Phase I Study of N1-N11-Diethylnorspermine (DENSPM) Administered TID for 6 Days in Patients with Advanced Malignancies

This was a dose escalation Phase 1 trial designed todetermine the maximum tolerated dose (MTD) and dose-limitingtoxicities (DLT) of DENSPM. Methods: Adult patientswith refractory solid tumors were treated with DENSPMadministered by intravenous infusion in 100 ml of normalsaline over 30 minutes. The daily dose of DENSPM was dividedinto three equal doses administered approximately every eighthours for six days. Courses were repeated every 28 days.Results: Twenty-eight patients were enrolled in thestudy. Dose levels of DENSPM explored were 25mg/m²/day (3 patients), 50 mg/m²/day (9patients), 60 mg/m²/day (5 patients), 75mg/m²/day (6 patients), 94 mg/m²/day (3patients) and 118 mg/m²/day (2 patients). The DLTfor DENSPM was central nervous system toxicity characterizedby aphasia, ataxia, dizziness, vertigo and slurred speechoccurring at dose levels 94 mg/m²/day, whichwas also the MTD. Safety: The most frequent drug-relatedadverse events were asthenia (9 patients), injection sitereaction (6 patients) and anemia (6 patients). One patient wasremoved from the study due to CNS toxicity. There were notreatment-related deaths. No trends were observed regardinghematologic toxicities, biochemical changes or changes invital signs. Efficacy: Nineteen of the 28 patients enrolled inthe study were assessed for response. No objective responseswere observed. Five patients had stable disease as the bestresponse to therapy. Conclusions: Because the DLT wasCNS and because of the relatively low doses that could besafely administered on this schedule as compared with aonce-a-day schedule, this regimen was not recommended forPhase 2.     

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 DLT's: 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.     

Phase I study of Vinflunine administered as a 10-minute infusion on days 1 and 8 every 3 weeks

Summary Vinflunine is a novel vinca alkaloid developed through the selective modification of vinorelbine using super-acidic chemistry. In preclinical testing, vinflunine demonstrated significantly enhanced anti-tumour activity in human tumour xenograft models when compared to its parent compound. A phase I study was conducted to evaluate the safety and toxicity of vinflunine administered as a 10 minute intravenous infusion on days 1 and 8 every three weeks. Sixteen patients with advanced solid tumours were treated. Two of four patients experienced dose limiting toxicities (DLT) at 190 mg/m² and this was established as the maximum tolerated dose (MTD). At the MTD, the DLT of vinflunine consisted of constipation and neutropenia. Fatigue was notable but not dose limiting. No objective responses were observed. A dose of 170 mg/m² given on a day 1 and 8 schedule every three weeks would be suitable for future studies.     

Phase I trial of weekly cisplatin,irinotecan and paclitaxel in patients with advanced gastrointestinal cancer

Summary   Objectives: To determine the maximum tolerated dose (MTD), toxicities, and suitable dose for weekly 1-h paclitaxel combined with weekly cisplatin and irinotecan to treat advanced gastrointestinal malignancies. Methods: Thirty patients with metastatic or locally advanced (unresectable or recurrent) gastrointestinal solid tumors were enrolled on this single-center, phase I study. Patients were treated with paclitaxel given over 1h at 1 of 4 dose levels (40, 50, 65, or 80 mg/m²). Paclitaxel was followed by fixed doses of cisplatin (30 mg/m²) and irinotecan (50 mg/m²). All treatment was administered sequentially, once a week, in 6-week cycles (4 weeks on, 2 weeks off). Dose-limiting toxicity (DLT) was defined as a 2-week delay in treatment for grade 3 or 4 non-hematologic toxicity, neutropenic fever, a 1-week delay for grade 4 hematologic toxicity, or a 2-week delay for grade 3 hematologic toxicity. Results: Thirty patients were recruited; 28 patients were assessable for safety. Most of the patients (70%) had no prior chemotherapy. The primary first-cycle DLTs were neutropenia, diarrhea, and nausea. Paclitaxel at 65 mg/m² was defined as the MTD. The most common grade 3–4 toxicities observed during all cycles were neutropenia (57%), febrile neutropenia (11%), diarrhea (29%), fatigue (29%), and nausea (18%). No patients had G-CSF (Neupogen, Amgen Inc., Thousand Oaks, CA) support. Responses were observed in gastric, esophageal, and pancreatic cancers. Conclusion: Paclitaxel at 65 mg/m², cisplatin (30 mg/m²), and irinotecan (50 mg/m²) given weekly can be safely administered to patients with solid tumor malignancies. To improve cumulative toxicities, a schedule modification was required (3-week cycle; 2-on, 1-off) Neutropenia was the most common DLT. This combination showed substantial activity, particularly in patients with gastric and esophageal adenocarcinoma, and phase II evaluation could be considered.     

