Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab - study protocol.

BACKGROUND: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. METHODS: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. DISCUSSION: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.

The meaning of screening: detection of brain metastasis in the adjuvant setting for stage III melanoma.

BACKGROUND: The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is considered in patients with completely resected stage III melanoma before the start of adjuvant treatment. The aim of this study was to assess the yield of screening for BM in these patients. MATERIALS AND METHODS: A single-center cohort study was carried out in the Erasmus MC, Rotterdam, The Netherlands, a large tertiary referral center for patients with melanoma. Eligible patients with complete resection of stage III melanoma and a screening MRI of the brain, made within 12 weeks after resection and before adjuvant treatment (programmed cell death protein 1 inhibitors, dabrafenib-trametinib), available between 1 August 2018 and 1 January 2021, were included. RESULTS: A total of 202 patients were included. Eighteen (8.9%) of 202 patients had extracranial metastasis at screening. Two (1.1%) of the remaining 184 patients had BM at screening, resulting in a switch from adjuvant treatment to ipilimumab-nivolumab. At a median follow-up of 21.2 months, BM was detected in another 4 (2.4%) of 166 patients who started with adjuvant treatment. CONCLUSIONS: The yield of screening MRI of the brain is low after complete resection of stage III melanoma, before the start of adjuvant treatment. Therefore, routine screening MRI is not recommended in this setting.

The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs.

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.

The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies.

BACKGROUND: Early signs of efficacy are critical in drug development. Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST, however, emphasizes the value of tumor shrinkage, while many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a time to progression (TTP) end point based on prospective volumetric measurements and an intra-patient control, the TTP ratio. PATIENTS AND METHODS: Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pretreatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined. RESULTS: Seventy-three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (n = 43) of the treated patients. The inter-observer agreement for volumetric progression was 0.78 (95% confidence interval 0.70-0.87) (Krippendorff's α-coefficient). According to RECIST, 35 patients (59%) had stable disease (SD) and 1 patient demonstrated a partial response (PR), whereas only 21 patients (36%) met the prespecified criteria for treatment efficacy according to the TTP ratio. Treatment response according to both the TTP ratio and RECIST (SD + PR) correlated with overall survival (OS) [P(log-rank) < 0.001]. The TTP ratio, however, was also able to differentiate which patients had a better OS within the RECIST SD group [P(log-rank) = 0.0496]. CONCLUSION: The TTP ratio had a high inter-observer agreement, correlated with OS and identified which patients within the RECIST SD group had a longer OS. CLINICALTRIALSGOV IDENTIFIER: NCT01566279.

Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study.

BACKGROUND: This multi-centre phase II trial assessed the activity, safety (CTCAE 3.0) and pharmacokinetics (PK) of the pan-Aurora kinase inhibitor danusertib hydrochloride (PHA-739358) in breast (BC), ovarian (OC), pancreatic (PC), colorectal (CRC), small-cell (SCLC) and non-small-cell lung (NSCLC) cancers. METHODS: Consenting adult patients with good performance and organ function with advanced/metastatic tumours who had failed systemic therapy were treated in independent, disease-specific cohorts with danusertib 500 mg/m(2) given as 24-h i.v. infusion every 14 days with until progression or unacceptable toxicity. A two-stage design was applied. Primary end point was the progression-free rate (PFR) at 4 months (RECIST1.1). RESULTS: A total of 223 patients were enrolled with 219 actively treated. The median relative dose intensity of danusertib was similar for all tumour types (84.6%-99.6%). The median number of biweekly treatment cycles ranged from 3 to 4/patient (maximum 5-40 cycles/entity) and the median treatment duration varied between 7.6 and 10.0 weeks per histotype. Danusertib did not meet pre-specified protocol criteria for clinically relevant activity in any of the treated cancers. The PFR at 4 months was 18.4% in BC, 12.1% in OC, 10.0% in PC, 10.4% in NSCLC (all histotypes), 16.1% in squamous NSCLC and 0% in SCLC and CRC. Some radiological and/or biochemical indication of antitumor activity was seen in BC, OC, PC and NSCLC, including two confirmed partial responses. The most frequent drug-related non-laboratory adverse events (AEs) were fatigue/asthenia, nausea, diarrhoea, anorexia, vomiting, alopecia, constipation and pyrexia. Common laboratory AEs included haematological toxicity, hypalbuminaemia and increases in liver enzymes. Treatment was discontinued due to AEs in only 5.5% of patients. Plasma concentrations of danusertib were in line with results from earlier studies. CONCLUSION: Single-agent danusertib did show only marginal anti-tumour activity in common solid tumours after failure of prior systemic therapies. The safety and PK profile was consistent with previous experience. CLINICAL TRIAL NUMBER: 2006-003772-35.

