Herman Burger

Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation

PURPOSEnTo evaluate the safety and tolerability of LiPlaCis, a liposomal formulated platinum compound, in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous (i.v.) LiPlaCis. and to assess plasma and urine pharmacokinetics and plasma biomarkers.nnnPATIENTS AND METHODSnPatients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3weeks until RECIST progression or unacceptable toxicity. Cohorts of 3-6 patients were treated at each dose level until MTD was reached.nnnRESULTSnEighteen patients were enrolled and 64 cycles were delivered. At the first dose level 3 patients experienced an infusion reaction. Despite prophylactic pre-medication and prolongation of the infusion to 2 h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients. Peak plasma concentrations and AUC were dose proportional. The interpatient variability in the clearance of total LiPlaCis-derived platinum was 41%. Platinum was excreted via the urine mainly during the first 24 h after administration. Investigated plasma biomarkers sPLA(2) and SC5b-9 were related to, but not predictive for, acute infusion reactions.nnnCONCLUSIONnThe observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development.

A Phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors

SummaryBackground A Phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics of afatinib (BIBW 2992), a novel irreversible ErbB Family Blocker, administered orally once daily in a 3-week-on/1-week-off dosing schedule. Methods Patients with advanced solid tumors received single-agent afatinib at 10, 20, 40, 55 or 65xa0mg/day. Safety, antitumor activity, pharmacokinetics and pharmacodynamic modulation of biomarkers were assessed. Results: Forty-three patients were enrolled. Dose-limiting toxicities (DLTs) occurred in five patients in the dose escalation phase (1/8 at 40xa0mg/day; 1/6 at 55xa0mg/day; 3/6 at 65xa0mg/day). The MTD was established at 55xa0mg/day. In the expansion cohort at the MTD, 6 patients experienced a DLT in the first 28-day treatment period. The most frequent DLT was diarrhea. The most common adverse events were diarrhea, rash, nausea, vomiting and fatigue. Overall, the afatinib safety profile in a 3-week-on/1-week-off dose schedule was similar to that of our daily-continuous schedule. Afatinib displayed dose-dependent pharmacokinetics at doses up to and including 55xa0mg/day, with a terminal half-life suitable for once-daily dosing. Signs of clinical antitumor activity were observed. In biopsies taken from clinically normal forearm skin, afatinib caused a reduced proliferation rate, with a concomitant increase in differentiation of epidermal keratinocytes. Conclusion Afatinib in a 3-week-on/1-week-off schedule showed a good safety profile. The MTD was 55xa0mg/day, although excess DLTs in the expansion cohort indicated that the 40xa0mg/day dose would have an acceptable safety profile for future studies. Dose cohorts between 40 and 55xa0mg/day were not examined in this study.

Phase i and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours

Background:JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327.Methods:Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100u2009mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood.Results:JNJ-26483327 was well tolerated in doses up to 1500u2009mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100u2009mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500u2009mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27kip1, phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%).Conclusion:JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500u2009mg BID.

Identification of microRNA biomarkers for response of advanced soft tissue sarcomas to eribulin: Translational results of the EORTC 62052 trial

BACKGROUNDnRecent phase II and III clinical trials demonstrated anti-tumour activity of eribulin, a tubulin-interacting cytotoxic agent, in patients with metastatic soft tissue sarcoma (STS). In this exploratory study, we aimed to identify putative microRNA biomarkers that associate with eribulin sensitivity or resistance in STS.nnnMATERIALS AND METHODSnArchival tumour tissue from primary tumours or metastatic lesions was collected prior to eribulin treatment, from 65 consenting patients involved in the EORTC trial 62052. This phase II study (ClinicalTrials.gov identifier NCT00413192) included multiple subtypes of STS. Tissue was available from 21 leiomyosarcomas, 14 adipocytic sarcomas, 9 synovial sarcomas and 21 other sarcoma histotypes. Total RNA was isolated from formalin-fixed, paraffin-embedded tumour samples and analysed using Taqman® Low Density Arrays to determine microRNA expression profiles. The expression of a total of 756 microRNAs was assessed. Progression-free survival at week 12 (RECIST 1.0) measured as a binary variable, was the primary end-point of the clinical trial and used as a primary response measure for correlative studies. Seventeen of 53 (32.1%) evaluable patients in the analysed subset had non-progressive disease at week 12 and were defined as responders.nnnRESULTSnThe expression of 26 individual microRNAs (pxa0<xa00.05) differed significantly between non-responders and responders. Additional microRNAs of potential relevance were identified when considering the different histological subgroups.nnnCONCLUSIONSnThe expression level of particular microRNAs in STS tissue samples may predict response to eribulin. Further validation studies as well as a preclinical assessment of the underlying molecular mechanisms are required.

Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation

Resistance to docetaxel is common in metastatic castration‐resistant prostate cancer (mCRPC) and may be caused by sub‐therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in docetaxel‐pretreated and docetaxel‐refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of docetaxel following treatment with novel androgen receptor (AR)‐targeted agents, we also investigated taxane efficacy in an enzalutamide‐resistant tumor model.