Phase I study of paclitaxel administered by ten-day continuous infusion

Purpose: Pre-clinical data have suggested that prolonged exposure to paclitaxel enhances its cytotoxicity, but various clinical trials utilizing long-term infusions of paclitaxel have been limited by unacceptable hematologic toxicity, most notably significant neutropenia. A phase I study of paclitaxel administered over 10 days, was performed to evaluate the hematologic and non-hematologic toxicities as well as to determine the maximum-tolerated dose for the 10-day infusion duration.Patients and methods: Twenty-nine solid tumor patients (predominantly non-small cell lung cancer and head and neck cancer) were treated with paclitaxel at doses ranging from 5 mg/m2/day to 25 mg/m2/day administered as a 10-day continuous infusion via a pump every 21 days. Dose escalation was permitted within individual patients. Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity, ANC 500 or platelet count 25,000 for 7 days or febrile neutropenia. The maximum tolerated dose (MTD) was defined as the highest dose level at which less than two out of six patients developed DLT. All of the patients had received prior chemotherapy; approximately two-thirds had received prior radiation as well. All patients received standard pre-medications for paclitaxel, including anti-histamines and corticosteroids. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used.Results: A total of 110 courses of paclitaxel were administered to 29 patients. The incidence of hematologic and non-hematologic toxicity was quite low among the patients treated at dose levels below 17 mg/m2/day. At higher doses, non-hematologic toxicities including arthralgias, myalgias, fatigue, nausea, stomatitis, and peripheral neuropathy were seen, although nearly all of the toxicities were less than grade 3 (NCI toxicity criteria). Hematologic toxicity mostly consisted of neutropenia and was more common at dose levels of 17 mg/m2/day or higher. Nevertheless, even at the highest dose levels (21 mg/m2/day and 25 mg/m2/day) grade 3 or 4 neutropenia occurred in only 50% of patients. Dose-limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25 mg/m2/day dose level.Conclusion: Paclitaxel can be safely administered as a 10-day infusion. The MTD for this schedule is 210 mg/m2. Unlike the 96-hour paclitaxel infusions, dose-reduction for myelosuppression may not be necessary because the MTD of paclitaxel when administered over a 10-day infusion is similar to the MTD of paclitaxel when infused over 3 or 24 hours.     

Phase I study of 17-allylamino-17 demethoxygeldanamycin,gemcitabine and/or cisplatin in patients with refractory solid tumors

