Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.

BACKGROUND: Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial. METHODS: Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers. RESULTS: In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47-0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65-1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13-0.70). CONCLUSIONS: SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175).

Intrinsic Charge Dynamics in High-T_{c} AFeAs(O,F) Superconductors.

We report the first determination of the in-plane complex optical conductivity of 1111 high-T_{c} superconducting iron oxypnictide single crystals PrFeAs(O,F) and thin films SmFeAs(O,F) by means of conventional and microfocused infrared spectroscopy, ellipsometry, and time-domain THz transmission spectroscopy. A strong itinerant contribution is found to exhibit a dramatic difference in coherence between the crystal and the film. Using extensive temperature-dependent measurements of THz transmission, we identify a previously undetected 2.5-meV collective mode in the optical conductivity of SmFeAs(O,F), which is strongly suppressed at T_{c} and experiences an anomalous T-linear softening and narrowing below T^{*}≈110 K≫T_{c}. The suppression of the infrared absorption in the superconducting state reveals a large optical superconducting gap with a similar gap ratio 2Δ/k_{B}T_{c}≈7 in both materials, indicating strong pairing.

Weak-coupling superconductivity in a strongly correlated iron pnictide.

Iron-based superconductors have been found to exhibit an intimate interplay of orbital, spin, and lattice degrees of freedom, dramatically affecting their low-energy electronic properties, including superconductivity. Albeit the precise pairing mechanism remains unidentified, several candidate interactions have been suggested to mediate the superconducting pairing, both in the orbital and in the spin channel. Here, we employ optical spectroscopy (OS), angle-resolved photoemission spectroscopy (ARPES), ab initio band-structure, and Eliashberg calculations to show that nearly optimally doped NaFe0.978Co0.022As exhibits some of the strongest orbitally selective electronic correlations in the family of iron pnictides. Unexpectedly, we find that the mass enhancement of itinerant charge carriers in the strongly correlated band is dramatically reduced near the Γ point and attribute this effect to orbital mixing induced by pronounced spin-orbit coupling. Embracing the true band structure allows us to describe all low-energy electronic properties obtained in our experiments with remarkable consistency and demonstrate that superconductivity in this material is rather weak and mediated by spin fluctuations.

Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma.

BACKGROUND: A prospective, randomized phase II study, with mandatory tumor sampling at current disease stage, aimed to identify biomarkers predictive of improved progression-free survival (PFS) in patients with pancreatic cancer treated with erlotinib. PATIENTS AND METHODS: Patients with histologically/cytologically confirmed, unresectable, locally advanced/metastatic pancreatic cancer, who had failed on or were unsuitable for first-line chemotherapy, underwent a tumor biopsy and were then randomized to receive once-daily erlotinib 150 mg or placebo. The primary end point was identification of biomarkers predicting improved PFS with erlotinib. Secondary end points included PFS, overall survival, response and toxicity. RESULTS: At data cut-off, 207 patients were enrolled and analyzed. Prespecified biomarker analyses of EGFR protein expression, EGFR gene copy number/mutations/polymorphisms and KRAS mutations did not identify any subgroups with a detrimental effect or a strong benefit for PFS with erlotinib. In the primary analysis, the median PFS was 6.1 versus 5.9 weeks in the erlotinib and placebo arms, respectively [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.63-1.10; P = 0.1909]. However, observed baseline imbalances indicated worse prognosis in the erlotinib arm. After adjustment for baseline characteristics, a significant PFS benefit for erlotinib was observed (HR 0.68; 95% CI 0.50-0.91; P = 0.0102). Exploratory biomarker analyses showed patients with high baseline serum amphiregulin levels might benefit from erlotinib. CONCLUSION: This study in patients with inoperable pancreatic cancer did not identify any prespecified biomarkers predictive of PFS benefit with erlotinib. Exploratory analyses suggested high amphiregulin might predict PFS benefit from erlotinib. CLINICALTRIALSGOV NUMBER: NCT00674973.

A case of insulin and ACTH co-secretion by a neuroendocrine tumour.

