Phase II trial of piroxantrone in metastatic gastric adenocarcinoma

Summary Piroxantrone, a synthetic intercalating agent, was studied in patients with advanced, measurable gastric adenocarcinoma who had not received prior chemotherapy. The starting piroxantrone dose was 150 mg/m² given intravenously over 1 hour on day 1 and repeated every 21 days. Response and toxicity could be evaluated in 15 patients. No complete, partial, or minor responses were observed. Toxic effects included granulocytopenia, anemia, vomiting, nausea, anorexia, fatigue, stomatitis, alopecia, hyperbilirubinemia, and increased alkaline phosphatase levels. At the stated dose and schedule, piroxantrone does not possess significant activity against advanced gastric cancer.     

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 II trial of ixabepilone,an epothilone B analog,given daily for three days every three weeks,in metastatic breast cancer

Summary Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m²/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m²/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m², 8 mg/m² and 10 mg/m² dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8–10 mg/m² daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.     

A phase II trial of paclitaxel (Taxol®) as first line treatment in advanced breast cancer

Summary Paclitaxel (Taxol®) is a natural product with a broad spectrum of activity against various solid tumors. This report includes nineteen patients with advanced breast cancer who have not previously received chemotherapy for metastatic disease. Fifteen patients had received adjuvant chemotherapy, eight of which were doxorubicin based. Patients were treated with 135 mg/m² over 24 hours by continuous infusion given every 21 days. There were 2 complete and 4 partial responses for an objective response rate of 32% (95% C.I.: 14%, 57%) and eight patients or 42% with stable disease. Three of eight patients (38%) who had received adjuvant doxorubicin did respond to paclitaxel. Responses occurred in lung, liver, and soft tissue. The primary toxicity was hematologic with 13 hospitalizations for febrile neutropenia in 180 cycles (7%). Paclitaxel has moderate activity in a small number of patients with metastatic breast cancer at the dose of 135 mg/m² over 24 hours in this study.     

Phase II study of CT-2103 as first- or second-line chemotherapy in patients with metastatic breast cancer: unexpected incidence of hypersensitivity reactions

Summary This study evaluated the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-l-glutamate, in patients with HER2-negative, metastatic breast cancer who had received 0 or 1 prior lines of chemotherapy. Although CT-2103 had activity in this small study, neurotoxicity and hypersensitivity reactions were more frequent in this patient population than expected, and led to early termination of the trial. Purpose To evaluate the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-l-glutamate, in patients with metastatic breast cancer who had received 0 or 1 prior lines of chemotherapy. Patients and Methods Eighteen women with HER2-negative breast cancer were enrolled. Patients received intravenous CT-2103 at a dose of 175 mg/m² of conjugated paclitaxel over 10 min every 3 weeks, without routine premedication. Eighty-three percent of women had received prior chemotherapy as part of adjuvant (39%), metastatic (17%), or both adjuvant and metastatic (28%) treatment. Three patients (17%) had previously received a taxane in the adjuvant setting. Results Objective responses were observed in 4 of 18 patients (overall response rate, 22%, 95% confidence interval, 6 to 48%). Grade 3 or 4 neuropathy was observed in four patients. Grade 3 or 4 hypersensitivity reactions (HSR) were observed in four patients; none occurred prior to cycle 4 of therapy. Because of the higher-than-expected rate of HSR, the study was terminated early. Conclusion Although CT-2103 had activity in this small study of women with HER2-negative metastatic breast cancer, neurotoxicity and hypersensitivity reactions were more frequent in this patient population than expected. Hypersensitivity reactions were most likely to occur in later cycles of treatment, suggesting a true drug allergy, distinct from the HSR typically seen with standard paclitaxel.     

Phase I/II trial of dipyridamole, 5-fluorouracil,leukovorin, and mitoxantrone in metastatic breast cancer

Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m² by mouth every 6 h (700 mg/m²/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m² was given intravenously immediately prior to 5-FU 375 mg/ m² intravenously on days 1–5. Mitoxantrone 6 mg/m² was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m² days 1–2, 5-FU 375 mg/m² days 1–2, mitoxantrone 6 mg/m² on day 2, and dipyridamole 175 mg/m² every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.     