Purpose: To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of 17-AAG, gemcitabine and/or cisplatin. Levels of the proteins Hsp90, Hsp70 and ILK were measured in peripheral blood mononuclear cell (PMBC) lysates to assess the effects of 17-AAG. Experimental design: Phase I dose-escalating trial using a “3 + 3” design performed in patients with advanced solid tumors. Once the MTD of gemcitabine + 17-AAG + cisplatin was determined, dose escalation of 17-AAG with constant doses of gemcitabine and cisplatin was attempted. After significant hematologic toxicity occurred, the protocol was amended to evaluate three cohorts: gemcitabine and 17-AAG; 17-AAG and cisplatin; and gemcitabine, 17-AAG and cisplatin with modified dosing. Results: The 39 patients enrolled were evaluable for toxicity and response. The MTD for cohort A was 154 mg/m² of 17-AAG, 750 mg/m² of gemcitabine, and 40 mg/m² of cisplatin. In cohort A, DLTs were observed at the higher dose level and included neutropenia, hyperbilirubinemia, dehydration, GGT elevation, hyponatremia, nausea, vomiting, and thrombocytopenia. The MTD for cohort C was 154 mg/m² of 17-AAG and 750 mg/m² of gemcitabine, with one DLT observed (alkaline phosphatase elevation) observed. In cohort C, DLTs of thrombocytopenia, fever and dyspnea were seen at the higher dose level. The remaining cohorts were closed to accrual due to toxicity. Six patients experienced partial responses. Mean Hsp90 levels were decreased and levels of Hsp70 were increased compared to baseline. Conclusions: 17-AAG in combination with gemcitabine and cisplatin demonstrated antitumor activity, but significant hematologic toxicities were encountered. 17-AAG combined with gemcitabine is tolerable and has demonstrated evidence of activity at the MTD. The recommended phase II dose is defined as 154 mg/m² of 17-AAG and 750 mg/m² of gemcitabine, and is currently being investigated in phase II studies in ovarian and pancreatic cancers. There is no recommended phase II dose for the cisplatin-containing combinations.     

Phase I study of paclitaxel administered by ten-day continuous infusion

PURPOSE: Pre-clinical data have suggested that prolonged exposure to paclitaxel enhances its cytotoxicity, but various clinical trials utilizing long-term infusions of paclitaxel have been limited by unacceptable hematologic toxicity, most notably significant neutropenia. A phase I study of paclitaxel administered over 10 days, was performed to evaluate the hematologic and non-hematologic toxicities as well as to determine the maximum-tolerated dose for the 10-day infusion duration. PATIENTS AND METHODS: Twenty-nine solid tumor patients (predominantly non-small cell lung cancer and head and neck cancer) were treated with paclitaxel at doses ranging from 5 mg/m2/day to 25 mg/m2/day administered as a 10-day continuous infusion via a pump every 21 days. Dose escalation was permitted within individual patients. Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity, ANC < or = 500 or platelet count < or = 25,000 for > or = 7 days or febrile neutropenia. The maximum tolerated dose (MTD) was defined as the highest dose level at which less than two out of six patients developed DLT. All of the patients had received prior chemotherapy; approximately two-thirds had received prior radiation as well. All patients received standard pre-medications for paclitaxel, including anti-histamines and corticosteroids. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used. RESULTS: A total of 110 courses of paclitaxel were administered to 29 patients. The incidence of hematologic and non-hematologic toxicity was quite low among the patients treated at dose levels below 17 mg/m2/day. At higher doses, non-hematologic toxicities including arthralgias, myalgias, fatigue, nausea, stomatitis, and peripheral neuropathy were seen, although nearly all of the toxicities were less than grade 3 (NCI toxicity criteria). Hematologic toxicity mostly consisted of neutropenia and was more common at dose levels of 17 mg/m2/day or higher. Nevertheless, even at the highest dose levels (21 mg/m2/day and 25 mg/m2/day) grade 3 or 4 neutropenia occurred in only 50% of patients. Dose-limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25 mg/m2/day dose level. CONCLUSION: Paclitaxel can be safely administered as a 10-day infusion. The MTD for this schedule is 210 mg/m2. Unlike the 96-hour paclitaxel infusions, dose-reduction for myelosuppression may not be necessary because the MTD of paclitaxel when administered over a 10-day infusion is similar to the MTD of paclitaxel when infused over 3 or 24 hours.     

