S. A. Krauss

Phase I study of vinorelbine, cisplatin, and concomitant thoracic radiation in the treatment of advanced chest malignancies.

PURPOSE The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer (NSCLC). We conducted a phase I trial to identify the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this regimen with concomitant thoracic radiation (RT) in patients with advanced chest malignancies. PATIENTS AND METHODS Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of standard chest radiation (30 daily 2-Gy fractions for a total of 60 Gy) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk. RESULTS Thirty-seven patients were treated on this study. Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT (neutropenia), which required deescalation. The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk, although tolerated acutely, produced delayed esophagitis, which proved dose-limiting. The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT. CONCLUSION Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible. The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule. Esophagitis is the DLT, with neutropenia occurring at higher dose levels. A Cancer and Leukemia Group B (CALGB) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC.

A phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer

BACKGROUND Bryostatin-1 is a macrocyclic lactone, which exhibits pleiotropic biological effects via protein kinase C and has shown preclinical synergy with paclitaxel for enhanced tumor cell apoptosis. PATIENTS AND METHODS Patients had stage IIIB (pleural effusion)/IV non-small cell lung cancer, measurable disease, performance status 0-2 Eastern Cooperative Oncology Group, adequate organ function, and no prior chemotherapy. Patients received dexamethasone premedication followed by paclitaxel at a dose of 90 mg/m(2) on days 1, 8, and 15 along with bryostatin-1 50 microg/m(2) on days 2, 9, and 16 every 28 days until disease progression. Correlative assays measuring serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and T-lymphocyte numbers were performed based on a previous study showing cytokine induction in vivo by bryostatin-1. Fifteen patients were enrolled. RESULTS Thirty cycles of the bryostatin-1 and paclitaxel were delivered with a median of 2 per patient (range 1-4). Myalgia was the predominant non-hematologic toxicity encountered as 3 patients developed grade 4 and 1 patient developed grade 3 myalgia. Four patients were removed from the study during cycle 1 for rapid disease progression or myalgia. Eleven patients could be evaluated for response. Five patients had stable disease, two had a mixed response, and four had progressive disease. Ten patients received second-line chemotherapy after leaving the study. Median survival was 31 weeks (95% confidence interval: 5.4-49.3). Correlative data showed a trend towards decreased plasma IL-6 and TNF-alpha after each cycle of therapy presumably due to the dexamethasone premedication and/or paclitaxel. CONCLUSIONS This drug combination showed no significant clinical response and was associated with reproducible toxicity. The predominance of myalgia in the absence of elevated serum cytokines suggests a non-inflammatory etiology of this toxicity.

A phase II trial of 9-aminocaptothecin (9-AC) as a 120-h infusion in patients with non-small cell lung cancer.

In a previous phase II trial of thesynthetic topoisomerase I inhibitor,9-aminocamptothecin (9-AC), given as a72-h infusion, we identified modestsingle agent activity of 9% in patientswith previously untreated advancednon-small cell lung cancer (NSCLC).Preclinical studies suggested that a moreprolonged continuous infusion of the drugmight lead to greater antitumor activity. Aphase I study recommended a phase II doseof 25 μg/m2/hr for 120 h(3000 μg/m2 over 5 days),administered for 2 consecutive weeks of a3-week cycle. We utilized this schedule andenrolled 13 chemotherapy-naıve patientswith Stage IIIB and IV NSCLC in this trial:median age 67 (range 57–74); 46% male;92% stage IV; and median performancestatus 1. Twelve patients are availablefor response and toxicity evaluation after2 cycles of therapy. One patient achieveda partial response. Four patients hadstable disease while seven patients hadprogressive disease. Patients with stableor progressive disease after two cyclesreceived no additional 9-AC, and wereoffered conventional chemotherapy. Themedian survival time was 10.2 months andthe one-year survival rate 28% (95%confidence interval, 5–58%). Significant toxicities includedmyelosuppression, fatigue, and anorexia. One patient had grade 4 neutropeniafollowing the first week of cycle 2, anddid not receive additional therapy. Therewere no neutropenia-related infections.These data suggest that this prolongedschedule is unlikely to increase 9-ACsvery modest activity in NSCLC above thatseen with the simpler 72-hadministration schedule. Furtherevaluation of 9-AC in NSCLC is notrecommended.