Abstract A108: A phase I and pharmalogical study of the broad‐spectrum tyrosine kinase inhibitor JNJ‐26483327, administered to subjects with advanced or refractory solid tumors

Background: JNJ‐26483327 is a potent reversible multi‐targeted tyrosine kinase inhibitor. Tyrosine kinases of Epidermal Growth Factor Receptor (EGFR), Her2, Her4, RET receptor, Vascular Epidermal Growth Factor Receptor (VEGFR)‐3, and Src family (Lyn, Fyn, Yes) are inhibited at low nanomolar concentrations. Methods: Objectives were to (1) determine safety, maximum tolerated dose (MTD) and dose‐limiting toxicity (DLT), (2) characterize the pharmacokinetic (PK) profile, (3) explore preliminary evidence of antitumor activity, and (4) explore pharmacodynamic (PD) effects in skin biopsies and blood. Results: 19 patients, 16 M/3F, median age 61 yrs (47‐74) received JNJ‐26483327 twice daily (BID) continuously at 100 mg (n=1), 200 mg (n=1), 400 mg (n=1), 800 mg (n=3), 1200 mg (n=3), 1500 mg (n=6) and 2100 mg (n=4). JNJ‐26483327 was administered as oral solution (dose ≤ 1200 mg) or capsules (dose ≥ 1500 mg, 300 mg capsule). Skin biopsies were taken at days 0 and 28. At 2100 mg DLT consisted of a combination of grade 3 anorexia and fatigue in one patient, and due to substantial difficulty in intake in most patients, pill load at 2100 mg was dose limiting. JNJ‐26483327 was well tolerated up to 1500 mg BID, with most common reported toxicities being nausea, vomiting, diarrhea, fatigue, skin rash. Plasma concentrations of JNJ‐26483327 rapidly increased till about 3–4h post dose. PK showed significant inter‐individual variability, but no marked deviation in dose‐proportionality was observed up to 1500 mg BID. At 1500 mg BID, steady state plasma concentrations were 2–6 µg/l and AUCs 13–53 µg.h/ml and were in the active range as observed in xenograft mouse models. PD evaluation failed to show a substantial effect on expression of Ki‐67, p27kip1, pMAPK, pAKT, and EGFR in paired skin biopsies. Serum levels of sVEGFR‐2, VEGF‐C and VEGF‐D remained unchanged. No antitumor activity was observed in this study. Conclusion: The recommended dose of JNJ‐26483327 is 1500 mg BID. JNJ‐26483327 shows a predictable pharmacokinetic profile. Additional PD research is planned to demonstrate biological activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A108.

Abstract C32: First‐in‐human clinical, pharmacokinetic (PK) and pharmacodynamic (PD) phase I study of the first‐in‐class spliceosome inhibitor E7107 administered IV (bolus) on days 1, 8, and 15 every 28 days to patients with solid tumors

Background: E7107 is a first‐in‐class inhibitor of the spliceosome, most likely by interacting with spliceosome‐associated protein‐130 (SAP 130). Splicing removes intron sequences from pre‐mRNA and exons are fused resulting in the formation of mature mRNA. Alternative splicing frequently encodes oncoproteins. E7107 interferes the maturation process of pre‐mRNA to mRNA, with consequent changes in protein expression profiles. Methods: Objectives of this study were to explore (1) tolerability and safety profile, (2) PK, (3) PD effects on pre‐mRNA splicing, and (4) anti tumor activity of E7107 administered as bolus infusion on days 1, 8, 15 of a 28‐day schedule Results: 36 patients (21M/15F, median age 61yrs (45–79)) received E7107 doses of 0.6 mg/m 2 (n=4), 0.9 mg/m 2 (n=3), 1.3 mg/m 2 (n=3), 2.0 mg/m 2 (n=3), 3.0 mg/m 2 (n=4), 4.5 mg/m 2 (n=3) and 4.0 mg/m 2 (n=16). At 4.5 mg/m 2 two episodes of DLT (grade 3 and 4 diarrhea) and at 4.0 mg/m 2 one episode of DLT (a combination of grade 3 nausea, vomiting and abdominal cramps) were observed. Other frequently occurring side effects were mainly gastrointestinal. After drug discontinuation, one patient at 4.0 mg/m 2 experienced reversible grade 4 blurred vision. The maximum tolerable dose (MTD) is 4.0 mg/m 2 . No complete or partial responses were observed. Pharmacokinetic analysis revealed large volume of distribution (Vss: 279 to 1369 L), high systemic clearance (CL: 111 to 253 L/hr), and moderate elimination half‐life (t 1/2 : 5.3 to 15.1 hr). Systemic exposure on days 1 and 15 (Cmax, AUC0‐∞) increased in a dose‐dependent manner. At the MTD, mRNA levels of selected target genes (TRAPPC4, SLC25A19, GTF2H1), monitored in PBMC9s, showed a 15–25‐fold decrease, whereas unspliced pre‐mRNA levels of DNAJB1 and EIF4A1 showed a 10–25‐fold increase. Notably, at days 1 and 15, modulations generally peaked at 2–6 hr after end of the infusion and almost completely recovered to base‐line levels at 24–48 hr. Conclusion: The MTD for E7107 using this schedule is 4.0 mg/m 2 . PK is dose‐dependent and reproducible within subjects. PD analysis revealed dose‐dependent reversible inhibition of pre‐mRNA processing of target genes, confirming proof‐of‐principle activity of E7107. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C32.