A phase I study of ispinesib,a kinesin spindle protein inhibitor,administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors

Purpose To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic profile of ispinesib when administered as a 1-h intravenous infusion weekly for three consecutive weeks of a 28 day treatment period to patients with advanced solid tumors. Experimental Design Thirty patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase at doses ranging from 1–8 mg/m²/week. Pharmacokinetic samples, skin punch biopsies, and tumor biopsies (in patients with accessible tumor) were obtained during cycle 1 of treatment. Disease assessment was performed every two treatment cycles. Results The MTD was defined as 7 mg/m² administered as a 1-h infusion weekly for three consecutive weeks of a 28 day schedule. The MTD was exceeded at 8 mg/m² due to DLTs of grade 2 (one patient) and grade 3 neutropenia (one patient) that resulted in the inability to administer the Day 15 dose in Cycle 1. The neutrophil nadir occurred at approximately Day 8 with a 3–7 day recovery period. The most common toxicities were nausea, diarrhea, fatigue, and neutropenia. Alopecia, mucositis, and neuropathy were not observed. Stable disease was reported as the best response to treatment in nine patients. Conclusion The recommended dose of ispinesib is 7 mg/m² over 1 h weekly for three consecutive weeks of a 28 day treatment cycle.     

Phase I/II study of amrubicin,a novel 9-aminoanthracycline,in patients with advanced non-small-cell lung cancer

Purpose: Amrubicin is a novel, totally synthetic 9-aminoanthracycline. The present phase I/II study was performed to define its maximum-tolerated dose (MTD), efficacy and toxicity in the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Chemonaive patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and adequate organ functions. Amrubicin was administered by daily intravenous injection for 3 consecutive days every 3 weeks. Results: In a phase I study, four patients were enrolled at dose level 1 (40 mg/m²/day) and four at dose level 2 (45 mg/m²/day). No dose limiting toxicity (DLT), which was defined as toxicity consisting of grade 4 neutropenia and leukopenia lasting four days or more, and grade 3 or 4 toxicity other than neutropenia, leukopenia, anorexia, nausea/vomiting, and alopecia, was observed at these dose levels. Subsequently, at dose level 3 (50 mg/m²/day), 3 of 5 patients experienced DLTs (leukopenia, neutropenia, thrombocytopenia, or gastrointestinal complications). The MTD and recommended dose (RD) were determined to be 50 mg/m²/day and 45 mg/m²/day, respectively. Three partial responses (PRs) were achieved in 13 patients (response rate, 23.1%) in a phase I study. In a phase II study, 15 patients were assessable for efficacy and toxicity at the RD, and four PRs were obtained (response rate, 26.7%). The major toxicities were leukopenia and neutropenia, while non-hematologic toxicities were mild. The overall response rate in the combined patient population of the phase I/II study was 25.0% (7 PRs in 28 patients), with a 95% confidence interval of 10.7% to 44.9%. Conclusion: Amrubicin exerted promising antitumor activity on NSCLC with acceptable toxicity.     

Phase I study of oral irinotecan as a single-agent and given sequentially with capecitabine

Purpose To assess the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of orally administered irinotecan in the semi-solid matrix (SSM) formulation, both as a single agent and in sequential combination with capecitabine, in patients with advanced solid tumors. Patients and Methods Forty-three patients were treated with irinotecan given as a single oral daily dose on days 1–5 every three weeks. An additional forty patients were treated with sequential oral irinotecan given daily on days 1–5 followed by capecitabine given orally as a divided dose twice daily on days 6–14 of each three week cycle. Results The MTD of single-agent oral irinotecan was estimated to be 60 mg/m²/day, and DLT included diarrhea, nausea, and neutropenia. In an initial group of patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, the MTD of sequential oral irinotecan/capecitabine was estimated to be 40/1600 mg/m²/day with DLT of delayed diarrhea. In a subsequent group of patients with ECOG PS of 0 or 1, the MTD for the sequential combination was 50/2000 mg/m²/day. The most common adverse events were fatigue, diarrhea, nausea/vomiting and dehydration. Pharmacokinetic (PK) evaluation showed that oral irinotecan was rapidly absorbed and effectively converted to the active metabolite, SN-38, achieving approximately 50% of the SN-38 systemic exposure resulting from an equivalent IV dose. Conclusions Oral irinotecan can be safely administered as a single agent or in sequential combination with capecitabine. The efficacy of oral irinotecan should be explored further as a potentially convenient alternative to IV chemotherapy.     

