A Phase I Study of Escalating Interferon Alpha-2A Combined with 5-Fluorouracil and Leucovorin in Patients with Gastrointestinal Malignancies

On the basis of preclinical data showing synergy between 5-fluorouracil (5-FU), leucovorin (LV) and IFN-alpha-2a, a phase I study was carried out to determine the maximum tolerable dose (MTD) of IFN-alpha-2a with this combination in patients with gastrointestinal malignancies. The treatment consisted of 370 mg/m² 5-FU and 200 mg/m², LV on days 1 to 5, and IFN-alpha-2a on days 1 to 5 of the first week of chemotherapy and on days 1, 3, 5 of each subsequent week, on a 28-day cycle. Six patients with colorectal, 3 with pancreas, 2 with oesophagus, 2 with hepatocellular and one with gastric cancer were treated. At level III (5 × lo⁶ U/m²) all patients experienced grade 3 or 4 toxicity during the first 56 days of treatment and the MTD was declared level II. Grade 3 toxicity comprised of anorexia, mucositis, diarrhoea, and fatigue; in one instance, grade 4 neutropenia occurred. Ten patients were evaluable for response, one patient with an oesophageal cancer had a minor response and one patient with rectal cancer and liver metastases had a radiological complete response lasting 3 months. The recommended dose for this schedule in phase TI studies is 5-FU 370 mg/m², LV 200 mg/m², and IFN-alpha-2a 4 × 10⁶ U/m².     

Results of A trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall cell lung cancer

: To conduct a dose escalation clinical study with topotecan and concurrent standard dose thoracic irradiation to assess its feasibility and toxicity in the treatment of patients with locally advanced, inoperable nonsmall cell lung cancer (NSCLCA).

: Between April 1993 and August 1994, 12 patients with inoperable, loco-regionally advanced NSCLCA were entered in a prospective dose escalation trial and assigned to receive concurrent thoracic radiotherapy and topotecan. Patients received thoracic irradiation to a total tumor dose of 60 Gy in 30 fractions. Initial fields were to encompass the gross disease plus the mediastinum. Topotecan was delivered by bolus injection days 1 through 5, and days 22 through 26, beginning on the same day as the radiation therapy. The initial dose level was 0.5 mg/m². Two additional dose levels of 0.75 mg/m² and 1.0 mg/m² were tested.

: Six patients were accessioned to the 0.5 mg/m² dose level, three patients to the 0.75 mg/m² dose level, and three patients to the 1.0 mg/m² dose level. At the 0.5 mg/m² dose level, zero of six patients had ≥Grade 4 hematologic toxicity. One of the six had Grade 3 esophagitis. At the 0.75 mg/m² dose level, two of three patients had ≥Grade 3 nonhematologic toxicity including anorexia, fatigue, nausea, vomiting, and weakness; zero patients experienced ≥Grade 4 hematologic toxicity. At the 1.0 mg/m² dose level one of three patients had ≥Grade 3 esophagitis, and two of three patients experienced Grade 4 neutropenia. With a follow-up of 12 to 24 months, two patients are alive and free of disease, three patients are alive with disease (two with distant metastasis, one with local disease and distant metastasis), and the remaining seven patients are dead of disease.

: The combination of topotecan and thoracic radiotherapy for nonsmall lung cancer, in the manner given by this protocol, could be safely given at a dose level of only 0.5 mg/m² days 1 to 5 and 22 to 26 with 60 Gy of external beam radiotherapy. Higher doses of topotecan were associated with high hematologic and gastrointestinal toxicity. Distant metastasis was the primary pattern of failure.     

