Heike Richly

Phase I Clinical and Pharmacokinetic Study of the Novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor BAY 43-9006 in Patients With Advanced Refractory Solid Tumors

PURPOSE BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. PATIENTS AND METHODS BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. RESULTS Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. CONCLUSION Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.

Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: Results from a phase I extension trial

Sorafenib, an oral multikinase inhibitor, shows efficacy in renal cell and hepatocellular carcinoma (HCC) and is well tolerated when combined with doxorubicin in other solid tumours. Eighteen patients with inoperable HCC received doxorubicin 60 mg/m(2) IV for up to six 3-week cycles. Sorafenib 400mg bid was administered continuously starting day 4. Patients discontinuing doxorubicin were eligible for sorafenib monotherapy. The most frequent grade 3-4 drug-related adverse events were neutropaenia (61%), leukopaenia (45%) and diarrhoea (17%, grade 3). Seven of eight patients who completed six cycles of doxorubicin continued treatment with sorafenib for at least 3 months. Doxorubicin moderately increased AUC (21%) and C(max) (33%) when administered with sorafenib. The disease control rate for 16 evaluable patients was 69%. Sorafenib plus doxorubicin appears to be well tolerated and more effective in the treatment of HCC than doxorubicin alone. Follow-up with single-agent sorafenib in these patients also appears to be well tolerated.

First-in-Human Phase I Study of PRS-050 (Angiocal), an Anticalin Targeting and Antagonizing VEGF-A, in Patients with Advanced Solid Tumors

Background To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A). Methods Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety. Results Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti–PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug’s activity. Conclusions PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. Trial Registration ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257

A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR Central European Society for Anticancer Drug Research–EWIV

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.

Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours

PURPOSE This study was initiated to evaluate safety, toxicity, pharmacokinetics, and pharmacodynamics of treatment with MGN1703, a novel synthetic DNA-based toll-like receptor 9 (TLR9)-immunomodulator. METHODS The study consisted of an escalating single dose regimen followed by a multiple dose part. Dose levels of 0.25, 2, 10, 30, and 60 mg of MGN1703 were administered subcutaneously over 6 weeks twice weekly. Patients with at least stable disease (SD) could participate in the extension phase of the study for six further weeks. Effects on the immune status were monitored. RESULTS 28 patients with metastatic solid tumours were included. Fatigue and activated partial thromboplastin time (aPTT) prolongation were the only two cases of drug-related grade 3 Common Terminology Criteria adverse events (CTCAE). The most frequently reported drug-related adverse events were of CTC Grade ⩽2. There was no relationship between toxicity and dose and no patient was withdrawn from the study due to drug-related AE. No drug-related serious AE (SAE) were reported. Six out of 24 patients had SD after 6 weeks of treatment and three of those remained in SD after a total of 12 weeks. Four patients were further treated in a compassionate use programme showing long-term disease stabilisation for up to 18 months. Immune assessment of cell compartments showed a non-significant increase of TLR9 expressing naïve B cells during therapy. CONCLUSION Twice weekly subcutaneous applications of MGN1703 in a dose of up to 60 mg are safe and well tolerated without dose-limiting toxicities. MGN1703 shows immune activation and anti-tumour efficacy in heavily pretreated patients. The recommended dose of 60 mg twice weekly is currently used in a phase II trial in small cell lung cancer and a phase III trial in colorectal cancer patients.

Results of a phase I trial of BAY 43-9006 in combination with oxaliplatin in patients with refractory solid tumors