A phase I study of gemcitabine, 5-fluorouracil and leucovorin in patients with advanced, recurrent, and/or metastatic solid tumors

Introduction: This was a dose escalation phase I trial designed to establish the MTD (maximum tolerated dose) and toxicity profile of the combination of gemcitabine, leucovorin and 5-fluorouracil (5-FU).Methods: Standard eligibility criteria were required for patients with advanced malignancy to enrol. Gemcitabine was escalated from an initial dose of 800 mg/m². Gemcitabine was administered prior to leucovorin (25 mg/m²) followed by bolus 5-FU (600 mg/m²) every week for 3 weeks followed by 1 week of rest.Results: Of 21 patients enrolled, 20 were eligible for MTD determination. Patients received a median of three 4-week cycles of chemotherapy (range: 1 to 8 cycles). Toxicity was predominantly hematologic or gastroenterologic. Four dose levels were studied. At a gemcitabine dose of 1,500 mg/m² systemic symptoms of fatigue accompanied hematologic toxicity and patients refused further therapy. At 1,250 mg/m², full dose intensity was not delivered during the first cycle in 7 of 8 patients treated. Therefore, 1,000 mg/m² was established as the recommended phase II dose for gemcitabine in this study. Antitumor activity was seen at all dose levels.Conclusions: The combination of gemcitabine, leucovorin and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile. Recommended phase II dose for gemcitabine was 1,000 mg/m². Initial evidence of clinical activity was seen in a variety of tumor types.     

Phase I trial of oblimersen (Genasense®) and gemcitabine in refractory and advanced malignancies

Background: Overexpression of Bcl-2 is associated with worse prognosis for a number of cancer types. The present study was designed to determine the maximum tolerated dose (MTD) of oblimersen (antisense Bcl-2) and gemcitabine when administered to patients with refractory malignancies. Materials and methods: Sixteen patients with advanced solid tumors refractory to standard therapies were treated with escalating doses of oblimersen continuous, 120-h intravenous infusion given every 14 days, with a fixed-dose-rate intravenous infusion of gemcitabine administered on day 5 of each cycle. Serial plasma samples were collected to calculate the pharmacokinetics of oblimersen and gemcitabine, and also to measure the effect of oblimersen on Bcl-2 expression. Results: 7 women and 9 men, median age 55 years (range 35–74 years), received a 5-day infusion of oblimersen at dose levels of 5 mg/kg/day (n = 4) or 7 mg/kg/day (n = 12). On the 5th day of the infusion, gemcitabine was given at 10 mg/m²/h for a total dose of 1,000 mg/m² (n = 7; cohorts I and II), 1,200 mg/m² (n = 3; cohort III), or 1,500 mg/m² (n = 6; cohort IV). Edema was the dose-limiting toxicity (DLT), necessitating expansion of cohort IV. No subsequent DLTs were noted. Thus, the maximum planned doses were well tolerated, and a formal MTD was not determined. Most hematologic toxicities were grade 1 or 2. There was low-grade fatigue, nausea/vomiting, and myalgias/arthralgias. Oblimersen C_ss and AUC increased in relation to the dose escalation, but gemcitabine triphosphate levels did not correlate well with dose. There were no objective responses, though 5 patients had stable disease. A >75% reduction in Bcl-2 expression in peripheral blood mononuclear leucocytes was seen more frequently in patients who achieved stable disease than in progressing patients. Conclusions: The maximal planned dose levels of oblimersen and gemcitabine in combination were well tolerated. Only one DLT (edema) occurred. There was a correlation between Bcl-2 reduction and stable disease. The recommended doses of the drugs for future studies are 7 mg/kg/day of oblimersen on days 1–5, and gemcitabine 1,500 mg/m² on day 5, every two weeks.     

