Phase II study of oral platinum drug JM216 as first-line treatment in patients with small-cell lung cancer.

PURPOSE: This multicenter phase II trial was performed to determine tumor efficacy and tolerance of the oral platinum drug JM216 in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC limited disease unfit for intensive chemotherapy or those with extensive disease received JM216 120 mg/m(2)/d for 5 consecutive days every 3 weeks. Individual dose escalation to 140 mg/m(2)/d was allowed if toxicity was

Paclitaxel and carboplatin in the treatment of small-cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: a non-cross-resistant schedule.

PURPOSE: To evaluate the efficacy of paclitaxel and carboplatin (PC) in small-cell lung cancer (SCLC) patients resistant to cyclophosphamide, doxorubicin, and etoposide (CDE). PATIENTS AND METHODS: We performed a phase II study with PC in SCLC patients who relapsed within 3 months after first-line treatment with CDE. Paclitaxel administration (175 mg/m2 by a 3-hour intravenous infusion) was followed by a 30-minute infusion of carboplatin (area under the curve 7; Chatelut formula) once every 3 weeks for five cycles. Dexamethasone, clemastine, and ranitidine were standard premedication before every cycle. RESULTS: Included were 35 patients (median age, 59 years; 16 with limited disease and 19 with extensive disease; Eastern Cooperative Oncology Group performance status of < or = 1; median time off treatment 6 weeks) who were previously treated with CDE (n = 33), oral etoposide (n = 2), and reinduction CDE (n = 15); only one patient had received three CDE treatments of five cycles. The CDE regimen was followed by local thoracic radiotherapy in seven patients. Hematologic toxicity of grade 3 or 4, for leukopenia was 27% and 6%, for thrombocytopenia 21% and 13%, and for anemia 17% and 0%, respectively, for a total of 132 cycles. Two patients had neutropenic fever; no toxic death occurred. Nonhematologic toxicity was paresthesia CTC grade 3, diarrhea grade 4, and myalgia grade 3 in one patient each. Reversible paresthesia (CTC grade 1 and 2) in toes and fingers was reported in 69% of patients. Thirty-four patients were assessable for response: complete response in two patients, partial response in 23 patients, stable disease in eight patients, and progressive disease in one patient (response rate, 73.5%; 95% confidence interval, 59% to 88%). One patient was found to have atypical carcinoid at pathologic review and was excluded. Median time to progression was 21 weeks (range, 3 to 40 weeks). Median survival was 31 weeks (range, 6 to 112 weeks). One-year survival was 9%. CONCLUSION: Second-line PC in CDE-resistant SCLC patients yields a high response rate and seems non-cross-resistant to CDE. Toxicity was mild in these poor-prognosis patients.

PNU-145156E, a novel angiogenesis inhibitor, in patients with solid tumors: a phase I and pharmacokinetic study.

Our aim was to establish, in patients with solid tumors, the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacology of PNU-145156E, a new sulfonated distamycin A derivative that blocked circulating angiogenesis-promoting growth factors in animal studies and exhibited an antitumor effect in murine solid tumors. In a Phase I study, PNU-145156E was administered i.v. every 6 weeks. Included were patients with solid tumors; an Eastern Cooperative Oncology Group performance score

Expression of apoptosis-related proteins and morphological changes in a rat tumor model of human small cell lung cancer prior to and after treatment with radiotherapy, carboplatin, or combined treatment.