3056 Background:BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. Previous single-agent phase I trials show BAY is well tolerated with manageable and reversible side effects, most commonly hand-foot skin (HFS) reaction, rash, fatigue, and diarrhea. This study was initiated to determine safety and pharmacokinetics (PK) of BAY in combination with oxaliplatin (OXAL). METHODS Patients (pts) received continuous BAY at 200 mg bid (cohort 1) followed by escalation to 400 mg bid (cohort 2) given with a fixed dose of OXAL at 130 mg/m2 q3wks. RESULTS 24 pts (M:F ratio =16:8; median age 60.5 yrs range 32-73) entered the study. Common tumor types were CRC (21%), Mel (21%) and RCC (13%). Drug-related dose-limiting toxicities to either drug were gr 3 thrombocytopenia and gr 3 diarrhea in cohort 1 (thrombocytopenia 1/8 pts; diarrhea 1/8 pts) and in cohort 2 (thrombocytopenia 2/16 pts; diarrhea 1/8 pts). Other toxicities consisted of non-hematologic: gastrointestinal-92% (diarrhea-58%, nausea-50%), constitutional-71% (fatigue-38%), neurological-67% (sensory neuropathy-46%), pain-50%, dermatological-46%. Hematologic AEs were uncommon. Single infusions of 130 mg/m2 OXAL did not significantly alter the steady state PK profile of BAY following multiple oral doses of 200 and 400 mg bid BAY. Similarly, PK profiles of total and unbound platinum were not significantly influenced by concomitant multiple doses of BAY. Prolonged stabilization of previously progressive disease was obtained in 2/8 pts in cohort 1 and 5/16 pts in cohort 2. Two additional pts with gastric cancer (1 in each cohort) had partial responses according to modified WHO criteria. CONCLUSIONS Continuous 400 mg bid BAY in combination with 130 mg/m2 OXAL (q3week) appears to be well tolerated with no clinically relevant PK interaction. Clinical activity has been observed and an extension in CRC pts is ongoing. The recommended dose of BAY for phase II studies in combination with OXAL is 400 mg bid BAY. [Table: see text].

Ceritinib in patients with advanced anaplastic lymphoma kinase–rearranged anaplastic large-cell lymphoma

To the editor: The anaplastic lymphoma kinase (ALK) gene is expressed in >50% of anaplastic large-cell lymphomas (ALCLs).[1][1] Although most patients with ALK-positive ALCL respond well to anthracycline-based chemotherapy, relapses do occur (5-year failure-free survival 60%) and require salvage

Abstract A212: First in human phase I study of PRS-050 (Angiocal), a VEGF-A targeting anticalin, in patients with advanced solid tumors: Results of a dose escalation study.

Background: Anticalins are a new class of therapeutic small protein (20kDa) antibody mimetics based on human lipocalins which can be engineered to bind key molecules involved in tumor progression with high affinity and specificity. PRS-050 (40kDa PEGylated Anticalin) targets VEGF-A. The first clinical trial of this putative therapeutic drug is reported. Methods: This Phase I study is a dose-escalation trial in patients with solid tumors according to the 3+3 escalation scheme investigating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of PRS-050 given via a 5–20 min iv infusion/bolus on days 1, 22, 29, 36, and 43 and in 2-weeks intervals thereafter until toxicity or tumor progression. PK was assessed after the first administration. Anti-PRS-050 antibodies and PD markers including target engagement (PRS-050:VEGF-A complex), free plasma VEGF-A, serum MMP-2 levels, and DCE-MRI were assessed repetitively. Tumor response was evaluated at day 43 according to RECIST. Results: Twenty-six patients (pts) with progressive solid tumors were enrolled and treated with doses ranging from 0.1 to 10 mg/kg. Tumor types included CRC (46%), malignant melanoma (12%), and pancreatic cancer (8%). The median treatment duration was 43 days (min. 1, max. 251). Drug-related adverse events (AEs) of all grades reported in >20% of pts were chills (46%, G3 4%), fever (23%, G3 4%), hypertension (39%, G3 12%), which were responsive to pretreatment with steroids, antipyretics, and/or H1/H2 blockers, or antihypertensive medication. DLT9s include 1 G3 hypertension at 1.5mg/kg and 1 G3 infusion reaction at 10mg/kg. As a result, infusion time was increased to 2 hrs in 4 pts and there was no further infusion reaction. There was one nonfatal intestinal perforation after dose 9. Anti-PRS-050 antibodies were not detected at day 43 (21 pts) or at day 71 (16 pts). PRS-050 showed a dose-dependent increase in exposure up to 10 mg/kg with a terminal half-life of 6 days. No patient achieved an objective response (PR/CR). Stable disease was observed in 9 pts with the longest duration, to date, of 8.5 months in a patient with melanoma. Free VEGF-A levels were detectable at baseline in 8/22 pts, becoming undetectable after 15 min subsequent to the infusion of PRS-050, and remained so for 21 days. PRS-050:VEGF-A complex formation was detectable for up to 3 weeks at all dose levels (22/22 pts) including pts with no detectable free VEGF-A at baseline. Furthermore, circulating MMP-2 levels and changes in the DCE-MRI response at day 2 suggest an anti-angiogenic effect. Conclusions: PRS-050 a small selective high affinity antibody mimetics is well-tolerated when administered with premedication as a 2 hour infusion at doses up to 10mg/kg. No formally defined MTD was reached. The recommended dose of PRS-050 for phase II is 6 mg/kg every 2 weeks, with premedication and 2 hour infusion time, based on results in preclinical xenograft models, preclinical and clinical PK/PD data of this phase I study. Most important, the drug demonstrates the intended PD effects and is ready for Phase II studies in patients with solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A212.