Phase I study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first line therapy in patients with non-resectable gastric cancer

A phase I trial of short-time oxaliplatin (E), capecitabine (X) and epirubicin (E) for patients with metastatic gastric cancer was initiated to establish the recommended dose for further therapy with short-time EXE. Patients received out-patient therapy with a fixed dose of epirubicin 50 mg/m² day 1; escalating doses of capecitabine (1 000 to 1 250 mg/m²/day continuously) and escalating doses of oxaliplatin (85 to 130 mg/m² day 1 as a 30 minutes infusion). Cycles were repeated every 21 days for a maximum of 8 cycles. From June 2003 to June 2004, 31 patients were treated. Median age was 61 years (39-75 years), and median performance status was 0 (0-2). At level 3, one of six patients developed DLT and at dose level 4, two of six patients developed DLT (both patients had grade 4 hematological toxicities) and thus further dose escalation was not attempted. Median number of cycles was 6 (1-8), median survival was 9.2 months and median TTP was 7.5 months. A combination of epirubicin 50 mg/m² day 1, capecitabine 1 000 mg/m² continuously and oxaliplatin 130 mg/m² day 1 each 3 weeks is an easily administered and well tolerated out-patient regimen for patients with non-resectable gastric cancer.     

Edta Clearance in Monitoring Cisplatin Dose Escalation in Patients with Bulky Metastatic Germ Cell Tumors of the Testis

A fast cisplatin clearance may reduce exposure time of tumor cells to the drug, and thus impair the expected effects of dose escalation. This hypothesis was tested in 23 patients with bulky metastatic germ cell tumors of the testis, treated with etoposide, bleomycin and high-dose cisplatin (60 mg/m²/24 h×4). The daily dose was retrospectively calculated in mg/1 EDTA clearance/24 h. A daily dose of 60 mg/m² of cisplatin in a person with a body surface of 1.7 m² and EDTA clearance of 100 ml/min was equivalent to 0.69 mg cisplatin/l EDTA clearance/24 h. In the whole group, 10 patients had complete remission (CR), 10 partial response (PR) and 3 progressive disease (PD). The mean daily cisplatin dose (×) in the whole group was 0.86 mg/1 EDTA clearance/24 h (range 0.35-2.00). For patients with CR, × × SD was 1.00±0.46, for those with PR 0.80±0.44, and for those with PD only 0.61±0.07. A cisplatin dose over 0.86 mg/1 EDTA clearance/24 h × 4 was obtained in 6/10 patients with CR versus 2/13 patients with PR + PD. Patients with PD received a significantly lower cisplatin dose than the whole group (0.61 versus 0.86 mg cisplatin/l EDTA clearance/24 h × 4.) The difference between the average toxicity grade after cisplatin dose over and below 0.69 mg/l EDTA clearance/24 h × 4 was significant only for leukocytes (WHO grade 2.17 versus 1.36). Thus, the effective escalated dose of cisplatin should preferably be calculated not per m² body surface but per 1 liter EDTA clearance. The 'ideal' escalated dose might be about 0.86-1.0 mg cisplatin/l EDTA clearance 24 h × 4.     

A phase I/II study of high-dose tamoxifen in combination with vinblastine in patients with androgen-independent prostate cancer

In this phase I/II clinical trial the antitumor activity of high-dose tamoxifen when administered in combination with vinblastine was assessed and the toxicity profile of this combination characterized. All 25 patients enrolled in this study were required to have androgen-independent prostate cancer and to maintain androgen ablation during treatment. Vinblastine was given by continuous infusion over 5 days. Doses were increased from 0.9 mg/m²/day to 1.5 mg/m²/day in successive cohorts of at least 3 patients, with no further escalation even in the absence of dose-limiting toxicity. Intra-patient dose escalation was permitted. Tamoxifen was administered at a dose of 200 mg/kg on day 1, then 120 mg/kg/day on day 2. Standard response criteria were utilized to assess antitumor activity and CTC toxicity criteria were used. Quality of life (QOL) pain assessments were evaluated at each visit to the clinic. Most patients tolerated the highest dose of vinblastine at 1.5 mg/m²/day by continuous infusion over 5 days with 200 mg/kg/day of tamoxifen on day 1 and day 2. One patient had a greater than 50% decline in prostate-specific antigen that lasted for 170 days. Two patients received dose reductions because of toxicity. The most common serious toxicities included neutropenia, and fatigue. Reversible neurosensory, neuromotor, neurocortical and neurocerebellar toxicities were reported. Six of the 25 patients enrolled in the study (24%) experienced reversible neurologic toxicity of at least grade III. No statistically significant differences between precycle assessment of QOL and subsequent cycles were observed. It is concluded that vinblastine at 1.5 mg/m²/day continuous IV infusion combined with tamoxifen 200 mg/kg/day on day 1 and day 2 is inactive, and not without toxicity in the treatment of advanced metastatic androgen-independent prostate cancer.     

