M.J.A. de Jonge

Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours.

Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-kappaB. Therefore, compounds that inhibit NF-kappaB stimulation might overcome chemotherapy resistance. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. Twenty patients were enrolled, and a total of 35 cycles were administered. The most frequent haematological side-effect was mild grade 1-2 anaemia. Non-haematological toxicities included fatigue, nausea, vomiting, diarrhoea and constipation, all grade 1-2. Two lethal events were observed in which an increase in caspase-3 activity and overt apoptosis in monocytes and neutrophils could be seen. Pharmacokinetic studies showed high inter-individual variability and rendered F60008 a far from optimal derivate of triptolide.

Phase I safety and pharmacokinetic study of SU-014813 in combination with docetaxel in patients with advanced solid tumours

BACKGROUNDnIn pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours.nnnMETHODSnIn this phase I study successive patient cohorts received docetaxel 60 or 75mg/m(2) every 3weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle.nnnRESULTSnTwenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75mg/m(2) in combination with SU-014813 50mg/day. There was no clinically relevant pharmacokinetic drug-drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy.nnnCONCLUSIONSnOral SU-014813 50mg/day with docetaxel 75mg/m(2) is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST.

A pharmacokinetic interaction study of docetaxel and cisplatin plus or minus 5-fluorouracil in the treatment of patients with recurrent or metastatic solid tumors

Background: The purpose of this study was to look at the pharmacokinetics of docetaxel, cisplatin-derived platinum and 5-fluorouracil (5-FU), when used in combination, to exclude potential clinically relevant pharmacokinetic interactions. Methods: Fifteen patients with recurrent or metastatic solid tumors were randomized to receive docetaxel 75xa0mg/m2 and cisplatin 75xa0mg/m2 in the first treatment course on day 1 and the same combination plus 5-FU 750xa0mg/m2/day on days 1–5 in the second course, or the two treatment courses in reversed order. Cycles were repeated every 3xa0weeks. A pharmacokinetic analysis was performed during the first two cycles. Results: Full pharmacokinetic data was available for 12 of the 15 patients. Treatment was tolerated well, with frequency of toxicity consistent with the safety profile known for docetaxel, cisplatin and 5-FU. Mean clearance values for docetaxel and cisplatin showed no statistically significant difference across the “triple” and the “double” combination treatments, and the mean pharmacokinetic parameters of all agents were within the ranges for previously reported single agent treatment. Conclusion: No clinically relevant pharmacokinetic interactions between docetaxel, cisplatin and 5-FU used in combination were noticed in this study.

Irinotecan and cisplatin with concurrent thoracic radiotherapy in a once-every-three-weeks schedule in patients with limited-disease small-cell lung cancer: A phase I study

BACKGROUNDnIrinotecan and cisplatin with concurrent radiotherapy is a powerful treatment combination for patients with limited-disease small-cell lung cancer (LD-SCLC). The objective was to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of irinotecan and cisplatin with concurrent thoracic radiotherapy (TRT) as a once-every-three-weeks schedule.nnnPATIENTS AND METHODSnPatients with LD-SCLC received a fixed-dose of irinotecan (340 mg) and cisplatin (135mg) at day 1 in cycles 1 and 4. During cycles 2 and 3, irinotecan and cisplatin were given in a dose-escalation schedule with concurrent TRT (once daily, total dose 45Gray).nnnRESULTSnNo DLT was observed at first two levels (irinotecan 100mg or 120 mg and cisplatin 100mg at day 1 of cycles 2 and 3). In the first five patients, four episodes of grade III diarrhoea/dehydration were observed at cycles 1 and 4. Therefore, from the sixth patient on, fixed-dose irinotecan at cycles 1 and 4 was reduced to 250 mg. At the subsequent level of irinotecan 140 mg and cisplatin 100mg in cycles 2 and 3, two DLTs (severe oesophagitis and late vertebral radiation toxicity) were observed in one patient.nnnCONCLUSIONnIrinotecan 140 mg and cisplatin 100mg with concurrent TRT was considered the MTD. Irinotecan and cisplatin in a once-every-three-weeks schedule is not recommended due to severe toxicity. Irinotecan may be more suited for intermittent weekly administration.

452PA STUDY OF ABT-767 IN ADVANCED SOLID TUMORS WITH BRCA 1 AND BRCA 2 MUTATIONS AND HIGH GRADE SEROUS OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL CANCER

