a cocktail the Cmax of furosemide was 19.1% lower and the Cmax and AUC0‐tz of rosuvastatin were 38.6% and 43.4% higher, respectively. In addition, the effects of increased doses of metformin or furosemide on the cocktail were investigated in 11 and 12 subjects, respectively. The cocktail explored in this trial has the potential to be used for the in vivo screening of transporter‐mediated drug–drug interactions.

Phase I dose-escalation study of afatinib, an ErbB family blocker, plus docetaxel in patients with advanced cancer

AIMS To determine the maximum tolerated dose (MTD), safety and anti-tumor activity of afatinib combined with docetaxel in advanced cancer. PATIENTS & METHODS The MTD was determined from dose-limiting toxicities in the first cycle. RESULTS Thirty-one patients received 10, 20 and 30 mg oral afatinib, plus 60 and 75 mg/m(2) intravenous docetaxel (six cohorts; 3-week cycles). The MTD of afatinib was 20 mg/day (days 2-21) with 75 mg/m(2) docetaxel (day 1). Dose-limiting toxicities were grade 3/4 diarrhea (n = 3) and febrile neutropenia (n = 6). Most frequently occurring adverse events were diarrhea, neutropenia and rash. Disease stabilization occurred in 14 patients. CONCLUSION Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile.

Pharmacokinetic Properties of Nintedanib in Healthy Volunteers and Patients With Advanced Cancer

Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef®) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma non‐small cell lung cancer (NSCLC) after first‐line chemotherapy, and as monotherapy (Ofev®) in the United States and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single and multiple doses and intravenous (IV) administration were assessed using 3 data sets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of 4 studies that enrolled a total of 107 healthy volunteers; and (3) a pooled data analysis of 4 studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean 1390 mL/min) and a high volume of distribution at steady state (Vss = 1050 L). Urinary excretion of IV nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after IV administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to IV dosing (4‐hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first‐pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice‐daily dosing. Nintedanibs PK was time‐independent; accumulation after repeated administration was negligible.

Treatment of lung cancer patients and concomitant use of drugs interacting with cytochrome P450 isoenzymes

OBJECTIVE The majority of anticancer medicines used in the therapy of lung cancer patients are metabolized by cytochrome P450 (CYP450) enzymes, but little is known about the frequency of prescribed concomitant medicines interacting via the same enzyme system. This study analyzed the use of medications that could cause drug-drug interactions (inhibition or induction) in lung cancer patients before and during anticancer treatment. RESEARCH DESIGN AND METHODS In this retrospective cross sectional study, all lung cancer patients (ICD-9 codes 162.2-162.9, 231.2) aged ≥18 years who received any anticancer medicines between 1/1/2004 and 6/30/2008 were identified in the US Thomson Reuters MarketScan(®) Claims Database. Patients had to have data for at least 12 months prior to (pre-period) and during their treatment, had no other cancer or use of other anticancer treatment in the pre-period. Patients with renal disease, renal failure, or liver failure were excluded. Drugs known to induce or inhibit P450 enzymes and used before and during lung cancer treatment were categorized with respect to their potency (strong, moderate, low). RESULTS Out of 144,959 lung cancer patients, 6647 (4.6%) patients met the study entry criteria. Mean age was 67 years, 53% were men, and mean Charlson combordity index was 3.5. 99% of patients received at least one drug known as a substrate, inhibitor or inducer of P450 (98% inhibitors, 93% inducers, 98% substrates) during the patients anticancer treatment episode. Mean co-treatment duration with any CYP450 agent was 99 days (76% of the episode length); ≥2 different CYP450 agents were prescribed during 98% of episodes, and ≥10 different CYP450 agents were prescribed during 44% of episodes. Use of CYP450 agents was similar in the pre-treatment period: at least one CYP450 agent was prescribed during 99% of episodes (99% inhibitors, 79% inducers, 98% substrates). CONCLUSIONS Drugs which may cause drug-drug interactions while affecting the CYP 450 enzymes are frequently prescribed both before and during anticancer treatment of lung cancer patients.

Randomized phase II study of nintedanib in metastatic castration-resistant prostate cancer postdocetaxel.

This open-label, phase II trial assessed the efficacy and safety of two doses of nintedanib, a triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor signaling, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on docetaxel-based regimens. Patients were randomized to nintedanib 150 mg (arm A, n=40) or 250 mg (arm B, n=41) twice daily for 6 months unless disease progression or adverse events (AEs) led to discontinuation. The primary endpoint was the prostate-specific antigen (PSA) response rate (confirmed PSA decline of ≥20% from baseline). Eighty-one patients were enrolled. The PSA response rate was 0% (0/32) in arm A versus 11.1% (4/36) in arm B (P=0.12); 5.6% of patients (2/36) in arm B showed a PSA reduction of at least 50%. In arm B, the rate of PSA increase was significantly decelerated on treatment versus before treatment (P=0.002). The median progression-free survival was 73.5 and 76.0 days for arm A and arm B, respectively (P=0.3). AEs included gastrointestinal disorders, asthenia, hypertension, and reversible elevated transaminases. The incidence of drug-related serious AEs (no drug-related deaths) was 20.0% (arm A) and 24.4% (arm B). The primary endpoint was not met. Nintedanib (250 mg) showed only modest activity with manageable AEs in patients with mCRPC post-docetaxel.

Phase I Study of Nintedanib Incorporating Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Patients With Advanced Solid Tumors

BACKGROUND This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors. METHODS Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28. RESULTS Fifty-one patients received nintedanib 100-450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily. CONCLUSION Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.