Impact of pazopanib on docetaxel exposure: results of a phase I combination study with two different docetaxel schedules.

PURPOSE: There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel. METHODS: In a 3 + 3 + 3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with docetaxel given either every 3 weeks (D3w) or weekly at days 1, 8, and 15 every 28 days (D1w). Pharmacokinetic data of docetaxel and pazopanib were obtained through extensive sampling and WinNonlin modeling. RESULTS: Forty-six patients were enrolled to six dose levels. Both schedules of docetaxel could be combined with 400 mg/day pazopanib. The MTD of D3w docetaxel was 50 mg/m(2), while for D1w MTD, it was 20 mg/m(2). In the D3w schedule, the administration of pazopanib led to a 33% lower docetaxel clearance (mean 31.5 vs 21.1 L/h/m(2); P = 0.019) and >50% increase in AUC(0-∞) (mean 1,602 vs 2,414 ng*h/mL; P = 0.029) compared with docetaxel single-agent data. Data for the D1w schedule were comparable. CONCLUSIONS: Both treatment schedules of docetaxel combined with pazopanib are feasible but at doses for both drugs that are considerably lower than the recommended single-agent doses. This is largely due to a clinically relevant pharmacokinetic interaction with pazopanib, substantially increasing docetaxel exposure. This interaction is most likely due to CYP3A4 and OATP1B1 inhibition.

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours.

BACKGROUND: Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels. METHODS: Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade ⩾3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade ⩾3 toxicity, the sunitinib dose was lowered by 12.5 mg. RESULTS: Twenty-nine out of 43 patients were evaluable for PK assessments. Grade ⩾3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity. CONCLUSIONS: In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.

Erlotinib 'dosing-to-rash': a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer.

BACKGROUND: To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of higher doses of erlotinib. METHODS: Patients initially received erlotinib 150 mg per day. The dose was successively increased in each patient to that associated with a TR. Anticancer activity was evaluated. Plasma, skin, and hair were sampled for PK and PD studies. RESULTS: Erlotinib dose escalation to 200-475 mg per day was feasible in 38 (90%) of 42 patients. Twenty-four (57%) patients developed a TR, but 19 (79%) did so at 150 mg per day. Five (12%) patients, all of whom developed a TR, had a partial response. Median progression-free survival (PFS) was 2.3 months (95% CI: 1.61, 4.14); median PFS was 3.5 months and 1.9 months, respectively, for patients who did and did not experience a TR (hazard ratio, 0.51; P=0.051). Neither rash severity nor response correlated with erlotinib exposure. CONCLUSION: Intrapatient dose escalation of erlotinib does not appreciably increase the propensity to experience a maximal level of tolerable skin toxicity, or appear to increase the anticancer activity of erlotinib in NSCLC.

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

BACKGROUND: In 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. METHODS: In 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. RESULTS: Twenty-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. CONCLUSIONS: Oral 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.

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 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood. RESULTS: JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, 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 1500 mg 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, p27(kip1), 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 1500 mg BID.

Aurora kinase inhibitors.

Most human cancer cells are characterized by changes in the amount or organization of DNA resulting in chromosome instability and aneuploidy. Several mitotic kinases, Aurora kinases amongst others, regulate the progression of the cell through mitosis. So far three Aurora kinases have been identified in man: Aurora-A, Aurora-B and Aurora-C. Aurora kinases were recently identified as a potential target in anticancer therapy, and various Aurora-A and Aurora-B kinase inhibitors are in development. In this review we provide a brief insight into the mechanism of action as far as currently available. We review the available pre-clinical data, discuss the clinical phase I data and try to give a direction for future headings.