PURPOSE: In order to understand the apoptosis pathway in tumor cells, differences in cell morphology and expression of apoptosis-related proteins induced by radiation and/or chemotherapy, were investigated in a rat double tumor model comparing cisplatin-sensitive and -resistant human small cell lung cancer tumors. METHODS: The cisplatin-sensitive human small cell lung cancer cell line (GLC4) and its cisplatin-resistant subline (GLC4-CDDP) were each injected subcutaneously in a different hind limb of the rat. After 15-17 days, radiation (10 Gy), carboplatin (25 mg/kg, intraperitoneal), combined treatment, or no treatment was administered. In combined treatment, carboplatin was administered 24 h before radiation. Tumors were removed and fixed 72 h after carboplatin or 48 h after radiation. Paraffin-embedded slides were stained with hematoxylin/eosin for morphology. Expression of the apoptosis-related proteins p53, p21, Rb, bcl-2, bax, c-myc, Fas and Fas-L was assessed immunohistochemically. RESULTS: In the GLC4 tumor, carboplatin treatment increased tumor cell size, tumor cell size heterogeneity, and number of apoptotic tumor cells. After radiation and combined treatment, these changes were more pronounced and multinuclear giant cells were observed. In GLC4-CDDP tumors, minimal changes were detected after carboplatin. Following radiation slight increases in tumor cell size, tumor cell size heterogeneity and number of apoptotic tumor cells were observed. No multinuclear giant cells were seen. After combined treatment, GLC4-CDDP showed cellular changes comparable to those in GLC4 cells after radiation or combined treatment, but no giant cells were observed. Untreated, both tumors were equally positive for p53, bax, Fas, Fas-L, c-myc and negative for Rb. Contrary to GLC4, untreated GLC4-CDDP tumors showed no p21 and bcl-2 expression. After combined treatment, an increase in number of bcl-2 positive cells was found in GLC4-CDDP tumors. No p21 was induced in GLC4-CDDP by any treatment modality. In GLC4 tumors, p21 was induced by radiation alone. No further changes in protein expression were induced by any treatment in GLC4 tumors. CONCLUSION: Following therapy, morphological changes in cell size and cell size heterogeneity were more pronounced in GLC4 than in GLC4-CDDP tumors. However, morphological changes in GLC4-CCDP tumors after treatment indicate that carboplatin plus radiotherapy may be effective also in cisplatin resistant tumor cells. An increase in p21 in GLC4 after radiation might facilitate apoptosis. The increase in number of Bcl-2 positive cells after combined treatment and the consistently negative p21 status after any treatment in GLC4-CDDP may protect these tumor cells from apoptosis as a part of their resistance mechanism to cisplatin.

Lack of nephrotoxicity of new oral platinum drug JM216 in lung cancer patients.

PURPOSE: The purpose of this study was to assess renal function in patients treated with the oral platinum drug JM216 [bisacetato-ammine-dichloro-cyclohexylamine-platinum(IV)], since the effects of JM216 on renal function have only partly been investigated using serum parameters or 51Cr-EDTA clearance. We used a sensitive method that assessed glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and indicators of tubular and glomerular damage. METHODS: A group of 24 patients with either non-small-cell lung cancer (NSCLC) stage IIIb/IV or small-cell lung cancer (SCLC), limited disease (LD) or extensive disease (ED), treated with JM216 were studied. All patients had no prior chemotherapy, a performance score < 2, a life expectancy of more than 3 months and normal liver, renal and bone marrow functions before treatment. All patients received oral JM216 120 mg/m2 per day for 5 consecutive days, repeated every 21 days with a maximum of six cycles. In six SCLC patients the dose was escalated to 140 mg/m2 per day after the first cycle. Prior to treatment, after the first cycle and after the end of treatment renal function was assessed by 125I-sodium thalamate and 131-hippurate clearances to determine acute and cumulative changes in GFR and ERPF, respectively. Furthermore, tubular and glomerular damage were assessed by urinary excretion of beta2-microglobulin, lactic dehydrogenase (LDH), alkaline phosphatase (ALP), gamma-glutamyltransferase (GT) and albumin. RESULTS: In 20 evaluable patients no significant acute impairment of renal function was observed. Median (range) GFR, ERPF and filtration fraction (FF) before treatment were 101 ml/min (53-164 ml/min), 417 ml/min (227-719 ml/min), and 0.25 (0.19-0.33), respectively. After the first cycle values were 117 ml/min (71-189 ml/min), 418 ml/min (228-709 ml/ min) and 0.28 (0.21-0.33), respectively. Also, no indications of tubular or glomerular damage were found. In four patients renal function was evaluated at the end of treatment (one after three cycles, one after five cycles and two after six cycles). Median (range) GFR, ERPF and FF were 99 ml/min (74-139 ml/min), 401 ml/min (277-496 ml/min) and 0.26 (0.23-0.30), respectively, revealing no delayed nephrotoxicity. CONCLUSION: We conclude that oral JM216 shows no nephrotoxicity.