Gemcitabine and mitoxantrone in metastatic breast cancer: A phase-I-study

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m²) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m²) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m² gemcitabine and 14 mg/m² mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m² based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m².     

Phase I escalation of gemcitabine combined with protracted oral etoposide in gynecologic malignancies: A Gynecologic Oncology Group study

Objective: Although improvementshave been made in the management ofpatients with advanced ovarian cancer,long-term survivors are still uncommon. Gemcitabine and prolonged oral etoposidehave shown reproducible single-agentactivity in patients withplatinum/paclitaxel-resistant ovariancancer. This, combined with preclinicalsynergism, prompted the GynecologicOncology Group to determine the maximumtolerated dose (MTD) of this combination. Methods: Eligible patients hadrecurrent epithelial ovarian cancer,primary papillary peritoneal, or fallopiantube carcinoma. All had received priorplatinum/paclitaxel-based chemotherapy andhad adequate hepatic, renal and bone marrowfunction. Oral etoposide was administeredat 50 mg/m² for ten days, with threeproposed dose levels for gemcitabine ondays 1 and 8: 400, 550 and 700 mg/m². Cycles were to be repeated every 28 days. Three patients were to enter at each doselevel. Results: Patients were enrolled onlyto dose level 1 as this dose exceeded MTD. Of six patients initially enrolled, one wasremoved after three days with fever,ascites and decreased albumin believed notto be treatment related. Five patientswere evaluable for toxicity and response. One of the first three patients developeddose limiting toxicity (DLT) manifested asgrade 4 neutropenia. A second DLT(neutropenic fever and thrombocytopeniaassociated with bleeding) occurred amongthe next three patients; therefore, MTD wasreached at dose level 1. Grade 4toxicities included episodes of neutropenia(4) and thrombocytopenia (3). No objectiveresponse was observed. Conclusions: Oral etoposide andgemcitabine at this dose and schedule wasassociated with substantial toxicity inthis population. Patients who are previously treated withplatinum/paclitaxel-based chemotherapy maybe at particular risk for toxicity.     

Phase I/II study of docetaxel, ifosfamide, and doxorubicin in advanced, recurrent, or metastatic soft tissue sarcoma (STS)

Summary Background: Based on reports of the efficacy of docetaxel (T) in STS, we undertook a phase I/II trial to determine the response rate (RR), dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of addition of T to doxorubicin (A) and ifosfamide (I) in advanced STS. Methods: Patients with advanced, recurrent, or metastatic STS, without prior chemotherapy, were enrolled in a dose escalation trial. Dose levels: I-A 40 mg/m²; I 4.0 gm/m²; T 40 mg/m², II-A 50; I 5.0; T 50, III-A 60; I 6.0; T 60, and IV-A 75; I 7.5; T 75. MTD was defined as the dose producing DLTs in ≥2 of 3–6 patients treated. Results: 21 patients were accrued. Median age: 55 (28–78) years. Histology: leiomyosarcoma 10, spindle cell sarcoma 3, synovial sarcoma 2, angiosarcoma 1, fibrous histiocytoma 1, epitheliod hemangio-endothelioma 1, and 3 not specified. MTD was level III (A 60, I 6.0, and T 60). DLT was myelosuppression. All grade 4 toxicities were hematologic. Patients received median 2 cycles (range 2–9). Eight patients (38%) achieved partial response (PR). PR occurred after six cycles in 5 patients. 18 patients died. Median overall survival: 17 months (95% CI, 9.1–33.6 months). Conclusions: The recommended Phase II dose of this combination is level III: A 60 mg/m², I 6.0 g/m², T 60 mg/m², with mesna and granulocyte-colony stimulating factor. The RR is similar to that of AI in other trials, but the survival is better than anticipated.     