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.

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.

BACKGROUND: Irinotecan 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. PATIENTS AND METHODS: Patients 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). RESULTS: No 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. CONCLUSION: Irinotecan 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.

A multicentre phase I and pharmacokinetic study of BN80915 (diflomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours.

BACKGROUND: BN80915 (diflomotecan) is an E-ring modified camptothecin analogue, which possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors. This phase I study was carried out using a daily times five administration schedule (dx5) repeated three weekly. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II studies. Secondary objectives were to determine the safety and pharmacokinetic (PK) profile, and to make a preliminary assessment of antitumour activity. PATIENTS AND METHODS: Diflomotecan was administered intravenously on days 1-5 every 3 weeks. Patients were treated in cohorts of three to six per dose level and the dose of diflomotecan was escalated according to modified Fibonacci schedule. Plasma concentrations of diflomotecan and its metabolite BN80942 were quantified. RESULTS: Thirty patients were assessable for toxicity. Dose levels explored were 0.05, 0.1, 0.125 and 0.15 mg/m(2)/day. The 0.15-mg/m(2) dose level was determined to be the MTD. Toxicity was acceptable at the 0.125-mg/m(2)/day dose level. PK analysis showed the principal parameters were neither time nor dose dependent. There was a wide interpatient variability in PK at all dose levels. One patient with colorectal cancer, previously treated with irinotecan, had a partial response. A further eight patients had disease stabilisation. CONCLUSIONS: The MTD and RD of diflomotecan administered according to a dx5 repeated three weekly are 0.15 and 0.125 mg/m(2)/day, respectively. In general, treatment was well tolerated; the principal toxicity was reversible myelosuppression. An objective response was seen in a patient previously treated with irinotecan.

Phase I and pharmacokinetic study of halofuginone, an oral quinazolinone derivative in patients with advanced solid tumours.

PURPOSE: Halofuginone (tempostatin) is a synthetic derivative of a quinazolinone alkaloid showing anti-angiogenic, anti-metastatic and anti-proliferative effects in preclinical studies. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics (PKs) of halofuginone when administered once or twice daily orally to patients with advanced solid tumours. METHODS: Patients were treated with escalating doses of halofuginone at doses ranging from 0.5 to 3.5 mg/day. For pharmacokinetic analysis plasma sampling was performed during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. RESULTS: Twenty-four patients received a total of 106 courses. The 'acute' MTD was reached at 3.5 mg/day, with nausea, vomiting, and fatigue as DLT. The recommended dose for chronic administration was defined as 0.5mg/day with the requirement of 5HT3 antagonists to control nausea and vomiting considered as DLT. Several patients experienced bleeding complications on treatment with halofuginone in which a causal relationship could not be excluded. The PKs of halofuginone were linear over the dose range studied with a large interpatient variability. CONCLUSIONS: In this study the DLT of halofuginone was nausea, vomiting, and fatigue. The recommended dose for phase II studies of halofuginone is 0.5mg administered orally, once daily.

Multiple targeted tyrosine kinase inhibition in the clinic: all for one or one for all?

Recent insight into the role of receptor tyrosine kinase function in cancer cells culminated in the design of highly selective tyrosine kinase inhibitors. After proof of concept for the clinical efficacy and tolerability of selective tyrosine kinase inhibitors, it was conceived that most tumours will depend on more than one signalling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signalling pathways or multiple steps in the same pathway either by the development of multi-targeted agents or the combination of single targeted drugs. The use of a combination of different compounds will be less convenient to the patient, may result in dosing mistakes and drug-drug interaction should be anticipated. However, this approach will enable the titration of the dose of either agent to optimize target inhibition. The use of multi-targeted agents will circumvent several of the problems of combination therapy. Clinical activity resulting in FDA approval for both BAY 43-9006 and SU11248 has been noted. However, optimal inhibition of several targets might not be feasible at a dose with acceptable toxicity.