A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest

JM216 is an orally administered platinumanalogue. We undertook this study todetermine the maximally tolerated dose(MTD) of JM216 when administered withconcomitant radiotherapy to the chest(200 cGy daily, 5×/week) in patients withlocoregionally advanced non-small cell lung(NSCLC) or esophageal cancer. Patientswere excluded for inadequate bone marrowreserve, prior radiotherapy to the primarytumor or previous treatment with platinumdrugs. A dose-limiting toxicity (DLT) wasdefined using the National Cancer Institute(NCI) Common Toxicity Criteria (CTC) andconsisted of grade ≥2 renal, hepatic,cardiac, or pulmonary toxicity or grade ≥3hematologic, neurological, orgastrointestinal toxicity. A total of 23patients were registered; two neverreceived treatment and are excluded fromanalyses. Six patients were treated at adose of 30 mg/m2/day for 5 days withtwo grade 2 DLTs: cough (1 pt) andelevated trans-aminases (1 pt). Sevenevaluable patients were treated at60 mg/m2/day and seven experiencedgrade 3 or 4 toxicity, five related tomyelosuppression. The dose was thenreduced to 45 mg/m2/d. Eight patientswere evaluable for toxicity, of which 5experienced DLT: myelosuppression (3 pts),esophagitis (2 pts), dyspnea (1 pt), andelevated creatinine (1 pt). Fourteenpatients were evaluable for efficacy, ofwhich 6 had an objective response,including one complete response. Therecommended phase II dose of JM216 withconcurrent radiation therapy is30 mg/m2/d for 5 days. The major DLTis myelosuppression with only limitedincreased toxicity within the field ofradiation. This conceivably may limit theuse of JM216 as a radiation sensitizer.

Aziridinylbenzoquinone in recurrent, progressive glioma of the central nervous system. A phase ii study by the illinois cancer council

Aziridinylbenzoquinone (AZQ) was studied in a Phase II protocol for persons with glioma of the central nervous system (CNS) recurrent or progressive after surgery and radiotherapy. Patients received AZQ, 30 mg/m2 intravenously every 3 weeks if previously untreated or 27.5 mg/m2 if previously exposed to cytotoxic drugs. Partial response was defined as a reduction of at least 50% reduction in the product of the two longest perpendicular diameters of the indicator lesion persisting for a minimum of 28 days. Twenty‐eight patients are evaluable for response at this time. Objective response (OR) occurred in four (14.3%): two complete and two partial. Stabilization of disease (SD) was seen in 7 (25.0%). Median survival, in weeks, was >46.0 for responders, 41.7 for SD, and 19.3 for those with progressive disease. The survival experiences are significantly different (P = 0.030 [Breslow]). The OR rate was 21.1% in 19 without prior chemotherapy and 0% in 9 previously treated patients. There were two AZQ‐related deaths in patients with prior exposure to nitrosoureas (1 CNS hemorrhage; 1 aspiration pneumonia). One patient had an anaphylactic reaction. Three patients whose tumor initially increased in size subsequently had marked tumor shrinkage. AZQ is an active agent that must be used with added caution in patients who have received nitrosoureas. Initial tumor enlargement may precede response. Although response appears to prolong survival, the correlation between stabilization of disease and survival is not well‐defined.