A Phase I Pilot Study of BCNU plus Thymidine in Patients with Refractory Cancer

Thymidine (dThd) has been shown to increase the activity of BCNU in mice, possibly due to its ability to inhibit poly(ADP-ribose)polymerase (PADPRP), an enzyme thought to be active in DNA repair. The present phase I study characterized the pharmacokinetics and toxicity of dThd combined with BCNU. Sixty patients with refractory malignancies were infused with escalating doses of dThd from 7.5g/m²/day to 105.5 g/m²/day for 48 hr, along with 100 mg/m²/day of BCNU for 2 doses. Further dose escalation of dThd was limited by large fluid volumes required; therefore, the BCNU dose was escalated to a maximum of 160 mg/m²/day for 2 days. Plasma dThd concentrations were determined using high-performance liquid chromatography. At doses above 37.5 g/m /day, steady-state concentrations of dThd approached or exceeded 1 mM, a concentration that nearly completely abolished BCNU-induced PADPRP activity in preclinical studies. Myelosuppression was consistent with BCNU dose but was not apparently increased by the coadministration of dThd. One patient had a partial response to therapy. Both the lack of effect of increasing dThd doses on BCNU-induced myelosuppression and the low response rate suggest that the schedule of drug administration was not optimal to inhibit PADPRP, or that PADPRP may not be essential in repairing BCNU-mediated DNA damage in humans.     

Phase I Trial ofU racil-Tegafur (UFT) plus Oral Leucovorin: 28-Day Schedule

UFT [Taiho Pharmaceutical Co. Ltd., Tokyo, Japan; (BMS-200604), Bristol-Myers Squibb, Princeton, NJ], a fluorouracil prodrug, is an oral 4:1 molar concentration of uracil plus tegafur. This study examined the dose-limiting toxic effects and maximum tolerated dose of UFT plus leucovorin administered for 28 consecutive days followed by a 7-day rest period. A course of therapy was repeated every 35 days. UFT dose levels examined were 200 mg/m²/day, with planned escalations to 250, 300, 350, and 400 mg/m²/day; the leucovorin dose remained at 150 mg/day. Three patients were initially enrolled at each UFT dose level. The total daily doses of both UFT and leucovorin were divided into three doses administered every 8 hr. Diarrhea became the dose-limiting toxicity at 400 mg/m²/day UFT, with grade 3 diarrhea noted in 2 of the 3 patients receiving that dose. To further define a phase II UFT starting dose, 3 additional patients were entered at the 350 mg/m² level; 3 of the 6 patients treated at this level developed grade 3 nonhematological toxic effects. No partial or complete responses were observed. The recommended phase II UFT starting dose is 300 mg/m²/day plus 150 mg/day leucovorin. Since neutropenia, significant mucositis, and “hand-foot syndrome“ were not observed with UFT plus leucovorin, the toxicity profile of this regimen appears favorable compared with that of intravenous regimens of fluorouracil plus leucovorin. This phase I trial of UFT served as the basis for a phase II trial, current phase III trials, and a national adjuvant therapy trial of UFT for high-risk colon cancer patients.     

Phase I clinical trial of topotecan and pegylated liposomal doxorubicin

Background: The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors. Patients and Methods: Patients were treated with intravenous topotecan (0.75-1.25 mg/m²) for 3 days followed by PLD (25-40 mg/m²) on Day 4. The following dose combinations (topotecan/PLD, mg/m²) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days. Results: Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1-19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m² every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m² every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer. Conclusions: This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m² on Days 1-3 followed by PLD 40 mg/m² on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m² on Days 1-3 and PLD 30 mg/m² on Day 4 of a 21-day cycle.     