A phase II study of chloroquinoxaline sulfonamide (CQS) in patients with metastatic colorectal carcinoma (MCRC)

Summary Purpose: Phase II multicenter study investigated the efficacy and toxicity of the novel halogenated derivative of sulfaquixonaline Chloroquinoxaline Sulfonamide (CQS) in metastatic colorectal cancer. Experimental design: Eligible patients with metastatic or recurrent colorectal cancer received CQS at a dose schedule of 2000 mg/m² over an hour weekly for 4 weeks every 42 days. Treatment was continued until unexpected toxicity or disease progression. Results: A total of seventeen patients were enrolled on this study. 94% of all patients enrolled had prior treatment. Sixteen patients were evaluable for response with fifteen patients showing evidence of disease progression and one patient with prolonged stable disease. One patient had non-evaluable disease. Following this interim analysis, the drug was considered ineffective and the study was terminated early. The most frequent adverse event was anemia. No patients discontinued the treatment because of toxicity. Conclusion: CQS, when given at a dose of 2000 mg/m² weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression.     

Phase II evaluation of teniposide (VM-26) in metastatic breast carcinoma

The Southeastern Cancer Study Group performed a Phase II study of teniposide in previously treated patients with metastatic breast cancer. No responses were observed in 11 evaluable patients who received teniposide 60 mg/m² by IV infusion for five consecutive days every three weeks. Toxicity was primarily gastrointestinal and hematologic and was frequently severe. This study demonstrated no therapeutic activity for teniposide when given in this dose and schedule to patients with heavily pretreated metastatic breast cancer.     

Phase II trial of fazarabine (ARA-AC,arabinosyl-5-azacytosine) in metastatic breast cancer

Fourteen consecutive female patients with metastatic breast cancer received a total of 31 courses of fazarabine at a dose of 2 mg/m²/hour×72 hours (48 mg/m²/day×3) as a continuous infusion. There were no responses seen, although one patient achieved stability of her disease for five courses. Because of encouragingin vitro results and the primarily hematologic dose-limiting toxicity, further study in combination with colony stimulating growth factors might be of interest.     

Phase I study of idarubicin administered orally on a daily × 3 schedule

Summary Twenty-one adult patients with refractory solid tumors were treated on a phase I study of idarubicin (4-demethoxydaunorubicin) administered daily for 3 days every 3 weeks. Nineteen of the patients had received previous chemotherapy (including 13 with prior anthracyclines), and 12 had received prior radiotherapy. Idarubicin dose levels of 10, 15, 17.5, 20, and 25 mg/m² were explored. Hematological toxicity was dose-related. Other toxicity was acceptable. Only one patient (treated with an idarubicin dose of 17.5 mg/m²/day) developed neutropenic fever, from which he recovered. Further dose escalations beyond 25 mg/m² were not carried out because of the increasing length of time required for recovery from granulocytopenia at higher doses. No patient experienced a major response, but minor responses were seen in 3 patients with carcinomas of the colon, breast, and kidney respectively. Further phase II studies of oral idarubicin at a starting dose of 20–25 mg/m² daily times 3 days in patients with good bone marrow reserves are recommended. Because of the degree of neutropenia expected, patients would have to be observed carefully.The Ontario Cancer Treatment and Research Foundation Ottawa Regional Cancer Centre, The Ottawa University Faculty of Health Sciences and Adria Laboratories Ltd.Presented in part at the 79th Annual Meeting of the American Association for Cancer Research, New Orleans, Louisianna, May 25–28, 1988 (1)     

Recombinant gamma interferon in advanced breast cancer: A phase II trial

Fifteen patients with advanced carcinoma of the breast who had failed prior chemotherapy, were treated with recombinant gamma interferon at a dose of 2mg/m² (1mg = 2.4 × 10⁷ international units) intravenously for five consecutive days every other week. The median patient age was 51 and all patients had a performance status of 0–2 (Karnofsky 50). Thirteen patients had two or three sites of metastatic disease and seven were estrogen receptor positive. No complete or partial responses were noted. Although some patients had brief periods of stable disease, almost all patients progressed after one or two courses. Only one patient was able to receive six courses of induction therapy and a brief course of maintenance. Flu-like symptoms and nausea were seen in all patients; vomiting and anorexia were frequent. Hepatic toxicity manifested by enzyme elevation was common and was most severe in patients with liver metastases. In this study a highly purified biologically active gamma interferon was not associated with anti-tumor activity in previously treated women with metastatic breast cancer.     