UNLABELLED: A 33-year-old male was diagnosed with a metastatic neuroendocrine carcinoma of uncertain primary. He defaulted from follow-up without therapy and some months later developed episodic severe hypoglycaemia, which was found to be associated with inappropriately elevated insulin and C-peptide levels. It was considered likely that the neuroendocrine tumour was the source of the insulin secretion. Diazoxide and somatostatin analogue were used to control hypoglycaemia. Much later in the course of the disease, he developed metabolic derangement, increased skin pigmentation and psychological disturbance, without frankly Cushingoid physical findings. Investigations revealed highly elevated cortisol levels (the levels having previously been normal) with markedly raised ACTH levels, consistent with the co-secretion of ACTH and insulin by the tumour. Treatment with metyrapone improved his psychological state and electrolyte imbalance. Unfortunately, despite several cycles of first-, second- and third-line chemotherapy from the start of the first hormonal presentation onwards, imaging revealed widespread progressive metastatic disease and the patient eventually passed away. This case highlights the importance of keeping in mind the biochemical heterogeneity of endocrine tumours during their treatment. LEARNING POINTS: The clinical presentation of insulin-secreting tumours includes symptoms of neuroglycopaenia and sympathetic overstimulation.Tumour-associated hypoglycaemia can be due to pancreatic insulinomas, and although ectopic hormone production occurs in a number of tumours, ectopic secretion of insulin is rare.A possible switch in the type of hormone produced can occur during the growth and progression of neuroendocrine tumours and, when treating neuroendocrine tumours, it is important to keep in mind their biochemical heterogeneity.

Nanoscale layering of antiferromagnetic and superconducting phases in Rb(2)Fe(4)Se(5) single crystals.

We studied phase separation in the single-crystalline antiferromagnetic superconductor Rb(2)Fe(4)Se(5) (RFS) using a combination of scattering-type scanning near-field optical microscopy and low-energy muon spin rotation (LE-µSR). We demonstrate that the antiferromagnetic and superconducting phases segregate into nanometer-thick layers perpendicular to the iron-selenide planes, while the characteristic in-plane size of the metallic domains reaches 10 µm. By means of LE-µSR we further show that in a 40-nm thick surface layer the ordered antiferromagnetic moment is drastically reduced, while the volume fraction of the paramagnetic phase is significantly enhanced over its bulk value. Self-organization into a quasiregular heterostructure indicates an intimate connection between the modulated superconducting and antiferromagnetic phases.

Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer.

BACKGROUND: Annualised figures show an up to 7-fold higher incidence of vascular thromboembolism (VTE) in patients with advanced pancreatic cancer (APC) compared to other common malignancies. Concurrent VTE has been shown to confer a worse overall prognosis in APC. METHODS: One hundred and twenty three APC patients were randomised to receive either gemcitabine 1000 mg/m(2) or the same with weight-adjusted dalteparin (WAD) for 12 weeks. Primary end-point was the reduction of all-type VTE during the study period. NCT00462852, ISRCTN: 76464767. FINDINGS: The incidence of all-type VTE during the WAD treatment period (<100 days from randomisation) was reduced from 23% to 3.4% (p = 0.002), with a risk ratio (RR)of 0.145, 95% confidence interval (CI) (0.035-0.612) and an 85% risk reduction. All-type VTE throughout the whole follow-up period was reduced from 28% to 12% (p = 0.039), RR = 0.419, 95% CI (0.187-0.935) and a 58% risk reduction. Lethal VTE <100 days was seen only in the control arm, 8.3% compared to 0% (p = 0.057), RR = 0.092, 95% CI (0.005-1.635). INTERPRETATION: Weight adjusted dalteparin used as primary prophylaxis for 12 weeks is safe and produces a highly significant reduction of all-type VTE during the prophylaxis period. The benefit is maintained after dalteparin withdrawal although decreases with time.

Neuroendocrine tumours of the gallbladder: three cases and a review of the literature.

Primary neuroendocrine tumours (NETs) of the gallbladder are rare. In the absence of any randomised controlled trials or prospective case series, we sought trends for clinical presentation and management based on 60 patients from published literature over the last 15 years, as well as three patients from our experience, and categorised them into various subgroups according to the WHO classification for NETs. Well-differentiated NETs have an indolent course and better prognosis. Poorly differentiated neuroendocrine carcinomas, which may be of large-cell or small-cell type and may coexist with other types of carcinoma, have a poor outcome. A variety of surgical and chemotherapeutic approaches have been adopted. Surgical excision appears to prolong life, with chemotherapy perhaps adding a marginal advantage.

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.

A phase II study to determine the ability of gefitinib to reverse fluoropyrimidine resistance in metastatic colorectal cancer (the INFORM study).