A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors

Summary Purpose To determine the maximum tolerated dose (MTD), recommended dose, dose limiting toxicities (DLT), safety and pharmacokinetics of irofulven combined with capecitabine in advanced solid tumor patients. Experimental design Irofulven was given i.v. over 30 min on days 1 and 15 every 4 weeks; capecitabine was given orally twice daily, day 1 to 15. Dose levels (DL) were: irofulven (mg/kg)/capecitabine (mg/m²/day): DL1: 0.3/1,700; DL2: 0.4/1,700; DL3: 0.4/2,000; DL4: 0.5/2,000. Results Between May 2002 and March 2004, 37 patients were treated and 36 evaluable for MTD. DLT occurred in 1/6 evaluable patients in DL1 (grade 3 thrombocytopenia); 1/6 in DL3 (grade 3 thrombocytopenia); 2/7 in DL4 (grade 3 febrile neutropenia, grade 3 thrombocytopenia). DL4 was defined as the MTD and DL3 was established as the recommended dose (RD). DLTs occurred in 1 of 14 additional patients treated at DL3. No treatment-related deaths or grade 4 non-hematological toxicity occurred, and grade 3 toxicities were infrequent. Antitumor activity was observed; two partial responses were noted in thyroid carcinoma (DL1, DL4); one unconfirmed partial response was observed in a patient with nasopharyngeal carcinoma, (DL3); 12 patients had disease stabilization >3 months; of eight patients with hormone refractory prostate cancer (HRPC), one patient had PSA normalization and four short-term stabilizations of PSA occurred. Capecitabine and irofulven pharmacokinetics results did not suggest drug–drug interactions. Conclusions Irofulven with capecitabine was adequately tolerated and evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and capecitabine 2,000 mg/m²/day. Work previously presented in part at the Annual Conference of the American Society for Clinical Oncology, Chicago, IL, 2003.     

Unusual central nervous system toxicity in a phase I study of N1N11diethylnorspermine in patients with advanced malignancy

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N¹N¹¹diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase.These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1h i.v. infusion every 12h for 5 days (10 doses). The starting dose was 25 mg/m²/day (12.5 mg/m²/dose) with escalation by a modified Fibonacci search.Doses of 25 and 50 mg/m²/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m²/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m²/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t² of 0.12h.We conclude that great caution is warranted in administering DENSPM on this schedule at doses of 83 mg/m²/day.     

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors

Vinorelbine (Navelbine®) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone®) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m². Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m². Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m² on days 1 and 8 and mitoxantrone 10 mg/m² on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.     

A phase 1 trial of XK469: Toxicity profile of a selective topoisomerase IIβ inhibitor

Summary Purpose: XK469, a member of the quinoxaline family of antitumor agents, is believed to be unique in its ability to selectively target topoisomerase IIβ. Based on encouraging pre-clinical data, a phase I trial was conducted to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Methods: A 2B accelerated titration schema was employed. XK469 was administered as a 5 or 20 min IV infusion on days 1–5 every 21 days. The starting dose was 9 mg/m². Pharmacokinetics (PK) were conducted in cycles 1–3. Results: 22 patients (21 evaluable, mean age: 56 years, median performance status: 1) were enrolled. At dose level 11 (260 mg/m²/daily X 5), 1/6 patients experienced a DLT of grade 4 neutropenia. At 346 mg/m²/daily X 5, 2/2 patients experienced DLT's with one episode of febrile neutropenia and one grade 3 infection. The MTD was identified as 260 mg/m²/day. XK469 peak plasma levels and systemic exposure were proportional to dose indicating linear pharmacokinetics. However, secondary peaks in the PK profiles and a rapid decline in drug level from 23 to 24 h occurred in some patients. Drug infusion in the afternoon followed by dense sampling of levels during the elimination phase supported the hypothesis that the drug was being sequestered. No anti-tumor activity was identified. Conclusions: Traditional PK sampling designs were inadequate to describe XK469 disposition. XK469 and related structures work through a unique mechanism of action. A further understanding of the specific mechanism of these compounds might uncover a unique avenue for future drug development.     

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors

Vinorelbine (Navelbine®) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone®) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m². Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m². Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m² on days 1 and 8 and mitoxantrone 10 mg/m² on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.