Multicenter phase I trial of induction chemotherapy with docetaxel and nedaplatin for oral squamous cell carcinoma

A phase I study of combination neoadjuvant chemotherapy with docetaxel (DOC) and nadaplatin (CDGP) was conducted in patients with untreated, advanced but operable oral squamous cell carcinoma. DOC was administered (one-hour i.v. infusion) on day 1 followed by CDGP (one-hour i.v. infusion). The dose levels of DOC and CDGP tested were 60/70, 60/80, 60/90, 60/100, and 70/100 (mg/m²). Fifteen patients enrolled in this study and median age was 60 years. Dose-limiting toxicity (DLT) occurred in one of six patients at DOC dose of 60 mg/m² and CDGP dose of 100 mg/m². The DLT was diarrhea. Because one additional patient at this dose-level developed grade 4 neutropenia lasting for 4 days that approached DLT and because fear of severe hematological problems was predicted, further dose escalation was not performed. This combination chemotherapy is active and well tolerated and warrants a phase II study. We recommended 60 mg/m² DOC and 100 mg/m² CDGP for phase II study.     

A single-institute phase I/II trial combining nedaplatin dose escalation with a fixed dose of docetaxel for induction chemotherapy of oral squamous cell carcinoma

The purpose of this clinical trial was to assess the toxicity and efficacy of docetaxel plus nedaplatin induction chemotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). Twenty-one patients were enrolled in this phase I/II clinical study. The toxicities, response rates, and the maximum tolerated dose of nedaplatin that could be safely given preoperatively were assessed. Patients received escalating doses of nedaplatin (60, 70, 80, 90 mg/m²) combined with a fixed dose of docetaxel (60 mg/m²) on day one. Dose-limiting toxicity (DLT), grade 4 leukopenia lasting for two days or more, was seen in one patient at dose level 3; no other DLT was observed at any dose level. The overall response rate was 66.7%. The response rate was 100% at nedaplatin dose level 4, while that at dose level 1 was low (33.3%). Given these results, the recommended dose of nedaplatin in this regimen combined with fixed dose docetaxel (60 mg/m²) was determined to be 90 mg/m². Docetaxel 60 mg/m² plus nedaplatin 90 mg/m² induction chemotherapy can be recommended for patients with locally advanced oral squamous cell carcinoma. Based on these results, an early phase II clinical study using this dose level was conducted; docetaxel plus nedaplatin induction chemotherapy appears to be a useful regimen for the treatment of OSCC. A late phase II clinical study is warranted.     

A Phase I—II Study of Cyclophosphamide, Epidoxorubicin, Levofolinic Acid/5-Fluorouracil and Recombinant Human Granulocyte Colony Stimulating Factor in Metastatic Breast Carcinoma

Thirty patients with measurable metastatic breast carcinoma were treated with a combination of cyclophosphamide 600 mg/m² on day 1, levofolinic acid 100 mg/m² plus 5-fluorouracil 375 mg/m² on days 1-3, and epidoxorubicin (EDXR) in three refracted doses on days 1-3 with G-CSF rescue for 10 days. In the phase I part of the study, groups of 3 patients received EDXR 20, 25, 30, 35, and 40 mg/m²/day until the dose limiting toxicity (DLT) was reached. At the dose of 40mg/m²/day prolonged grade 4 leukopenia, severe proctitis, and grade 3 diarrhea represented the DLT. All subsequent partients were treated at the maximal tolerated dose of EDXR (35 mg/m²/day). In the group of 18 patients treated at 35 mg/m²/day the overall response rate was 78%, with 22% CR and 56% PR. Four patients did not respond. Objective responses were seen at all tumor sites including bone and viscera, which usually are rather chemotherapy insensitive. Toxicity was generally acceptable. Although the response rate was quite high, the duration of objective tumor regression and patients' survival were not impressive. In conclusion, we do not recommend routine use of such an aggressive regimen for palliation of advanced breast cancer. Results of the present and similar studies may, however, be useful for planning of neoadjuvant or adjuvant trials with curative intent.     