Carboplatin plus vinorelbine with concomitant radiation therapy in advanced non-small cell lung cancer: a phase I study

This phase I study was designed to determine the maximum tolerated dose of carboplatin when administered in combination with a fixed dose of vinorelbine and concomitant radiation therapy in patients with advanced non-small cell lung cancer. Chemotherapy was administered on days 1 and 8 of two 21 day cycles. It consisted of vinorelbine at 15 mg/m(2) and carboplatin administered at an initial area under the curve (AUC) of 1.5, and increased by an AUC of 0.5 per dose level to a maximum AUC of 3, corresponding with an AUC of 6 per cycle of chemotherapy. Radiation was administered in daily fractions of 200 cGy over 5-7 weeks. We treated 36 patients, of whom 27 had stage II or III disease, and nine had stage IV disease but required thoracic radiation for palliation. Toxicities included neutropenia (three with Grade 4) and esophagitis (seven with Grade 3 and one with Grade 4). Four patients had radiation pneumonitis 4-7 months after completing therapy, three of whom died. The recommended phase II dose of carboplatin is an AUC of 3 on 2 consecutive weeks. Of 33 patients evaluable for response within the radiation field, 17 (52%) had complete or partial response, and 13 had stable disease. Of seven patients evaluable with distant metastatic disease, three had a complete or partial response, and two had stable disease. The median survival for the entire group and for patients with stage II/III disease was 13.5 months. We conclude that the combination of carboplatin, vinorelbine, and radiotherapy is feasible at these doses. It may be a useful alternative for patients not able to tolerate cisplatin-based therapy.

A phase I–II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer

PURPOSE We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

Phase I Study of Induction Chemotherapy and Concomitant Chemoradiotherapy with Irinotecan, Carboplatin, and Paclitaxel for Stage III Non-small Cell Lung Cancer

Background: The aim of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and determine the phase II dose for the combination of irinotecan-carboplatin-paclitaxel given as induction chemotherapy and with concomitant chest radiotherapy for patients with Stage III non-small cell lung cancer. Methods: Patients with Cancer and Leukemia Group B performance status of 0 to 2, stage IIIA and IIIB NSCLC patients with resectable or unresectable disease were treated with induction chemotherapy (irinotecan 100 mg/m2, carboplatin AUC 5, and paclitaxel 175 mg/m2 days 1 and 22) followed by concomitant chemotherapy (irinotecan, carboplatin, and paclitaxel) and chest radiotherapy (66 Gy for unresectable and 50 Gy for resectable disease) beginning on week 7. The primary objective was to escalate the dose of irinotecan during chemoradiation in sequential cohorts to determine the DLT and MTD of the regimen. Results: Thirty-eight patients were enrolled (median age 63 years, 57% male, 41% performance status 0, 30% resectable). Induction chemotherapy was tolerable and active (response rate 26%; stable disease 60%). Eight patients did not receive concurrent chemoradiotherapy because of progressive disease (5), death (1), hypersensitivity reaction to paclitaxel (1), and withdrawal of consent (1). Twenty-nine patients received concurrent chemoradiotherapy. The concomitant administration of chest radiotherapy with weekly irinotecan, carboplatin, and paclitaxel was not feasible at the first, second, and third dose levels. DLT was failure to achieve recovery to ≤ grade 1 absolute neutrophil count by the day of scheduled chemotherapy administration. Dose de-escalation to irinotecan 30 mg/m2, paclitaxel 40 mg/m2 (with omission of carboplatin) delivered on weeks 2, 3, 5, and 6 of radiotherapy was the MTD. After induction chemotherapy, partial responses, stable disease, and progressive disease was observed in 26%, 60%, and 14% of patients, respectively. After chemoradiotherapy, partial responses were attained in 16 (55%) patients, whereas 12 patients (41%) attained disease stabilization. Median overall survival was 21 months for the entire cohort. Resectable patients had a median survival of 24 months, whereas unresectable patients had a median survival of 19 months. Differences in overall and progression-free survival rates between resectable and unresectable patients was not statistically significant (p = 0.52 and p = 0.90, respectively). Discussion: Carboplatin, paclitaxel, and irinotecan with concurrent chemoradiotherapy was poorly tolerated as a result of neutropenia. Although dose de-escalation was required for delivery of the regimen, the response rates and survival outcomes were comparable to other similar regimens.