Phase II trial of piroxantrone in patients with recurrent and metastatic squamous cell carcinoma of the head and neck

Summary Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m² intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.     

Phase II trial of dolastatin-10 in patients with advanced breast cancer

Summary Purpose: Phase II multicenter cooperative group study investigated the efficacy and toxicity of the novel anti-microtubule agent dolastatin-10 in patients with advanced breast cancer.Patient and methods: Twenty-one patients with measurable metastatic breast cancer were treated with dolastatin-10 at a dose of 400 mcg/m² by intravenous bolus once every 3 weeks. Patients must have received a total of 1 or 2 prior chemotherapy regimens and have an Eastern Cooperative Oncology Group performance status of 0–2. Patients received this treatment as either a first (n = 11) or second-line (n = 10) chemotherapy for metastatic disease. Eighteen patients (86%) had received a prior anthracycline. The National Cancer Institute provided the dolastatin-10.Results: One out of 21 patients (5%; 95% CI: 0–24%) achieved a partial remission for a duration of 113 days. Four patients maintained stable disease for a median of 87 days. A total of 58 courses of dolastatin-10 were administered. Patients received a median of two cycles of dolastatin-10. Hematologic toxicity was moderate, with 8 patients developing grade 4 neutropenia, and 5 with grade 3 neutropenia; one grade 3 febrile neutropenia was observed. These episodes of grade 3 and 4 neutropenia were experienced on 36% of the treatment cycles. Non-hematologic toxicity was uncommon.Conclusion: While the toxicity profile of dolastatin-10 was acceptable, it had minimal activity in this advanced breast cancer study. We are not pursuing further clinical trials of this agent in the setting of advanced breast cancer.     

PCNU: Phase II evaluation in advanced colorectal carcinoma

Summary PCNU, a N-(2-chloroethyl)-N-nitrosourea, was administered to 37 previously treated patients with metastatic adenocarcinoma of the colon and rectum. The drug dose was 100 mg/m², intravenously, over one hour for good risk patients and 75 mg/m² for poor risk patients. Poor risk patients were defined as patients over 65 years of age or having liver enzymes greater than twice normal. The infusion was repeated at 6 week intervals. Seventeen patients (median performance status 80%) received PCNU at the 100 mg/m² dose; 20 patients (median performance status 70%) received PCNU at the 75 mg/m² dose. Complete responses were not observed. One patient treated with 100 mg/m² achieved a partial response. Toxicity was primarily hematological with life-threatening leukopenia and thrombocytopenia observed in six patients. PCNU administered in the described dose schedule demonstrated little therapeutic efficacy in this patient population.     

Phase II study of deoxyspergualin in metastatic breast cancer

We conducted a phase II trial of the novel immunomodulatory/cytotoxic agent 15-deoxyspergualin in patients with metastatic breast cancer who had failed treatment with front-line chemotherapy. Thirty-eight courses of treatment were administered to fourteen patients enrolled in this trial, 25 at a dose of 1800 mg/m²/ d (dose level 0) and 13 at a dose of 2150 mg/m²/d (dose level +1) administered by continuous intravenous infusion for 5 days. Treatment was well tolerated with neuromuscular side-effects (myalgias, paresthesias) and granulocytopenia (nadir granulocyte count of 0.50–0.99 x 10⁹/1) in two and three courses, respectively, as the only grade III toxicities. The neuromuscular toxicity of deoxyspergualin is probably related to the occurrence of hypomagnesemia. No partial or complete responses were observed in this study. One patient achieved a minor response but had progressive disease 65 weeks after enrollment. The response was observed coincident with an increase in T4/T8 ratio in the peripheral blood. The median time to progression for the entire cohort was eight weeks (range, 4–65 weeks). There was no clinical evidence of immunosuppression and no decrease in total peripheral blood lymphocyte counts or helper T-cells was observed. At the doses and schedule employed in this trial, deoxyspergualin does not appear to have significant activity against metastatic breast cancer resistant to front-line chemotherapy. The correlation between hypomagnesemia and neuromuscular toxicity of deoxyspergualin is an intriguing, previously unknown observation and requires further investigation.     