A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer.

The purpose of the study was to delineate the efficacy and toxicity of paclitaxel (Taxol, Bristol Myers Squibb) in the treatment of drug resistant small-cell lung cancer (SCLC). Patients with SCLC relapsing within 3 months of cytotoxic therapy received paclitaxel 175 mg m(-2) intravenously over 3 h every 3 weeks. The dose of paclitaxel was adjusted to the toxicity encountered in the previous cycle. Of 24 patients entered into the study, 24 and 21 were assessable for response and toxicity respectively. There were two early deaths and two toxic deaths. No complete and seven partial responses (29%) (95%CI 12-51%) were observed and five patients had disease stabilization. The median survival (n = 21) was 100 days. Life-threatening toxicity occurred in four patients; in others (non)-haematological toxicity was manageable. Paclitaxel is active in drug-resistant SCLC. Further investigation in combination with other active agents in this poor prognosis group is appropriate.

A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study.

The aim of this phase I study was to assess feasibility, pharmacokinetics and toxicity of methoxymorpholino doxorubicin (MMRDX or PNU-152243) administered as a 3 h intravenous infusion once every 4 weeks. Fourteen patients with intrinsically anthracycline-resistant tumours received 37 cycles of MMRDX. The first cohort of patients was treated with 1 mg m(-2) of MMRDX. The next cohorts received 1.25 mg m(-2) and 1.5 mg m(-2) respectively. Common toxicity criteria (CTC) grade III/IV nausea and vomiting were observed in 1/18 cycles at 1.25 mg m(-2) and in 2/11 cycles at 1.5 mg m(-2). Transient elevation in transaminases up to CTC grade III was observed in 2/16 cycles at 1.25 mg m(-2) and 4/11 cycles at 1.5 mg m(-2). No cardiotoxicity was observed. At 1.25 mg m(-2) CTC grade IV neutropenia occurred in 1/17 cycles. At 1.5 mg m(-2) CTC grade III neutropenia was seen in 2/7 and grade IV in 3/7 evaluable cycles. Thrombocytopenia grade III was observed in 2/9 and grade IV in 1/9 evaluable cycles. One patient treated at 1.5 mg m(-2) died with neutropenic fever. Therefore, dose-limiting toxicity was reached and 1.25 mg m(-2) was considered the maximum tolerated dose for MMRDX as 3 h infusion. No tumour responses were observed. Pharmacokinetic parameters showed a rapid clearance of MMRDX from the circulation by an extensive tissue distribution. Renal excretion of the drug and its metabolite was negligible. In conclusion, prolongation of MMRDX infusion to 3 h does not improve the toxicity profile as compared with bolus administration.

Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study.

PURPOSE: To determine the radiosensitizing effect of prolonged exposure of carboplatin in patients with locally unresectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with histologically proven NSCLC, performance score <2, weight loss <10%, and normal organ functions were randomized between carboplatin 840 mg/m2 administered continuously during 6 weeks of radiotherapy or thoracic radiotherapy alone (both 60 Gy). Toxicity was evaluated with National Cancer Institute Common Toxicity Criteria (NCI CTC) and the Radiation Therapy Oncology Group (RTOG) criteria. Quality of life was measured with European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/LC13 questionnaires. RESULTS: One-hundred and sixty patients were included. Pathologically confirmed persistent tumor was present in 53% of patients in the combination arm versus 58% in the radiotherapy alone arm (P=0.5). Median survival in the combination arm was 11.8 [95% confidence interval (CI) 9.3-14.2] months and in the radiotherapy alone arm 11.7 (95% CI 8.1-15.5) months; progression-free survival was not different between arms [6.8 and 7.5 months, respectively (P=0.28)]. Acute toxicity was mild, late toxicity was radiation-induced cardiomyopathy (three patients) and pulmonary fibrosis (five patients). Quality of life was not different between arms, but in all measured patients cough and dyspnea improved, pain became less, and slight paresthesia developed 3 months after treatment. CONCLUSION: Addition of continuously administered carboplatin as radiosensitizer for locally unresectable NSCLC does not improve local tumor control or overall survival.