There are data suggesting that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase signalling may reverse resistance to fluoropyrimidine treatment. To investigate this further, the INFORM study was an open-label, non-comparative phase II study of gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE, USA) 250 mg daily in combination with 5-fluorouracil (5-FU administered as an intravenous 400 mg m(-2) bolus injection followed by 2800 mg m(-2) infusion over 46 h and folinic acid administered as a 350 mg infusion over 2 h) every 2 weeks for up to 12 cycles in 24 patients with metastatic colorectal cancer refractory to previous fluoropyrimidine treatment. There were no objective responses. The stable disease rate was 37.5% (95% CI: 18.80, 59.41), median progression-free survival measured 116 days and overall survival was 226 days. Quality of life was unchanged compared to baseline values, and the commonest toxicities were diarrhoea, rash and fatigue with 7 out of 24 (29%) patients having a grade 3 or 4 toxicity. Gefitinib does not sensitise patients with fluoropyrimidine refractory metastatic colorectal cancer to 5-FU chemotherapy.

Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer.

A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0-2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m(-2) day(-1) days 1-5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 mug ml(-1). The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIalpha levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action.

A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer.

Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 mug m(-2). In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44-68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1-29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole-blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.

Measurement of renal tumour and normal tissue perfusion using positron emission tomography in a phase II clinical trial of razoxane.

Measurement of tumour and normal tissue perfusion in vivo in cancer patients will aid the clinical development of antiangiogenic and antivascular agents. We investigated the potential antiangiogenic effects of the drug razoxane by measuring the changes in parameters estimated from H(2)(15)O and C(15)O positron emission tomography (PET) to indicate alterations in vascular physiology. The study comprised 12 patients with primary or metastatic renal tumours >3 cm in diameter enrolled in a Phase II clinical trial of oral razoxane. Perfusion, fractional volume of distribution of water (VD) and blood volume (BV) were measured in tumour and normal tissue before and 4-8 weeks after treatment with 125 mg twice-daily razoxane. Renal tumour perfusion was variable but lower than normal tissue: mean 0.87 ml min(-1) ml(-1) (range 0.33-1.67) compared to renal parenchyma: mean 1.65 ml min(-1) ml(-1) (range 1.16-2.88). In eight patients, where parallel measurements were made during the same scan session, renal tumour perfusion was significantly lower than in normal kidney (P=0.0027). There was no statistically significant relationship between pretreatment perfusion and tumour size (r=0.32, n=13). In six patients scanned before and after razoxane administration, there was no statistically significant change in tumour perfusion: mean perfusion pretreatment was 0.81 ml min(-1) ml(-1) (range 0.46-1.26) and perfusion post-treatment was 0.72 ml min(-1) ml(-1) (range 0.51-1.15, P=0.15). Tumour VD and BV did not change significantly following treatment: mean pretreatment VD=0.66 (range 0.50-0.87), post-treatment VD=0.71 (range 0.63-0.82, P=0.22); pretreatment BV=0.18 ml ml(-1) (range 0.10-0.25), post-treatment BV=0.167 ml ml(-1) (range 0.091-0.24, P=0.55). Tumour perfusion, VD and BV did not change significantly with tumour progression. This study has shown that H(2)(15)O and C(15)O PET provide useful in vivo physiological measurements, that even highly angiogenic renal cancers have poor perfusion compared to surrounding normal tissue, and that PET can provide valuable information on the in vivo biology of angiogenesis in man and can assess the effects of antiangiogenic therapy.

Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000.

PURPOSE: XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks. PATIENTS AND METHODS: Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m2/120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([11C]XR5000) pharmacokinetics. RESULTS: The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m2/120 hours, and the MTD was 3,010 mg/m2/120 hours. Other grade 3-4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [11C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean +/- SD in m2/mL/sec) increased when [(11)C]XR5000 was administered during an infusion of XR5000 (0.242 +/- 0.4), compared with [11C]XR5000 given alone (0.209 +/- 0.04; P <.05), indicating that tumor drug exposure was not saturated [corrected]. CONCLUSION: The recommended dose for XR5000 in phase II studies is 3,010 mg/m2/120 hours. PET studies with 11C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.

Phase I and pharmacological study of the oral matrix metalloproteinase inhibitor, MMI270 (CGS27023A), in patients with advanced solid cancer.