Phase I clinical and pharmacokinetic study of BBR 3576, a novel aza-anthrapyrazole, administered i.v. every 4 weeks in patients with advanced solid tumors: a phase I study group trial of the Central European Society of Anticancer-Drug Research (CESAR).

BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.

Abstract C185: Register trial of sorafenib (S) for patients (pts) with metastatic uveal melanoma (metUvMel).

Background: There is no effective systemic therapy for patients (pts) with metastatic uveal melanoma (metUvMel). Due to the paucity of clinical trials pts are frequently offered individual treatment options. We have analyzed the outcome of pts treated for metUvMel with the oral multikinase inhibitor sorafenib (S) in an IEC-approved register trial of the West German Cancer Center, a national reference center for uveal melanomas. Methods: Pts with metUvMel were treated with S [at a dose of 400 mg bid in the first group (G1) and of 200 mg bid in the second group (G2)]. Overall survival (OS) and time to symptomatic progression (TTPsymp) were studied as primary outcome parameters. Secondary outcomes included time to radiologic progression (TTPrad) according to CT and safety. In addition, digital contrast-enhanced NMR (DCE-NMR) and contrast-enhanced ultrasound (CEUS) of liver metastases were performed in selected pts. Results: A total of 62 pts (median age 63 yrs, range 35–83 yrs; 31 female [50%], 31 male [50%], ECOG 0 44 pts [71%], ECOG 1 15 pts [26%], ECOG 2 2 pts [3%]) were included in the analysis on an intent to treat basis (ITT). Fortysix pts had no prior systemic treatment (74%). Metastatic sites included liver in 60 pts (97%) in addition to other organs in 20 pts (32%). Only two pts (3%) had exclusively extrahepatic metastases. Following 4 CTC-Grade 4 toxicities [hand-foot-syndrome (HFS) and/or diarrhea] in the first 31 pts (G1) (13%), the starting dose of S was reduced to 200 mg twice daily in the subsequent 31 pts (G2) effectively preventing further severe side effects. Median OS was 10.8 mths (CI 6.1–15.1 mths) in G1 and 14.0 mths (CI 6.4-nd mths) in G2, median TTPrad was 5.0 mths (CI 3.1–8.9 mths) in G1 and 4,5 mths (CI 1.5–6.0 mths) in G2 and TTPsymp was 4.1 mths (CI 3.1–5.2 mths) in G1 and 7.1 mths (CI 3.2–10.6 mths) in G2 (Wilcoxon 0.043), respectively. Conclusions: S at a dose of 200 mg bid is safe in pts with metUvMel predominantly metastatic to the liver and seems to be effective with a median OS of more than 10 mths. Treatment results are encouraging in an orphan malignant disease without established palliative systemic treatment options. A multicenter randomized discontinuation trial with S in pts with metUvMel will be performed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C185.