A phase II trial of piroxantrone in adenocarcinoma of the pancreas

Summary Thirty-five evaluable patients with advanced adenocarcinoma of the pancreas were treated with piroxantrone at a dose of 150 mg/m² intravenously every 21 days. No objective responses were observed (95% confidence interval 0% –10%). Toxicities of grade 3 were primarily hematologic and were seen in 28 patients. Piroxantrone is inactive in pancreatic cancer and no further investigation of this agent in this tumor is recommended.     

Chlorozotocin: results in colorectal carcinoma treated with high and low doses

Summary Clorozotocin was evaluated in patients with advanced colorectal cancer at 225 mg/m² every six weeks in 14 patients with no prior treatment, at 200 mg/m² in 43 patients with normal tolerance of prior chemotherapy, and at 100 mg/m² in 38 patients with extensive or poorly tolerated prior therapy. Median survival for the respective groups was 192, 107 and 79 days; these differences are best explained as a function of performance status. Partial response was reported for one patient, 15 had disease stabilization and two had improvement short of partial remission. Myelotoxicity was acceptable at all doses, with thrombocytopenia being dose limiting at 225 mg/m². Four patients developed azotemia during or after Chlorozotocin treatment. Chlorozotocin has minimal activity against colorectal carcinomas and no dose-response relationship is evident.     

Phase I — Preliminary phase II trial of iproplatin,a cisplatin analogue

Summary Iproplatin was administered intravenously over 30 min daily for 5 consecutive days every 3 weeks to 80 evaluable patients with a variety of refractory solid tumor malignancies. Thrombocytopenia was the dose-limiting toxicity. Reversible drug-induced renal dysfunction was observed in 3 patients. One patient sustained mild ototoxicity but neurotoxicity was not encountered. Transient neutropenia, anemia, nausea, vomiting, diarrhea, elevations of liver enzymes, alopecia, and skin rash also occurred. The spectrum and severity of toxicity of iproplatin were found to differ from those of cisplatin. The maximally tolerated dose (MTD) was 45 mg/m²/day in patients who received prior chemotherapy and 65 mg/m²/day in those who did not. No complete responses occurred. Partial responses were obtained in 2/15 patients with colon cancer, 3/18 with breast cancer, 2/4 with carcinoma of unknown primary site and 1/2 with pancreatic cancer. Thirteen patients with lung (5), breast (4), colon (2), head and neck (1) and cervical (1) cancers had stable disease. Based on the different toxicity profiles between iproplatin and cisplatin and the possible antitumor efficacy of the former, phase II investigation of iproplatin has been initiated.     

A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors

Summary The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received ≤2 prior cytotoxic regimens for recurrent disease were treated with gemcitabine over 90 min on days 1 and 8 plus BMS-247550 over 3 h on day 8, every 21 days in a phase I study. Dose-limiting toxicity definitions were based on severe myelosuppression, or grade 3 or 4 treatment-related non-hematologic toxicity, or dose delay of greater than 2 weeks due to treatment toxicity observed in the first treatment cycle. Dose cohort 1 received gemcitabine 900 mg/m² and BMS-247550 20 mg/m². Grade 4 neutropenia lasting ≥7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m² plus BMS-247550 30 mg/m²) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m² plus BMS-247550 30 mg/m²), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m² plus BMS-247550 25 mg/m²), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicites included neutropenia, thrombocytopenia, neutropenic fever, hypophosphotemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m² over 90 min days 1 and 8 plus BMS-247550 20 mg/m² on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.     

Leucovorin, 5-fluorouracil,and gemcitabine: A phase I study

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU).The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0–2, and signed informed consent.Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m², 5FU 255 mg/m² and gemcitabine 600 mg/m². 5FU and gemcitabine were escalated in tandem to 340 mg/m² and 800 mg/m² and thereafter to 425 mg/m² and 1000 mg/m², respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1–32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses.The maximum tolerated dose is leucovorin 20 mg/m², 5FU 340 mg/m², and gemcitabine 800 mg/m². The impact of drug sequence remains undetermined.