A phase I/IIa clinical trial of CLAOP21 and CLAOP14 in patients with high grade non-Hodgkins lymphoma

This study was performed to investigate hematotoxicity and occurrence of PPE in patients with high-grade non-Hodgkins lymphoma treated with a modified CHOP regimen (CLAOP), where doxorubicin had been substituted by a noncardiotoxic pegliposomal doxorubicin. An open-label phase I/IIa study was performed evaluating CLAOP21/20 with 20 mg/m² of pegliposomal doxorubicin every 21 days (12 patients), and a dose-dense filgrastim supported CLAOP14 regimen every 14 days with escalating doses of pegliposomal doxorubicin (24 patients) in elderly high-grade lymphoma patients or patients with comorbidity interfering with cardiac function. CLAOP21/20 was well tolerated. Hematotoxicity was similar to that reported with regular CHOP. In the CLAOP14 cohort, a pegliposomal doxorubicin dose of 25 mg/m² was associated with dose-limiting hematotoxicity, febrile episodes, and PPE. Both regimens were active with an overall response rate of 60% and 77%, respectively. The recommended dose of pegliposomal doxorubicin in the biweekly regimen for Phase II/III testing is 20 mg/m².     

Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma

Purpose: We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done.

Methods and Materials: Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily × 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m² days 1–3, cisplatin 30 mg/m² days 1–3 and 29–31, and etoposide 50 mg orally days 1–14 and 29–42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m² every 8 weeks × 4 cycles was given after radiation therapy.

Results: Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3–4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m² days 1–3, cisplatin 20 mg/m² days 1–3 and 29–31, and oral etoposide 50 mg days 1–21 and 29–49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m² every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 μg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean ± SD 2 hr and 6 hr plasma concentrations were 0.92 ± 0.43 μg/ml and 0.36 ± 0.12 μg/ml, respectively. Estimated duration of exposure to >0.1 μg/ml etoposide was 10–17 hr.

Conclusions: Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.     

A Phase I Trial of Combination Chemotherapy Employing Carboplatin, Vinca Alkaloids, with or without Bleomycin in Patients with Advanced Malignant Tumors

A Phase I trial of three carboplatin-based combination chemotherapy regimens was conducted. These included: carboplatin plus vindesine; carboplatin, vindesine, plus bleomycin; and, carboplatin plus vinblastine. Carboplatin was administered every 28 days as an intravenous bolus. The initial dose was 150 mg/m² and doses were escalated by 50 mg/m² in each successive group of patients. Vindesine was given at a dose of 3 mg/m² weekly for 5 doses, then every other week thereafter. Bleomycin, 10 units/m² IV bolus, was followed by 10 units/m²/day infusion for 4 days (3-7 and 31-35). Vinblastine was given at 5 mg/m² every other week. Doses of vindesine, vinblastine, and bleomycin were not escalated. The maximum tolerated dose (MTD) of the carboplatin, vindesine bleomycin regimens was reached at a carboplatin dose of 250 mg/m² and the MTD was influenced by the weekly vindesine in the initial 4 weeks of therapy. The MTD of the carboplatin and vinblastine regimen was reached at a carboplatin dose of 500 mg/m². Dose-limiting toxicity of all three regimens was leukopenia. Although nonhematological toxicity of the carboplatin and vinblastine regimen included peripheral neuropathy and emesis, therapy was easily administered in an outpatient setting. The recommended Phase II dose of carboplatin is 450 mg/m² in combination with vinblasrine at this dose and schedule for previously untreated patients. Twelve patients demonstrated major responses with the various regimens including 5 of 24 patients with adenocarcinoma of the upper gastrointestinal tract.     

High dose CHOP: a phase II study of initial treatment in aggressive non-Hodgkin lymphoma. Cancer and Leukemia Group B 9351