ABSTRACT Background: ABT-767 is a potent oral inhibitor of PARP-1 and -2. Malignancies with defects in homologous repair are more dependent on PARP for DNA repair than normal cells. Objectives of this study are to determine safety and PK of ABT-767 in pts with high grade serous ovarian cancer (OvC), fallopian tube, or primary peritoneal cancer or with BRCA1 or BRCA2 germ line mutation with associated solid tumors. Methods: ABT-767 was administered in escalating doses from 20mg QD to 500u2003mg BID on days 1 to 28 of a 28 day cycle to determine the RPTD. Treatment emergent adverse events (TEAEs) were reported according to NCI-CTCAE v 4.03; tumor response was measured by RECIST 1.1. PK analysis for single and multiple doses to assess dose proportionality, linear kinetics, and effect of food on bioavailability were performed. Results: A total of 92 pts were treated, 45% had germline BRCA mutations. 86 (93%) had received at least one prior platinum-containing regimen with 57/92 (62%) having a platinum-free interval of 6 months or less. ABT-767 Cmax and AUC were dose-proportional between 20 to 500u2003mg BID, with a half- life of approx. 3.7 hours. Food had no effect on ABT-767 bioavailability. The most common (≥ 30% of pts) TEAEs were nausea (77%), vomiting (56%), diarrhea (44%), constipation (43%), abdominal pain (42%), dyspepsia (34%) and anemia (30%). Dose limiting toxicities occurring during the first cycle of therapy included angina pectoris (n = 1, 20u2003mg BID) and anemia (n = 1; 500u2003mg BID) in the escalation cohorts. In the 400u2003mg-500u2003mg BID cohorts, a decrease in hemoglobin leading to grade 3 anemia was observed (nadir at approx. 6 weeks). 500u2003mg BID was deemed intolerable due to G3 anemia and general malaise, and the RPTD was determined to be 400mg BID. The response rate for pts with measurable disease at baseline (n = 79) was 18%. The 6 month TTP rate was 22% overall, 20% for OvC and 40% for all other cancers. Conclusions: ABT-767 at 400 mg BID has an acceptable safety profile for Phase 2 studies. Preliminary data suggests that ABT-767 has single-agent activity in BRCA-mutated tumors and high-grade serous OvC. Disclosure: S. Shepherd, M. Dunbar, R. Hetman, C. Serpenti, H. Xiong, M. Zhu and V.L. Giranda: The author is employed by AbbVie and may own stock. All other authors have declared no conflicts of interest.

784PPHARMACOKINETIC (PK) ACTIVITY OF CABAZITAXEL (CBZ) IN PATIENTS (PTS) WITH RENAL IMPAIRMENT (RI)

ABSTRACT Aim: Limited data are available on Cbz PK in pts with RI (14 with moderate RI, 1 with severe RI [Ferron, Cancer Chemother Pharmacol 2013]). This open-label, multicentre study assessed Cbz PK in pts with advanced solid tumours and normal or impaired renal function. Methods: Pts enrolled into cohorts A (normal control, creatinine clearance [CrCL] >80u2003ml/min/1.73 m2), B (moderate RI, CrCL 30– Results: Pts (n = 25) received a median of 3 Cbz cycles (range 1–20: cohort A, 5 [2–13]; cohort B, 3 [1–15]; cohort C, 5 [1–20]), and 24 were eligible for PK analysis (8/cohort). For moderate and severe RI vs controls, GMR estimates were: CL/BSA 0.95 (90% CI 0.80–1.13) and 0.89 (0.61–1.32); AUC/dose 1.06 (0.88–1.27) and 1.14 (0.76–1.71); FU 0.99 (0.94–1.04) and 0.97 (0.87–1.09), respectively. Estimated slope of linear regression of log parameters vs log CrCL was: CL/BSA 0.06 (90% CI -0.15–0.28); AUC/dose -0.07 (-0.30–0.16); Cbz FU 0.02 (-0.05–0.08). Cbz safety was consistent with previous reports. Conclusions: RI had no clinically meaningful effect on Cbz PK. Non-significant trends of increasing AUC and decreasing Cbz CL with greater RI were seen. PK parameter estimates for pts with moderate and severe renal impairment and controls GM estimate (90% CI) Control CrCL 90u2003ml/min/1.73 m2 Moderate renal impairment CrCL 40u2003ml/min/1.73 m2 Severe renal impairment CrCL 15u2003ml/min/1.73 m2 CL/BSA, l/h/m2 29.81 (24.18–36.75) 28.34 (24.44–32.86) 26.66 (20.15–35.27) AUC/dose, ng*h/ml/mg/m2 33.23 (26.65–41.44) 35.21 (30.24–40.99) 37.75 (28.29–50.39) Cbz FU, % 5.51 (5.08–5.96) 5.44 (5.13–5.76) 5.36 (4.95–5.80) Disclosure: J. Machiels: has been a member of advisory boards for Boehringer Ingelheim and Novartis and his institution has received research funding from Sanofi; S. Rottey: has attended advisory boards and received research funding from Sanofi; R. Baird: has received research funding from Sanofi; P. Clot and C. Wack: is an employee of Sanofi; L. Shen and D. Bobilev: is an employee and stock holder of Sanofi. All other authors have declared no conflicts of interest.

Early Clinical Trials with Cytotoxic Agents

The principles of phase I studies in oncology have been extensively outlined in Chap. 5. The systemic treatment of cancer has long been based on cytotoxic drugs, and, more recently, it has been extended with the use of drugs aiming at a molecular aberration in the cancer cell. The principles of cytotoxic drug treatment itself are outlined elsewhere. But as a consequence of these principles, cytotoxic drugs are commonly given in so-called cycles. This, in turn, is due to the fact that the effect of cytotoxic drugs is limited not only to the cancer cell itself, but also affects normal cells in the body. The cytotoxic drug effect mainly has a differential between these normal cells and the cancer cell in the capability of these cells to recover. This means that we have to allow the normal cells to first recover from the drug effects, before a new dose can be given. This recovery phase thus dictates intervals between drug administrations.