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 75 mg/m2 and cisplatin 75 mg/m2 in the first treatment course on day 1 and the same combination plus 5-FU 750 mg/m2/day on days 1-5 in the second course, or the two treatment courses in reversed order. Cycles were repeated every 3 weeks. 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.

Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1-5 of a 3-weekly cycle in patients with advanced solid tumours.

XR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1-5 every 3 weeks to patients with advanced solid tumours. Patients were treated with escalating doses of XR11576 at doses ranging from 30 to 180 mg day(-1). For PK analysis, plasma sampling was performed during the first and second courses of treatment and XR11576 concentrations were assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. In all, 21 patients received a total of 47 courses. The MTD was reached at 180 mg day(-1), with diarrhoea and fatigue as DLT. Nausea and vomiting, although not qualifying for DLT, was ubiquitous. Only in combination with an extensive prophylactic antiemetic regimen consisting of a combination of both dexamethasone and a 5HT3 antagonist was treatment with XR11576 at 120 mg day(-1) tolerable. The systemic exposure of XR11576 increased more than proportionally with increasing dose, with a large interpatient variability. No objective responses were seen; four patients experienced stable disease for periods of 12-30 weeks. In this study, the DLTs of XR11576 were diarrhoea and fatigue. The recommended dose for phase II studies of XR11576 is 120 mg administered orally, on days 1-5 every 21 days. Alternative regimens are currently being explored.

RFS2000 (9-nitrocamptothecin) in advanced small cell lung cancer, a phase II study of the EORTC New Drug Development Group.

Camptothecins have shown efficacy in terms of response rate in patients with small cell lung cancer (SCLC). RFS2000 is a new camptothecin derivative, which has shown objective responses in various tumour types. The aim of this phase II study was to determine the objective response rate of RFS2000 in patients with sensitive and refractory SCLC. RFS2000 was given orally at 1.5 mg/m(2) per day for five consecutive days (five days on - two days off) on a continuous basis. Patients were evaluated weekly for toxicity and every six weeks for response. Thirty seven patients were included, 36 patients (14 with sensitive and 22 with refractory SCLC) were evaluable for toxicity, and 35 patients were evaluable for response. No objective responses were observed. Toxicity was acceptable, with myelosuppression, nausea/vomiting, and diarrhoea as the main toxicities. RFS2000 therefore has an acceptable toxicity profile but is not active as a single agent in SCLC.

Phase II study on 9-nitrocamptothecin (RFS 2000) in patients with advanced or metastatic urothelial tract tumors.

OBJECTIVE: To investigate the antitumor activity and the safety of RFS2000, an oral topoisomerase I inhibitor, in patients with advanced or metastatic urothelial tract tumors refractory to one prior chemotherapy regimen. PATIENTS AND METHODS: Eligible patients were to have failed first line treatment for advanced or metastatic disease. Patients received RFS2000 as one daily oral intake at the dose of 1.5 mg/m(2)/day according to a "5 days on/2 days" off schedule continuously. One cycle was arbitrarily defined as a 3 week period. Sufficient oral fluid intake to prevent cystitis previously described in phase I trials with RFS2000 was recommended. Gehan design was used for sample size determination. Anti-tumor activity was evaluated according to the RECIST criteria and toxicity according to CTC version 2. RESULTS: Twenty patients received a total of 57 cycles (range 1-8). Grade 3-4 toxicity was observed in 10 patients requiring dose or schedule modifications. Hematological grade 3-4 toxicity was observed in 16% of the cycles. Only one patient experienced a partial response. CONCLUSIONS: RFS2000 could be administered orally as a "5 days on/2 days off" schedule continuously with a median dose intensity of 90.6% with an acceptable toxicity profile. However, RFS2000 did not exert significant activity in patients with advanced/metastatic urothelial tract tumors failing prior chemotherapy. The results of this study do not suggest further investigation of RFS2000 at the present dose and schedule for the treatment of urothelial tract tumors in this refractory population.