Cyclophosphamide and doxorubicin, two important drugs in the treatment of lymphoma, exhibit a relationship between dose and fractional cell kill, and because of their toxicity profiles, they are candidates for significant dose escalation. We performed a phase II trial to determine the response rate, toxicity, and feasibility of escalated doses of both drugs as part of high dose CHOP in diffuse aggressive lymphoma. Patients who had advanced, previously untreated diffuse aggressive lymphomas (IWF E-H) and an International Prognostic Index of intermediate to high risk were eligible. Treatment was cyclophosphamide 2 gm/m²/day intravenously on Days 1 and 2 (total cycle dose 4 gm/m²), doxorubicin 35 mg/m²/day as a continuous infusion on Days 1 and 2 (total 70 mg/m²), vincristine 1.4 mg/m² (maximum 2 mg) on Day 1 and prednisone 100 mg/day orally on Days 1 - 5 repeated every 3 weeks for a total of four cycles. G-CSF, prophylactic antibiotics, and mesna were provided. A total of 99 patients were enrolled; 98 received therapy. Major toxicities were Grade 4 neutropenia and thrombocytopenia occurring in 97% and 92%, respectively. Serious infections occurred in 53%. Treatment-related mortality was 2%. The overall response rate is 85%, and two-year failure free and overall survival are 39% and 64%, respectively. Persistent or relapsed lymphoma was the overwhelming cause of death. Six patients have developed AML or MDS. In view of the substantial toxicity accompanying high dose CHOP, the observed outcome suggests that its efficacy is not sufficient to make further study feasible.     

Phase I trial of gemcitabine and paclitaxel in advanced solid tumors

Purpose. Gemcitabine and paclitaxel are chemotherapeutic agents with clinical antitumor activity in a broad range of malignant solid tumors. Because of preclinical synergy, unique mechanisms of action and resistance, and nonoverlapping toxicities, gemcitabine and paclitaxel combinations are attractive for testing in clinical trials. Prior weekly gemcitabine and paclitaxel regimens administered on a 28-day cycle have been limited by cumulative hematological toxicity on day 15, thus reducing the planned gemcitabine dose intensity. We therefore conducted a phase I trial of a 21-day schedule of weekly gemcitabine and paclitaxel to determine the tolerability, maximum tolerated dose (MTD), and preliminary estimates of efficacy of this regimen. Patients and Methods. Forty-one patients with advanced malignant solid tumors were accrued. Gemcitabine was given at a fixed dose of 1000 mg/m² while paclitaxel was administered at an initial dose of 60 mg/m², then escalated by 15 mg/m² increments over seven dose levels to a prospectively planned maximum dose of 150 mg/m². Both agents were infused intravenously on days one and eight every 21 days. At least three patients were enrolled per dose level. No intrapatient dose escalation was allowed. Results. All patients were assessable for toxicity and 31 were assessable for response. The regimen was generally well-tolerated. Dose-limiting thrombocytopenia was observed in one patient at a paclitaxel dose of 135 mg/m²/week (dose level 6). After expansion of this dose level by 14 additional patients, no further dose-limiting toxicities were observed although one patient at dose level seven died of neutropenic sepsis after completing three cycles. There were eight partial responders for an overall response proportion of 26% (95% CI: 11, 41). Twelve patients (39%) had stable disease. Conclusion. This 21-day schedule of gemcitabine and paclitaxel is safe, well-tolerated, and active. The recommended phase II dose is gemcitabine 1000 mg/m² and paclitaxel 150 mg/m² on days one and eight every 21 days. The antitumor activity observed with this regimen warrants further investigation.     

A phase I human trial of mitoguazone and gemcitabine sequential bi-weekly treatment of cancer patients

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m², gemcitabine 1500 mg/m²), three at dose level 2 (mitoguazone 500 mg/m², gemcitabine 2000 mg/m²), and one at dose level 3 (mitoguazone 600 mg/m², gemcitabine 2000 mg/m²). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.     