This Phase I study of MMI270, an p.o. administered matrix metalloproteinase inhibitor, assessed toxicity, pharmacokinetics, and tumor response data and investigated markers of biological activity to recommend a dose for Phase II studies. MMI270 was administered continuously at seven dose levels (50 mg once daily to 600 mg three times/day). Patients were evaluated for toxicity and tumor response, and blood and urine samples were taken for pharmacokinetics, bone resorption markers, direct targets of the inhibitor [matrix metalloproteinase-2 (MMP-2), MMP-8, and MMP-9], indirect targets [tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, basic fibroblast growth factor, vascular endothelial growth factor, vascular cell adhesion molecule-1, soluble urokinase plasminogen activator receptor, and cathepsins B and H] and for a tumor necrosis factor-alpha cytokine release assay. Ninety-two patients were entered. There was no myelotoxicity. Eighteen patients developed a widespread maculopapular rash, which increased in frequency and severity at doses > or = 300 mg bid. Thirty nine patients developed musculoskeletal side effects, which were related to duration of treatment, not to dose level. Pharmacokinetics were linear, and MMI270 was rapidly absorbed and eliminated with minimal accumulation on chronic dosing. Sustained plasma concentrations in excess of 4 x mean IC(50) for the target enzymes were observed at dose levels > or = 150 mg bid. There were no tumor regressions; however, 19 patients had stable disease for > or = 90 days. There was a dose-response increase of MMP-2 and TIMP-1 with MMI270. Transient effects on the bone resorption markers were detected. MMI270 was generally well tolerated, with adequate plasma levels for target enzyme inhibition. The two main toxicities were rash, resulting in a maximum tolerated dose of 300 mg bid and musculoskeletal side effects. Biological marker data indicate drug effects. The rise in TIMP-1 suggests that a reflex rise in inhibitors could modify the effects of MMI270. The recommended Phase II dose is 300 mg bid.

Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C.

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses > or = 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve (0-24 hours) and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 micromol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.

Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha.

Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNalpha), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m(-2), 9 MIU m(-2) and 18 MIUm(-2). IFNalpha was administered on day 0 cycle two, day-1 and day 0 cycle three and day-2, day-1 and day 0 cycle four. A fourth cohort was treated with IFNalpha 9 MIU m(-2) three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNalpha. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNalpha led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P= 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNalpha. A single dose of IFNalpha as low as 3 MIU m(-2) can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNalpha for biomodulation of 5-FU.

Phase II study of second-line therapy with DTIC, BCNU, cisplatin and tamoxifen (Dartmouth regimen) chemotherapy in patients with malignant melanoma previously treated with dacarbazine.

This study assessed response rates to combination dacarbazine (DTIC), BCNU (carmustine), cisplatin and tamoxifen (DBPT) chemotherapy in patients with progressive metastatic melanoma previously treated with DTIC, as an evaluation of DBPT as a second-line regimen, and as an indirect comparison of DBPT with DTIC. Thirty-five consecutive patients received DBPT. The patients were divided into two groups. Group 1 comprised 17 patients with progressive disease (PD) on DTIC + tamoxifen therapy who were switched directly to DBPT. Group 2 comprised 18 patients not immediately switched to DBPT and included patients who had either a partial response (PR; one patient) or developed stable disease (SD; four patients) with DTIC, or received adjuvant DTIC (nine patients). All except four patients had received tamoxifen at the time of initial DTIC treatment. Median times since stopping DTIC were 22 days (range 20-41) and 285 days (range 50-1,240) in Groups 1 and 2 respectively. In Group 1, one patient developed SD for 5 months and the remainder had PD. In Group 2, there were two PRs, four patients with SD (4, 5, 6, and 6 months), and 11 with PD. These results indicate that the DBPT regimen is not of value in melanoma primarily refractory to DTIC. There were responses in patients not directly switched from DTIC to DBPT, suggesting combination therapy may be of value in a small subgroup of melanoma patients.

Phase II study of the oxygen saturation curve left shifting agent BW12C in combination with the hypoxia activated drug mitomycin C in advanced colorectal cancer.

BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglobin, causing a reversible left-shift of the oxygen saturation curve (OSC) and tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia. In this phase II study, 17 patients with metastatic colorectal cancer resistant to 5-fluorouracil (5-FU) received BW12C and MMC. BW12C was given as a bolus loading dose of 45 mg kg(-1) over 1 h, followed by a maintenance infusion of 4 mg kg(-1) h(-1) for 5 h. MMC 6 mg m(-2) was administered over 15 min immediately after the BW12C bolus. The 15 evaluable patients had progressive disease after a median of 2 (range 1-4) cycles of chemotherapy. Haemoglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting for approximately 50% of total haemoglobin. The predominant toxicities--nausea/vomiting and vein pain--were mild and did not exceed CTC grade 2. Liver 31P magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combining a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour oxygen delivery by at least 50%. However, BW12C in combination with MMC for 5-FU-resistant colorectal cancer is not an effective regimen. This could be related to drug resistance rather than a failure to enhance cytotoxicity.