Epirubicin and Ifosfamide in Advanced Soft Tissue Sarcoma: A Phase II Study

Thirty patients with previously untreated and measurable or evaluable advanced sofr tissue sarcoma entered this phase II study. Median age was 53 years (range: 24-71 years). Starting dose of Epirubicin was 100 mg/m² IV bolus on day I combined with Ifosfamide, 2.5 g/m², as a 6-hr IV infusion on day I and day 2 with uroprotection with Uromitexan, 1.6 g/m², on day 1 and day 2. This schedule was repeated every 3 weeks. In case of minimal myelosuppression, the dose of Epirubicin was increased by 10 mg/m² up to 130 mg/m². Ifosfamide dosage was not increased. Mean cumulative dose of Epirubicin received was 477 ± 272 mg/m² (range: 200-1200 mg/m²). Of 27 evaluable patients (WHO criteria), 13 had a partial response (48%), 4 showed no change (15%), and 10 had progressive disease (37%). Median time to progression was 27 weeks. Of 27 patients evaluable for toxicity. hemato-logical toxicity at day 21 was mild. Nonhematological toxicities consisted of nausea and vomiting in 82% of patients (WHO grade 3-4 = 19%). stomatitis in 44.5% (WHO grade 3 = 7.5%), and alopecia in 96% (WHO grade 2-3 = 89%). Appearance of cardiac dysfunction without heart failure during the treatment led to discontinuation of this chemotherapy in 3 patients. The results of this study show that the combination of Epirubicin and Ifosfamide is effective in advanced soft tissue sarcoma with an acceptable toxicity. However, we cannot conclude from this trial whether combination Epirubicin and Ifosfamide is superior to Epirubicin alone.     

A phase I trial of olanzapine (Zyprexa) for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study

Chemotherapy-induced delayed emesis (DE) can affect up to 50% to 70% of patients receiving moderately and highly emetogenic chemotherapy, although rates are improving. DE most commonly occurs within the first 24 to 48 hours of chemotherapy administration and can persist for 2 to 5 days. Olanzapine, due to its activity at multiple dopaminergic, serotonergic, muscarinic, and histaminic receptor sites, has potential as antiemetic therapy. A phase I study was designed with olanzapine, using a four-cohort dose escalation of 3 to 6 patients per cohort, for the prevention of DE in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, platinum, and/or irinotecan. All patients received standard premedication. Olanzapine was administered on days - 2 and - 1 prior to chemotherapy and continued for 8 days (days 0-7). Episodes of vomiting as well as daily measurements of nausea, sedation, and toxicity were monitored at each dose level. Fifteen patients completed the protocol. No grade 4 toxicities were seen, and three patients experienced a dose-limiting toxicity (grade 3) of a depressed level of consciousness during the study. The maximum tolerated dose appeared to be 5 mg (for days - 2 and - 1) and 10 mg (for days 0-7). Four of six patients receiving highly emetogenic chemotherapy (cisplatin, ≥ 70 mg/m²) and nine of nine patients receiving moderately emetogenic chemotherapy (doxorubicin, ≥ 50 mg/m²) had complete control (no vomiting episodes) of DE. Therefore, olanzapine may be an effective agent for the prevention of chemotherapy-induced DE. A phase II trial is underway.     

Phase I study of Doxil and vinorelbine in patients with advanced malignancies

Introduction. This study was designed to define the maximum tolerated dose of pegylated liposomal doxorubicin (Doxil®) and multiday vinorelbine (VNB), without and with prophylactic filgrastim, and to identify antineoplastic effect. Patients and Methods: Patients with resistant cancers were treated with Doxil 50 mg/m² every four weeks, and with VNB 15 mg/m² on the same day. The VNB dose escalations were accomplished in subsequent patient cohorts by adding VNB doses on consecutive days. When the maximum tolerated dose (MTD) of VNB with Doxil was defined, prophylactic filgrastim was added to define a second MTD. Results. Of 29 patients entered, two had early adverse events, and 27 received at least one full cycle with at least one month follow-up. The MTD of VNB, combined with Doxil 50 mg/m², was 15 mg/m² on day 1, with neutropenia as the dose-limiting toxicity. With prophylactic filgrastim, the MTD was15 mg/m² daily for two days, with neutropenia and stomatitis as dose-limiting toxicities. Palmar plantar erythrodysesthesia occurred frequently, usually after the third cycle. Objective responses were documented in six patients, all of whom received multiday VNB. Conclusion. Doxil 50 mg/m² on day 1 of a 28-day cycle can be safely combined with VNB 15 mg/m2 day 1, or with VNB 15 mg/m² days 1 and 2 with filgrastim prophylaxis. Antineoplastic activity was observed in this heavily pretreated population. Future studies of Doxil 35-40 mg/m² with multiday VNB may be worthwhile, especially in metastatic breast cancer.