Showing papers on "Phases of clinical research published in 1990"

Pharmacologically Guided Phase I Clinical Trials Based Upon Preclinical Drug Development

Abstract: Since our original proposal 4 years ago, considerable support has evolved for the concept of pharmacologically guided dose escalation in phase I clinical trials with new anticancer drugs. The original focus has been broadened to develop additional links between preclinical testing and phase I clinical trials. Recent experiences with very lengthy phase I trials for at least eight drugs have provided particular impetus for this project. The original pharmacodynamic hypothesis for the proposal was equal toxicity at equal plasma levels. Specifically, two facets of the concept were that (a) dose-limiting toxicity correlates with, and in turn is predicted by, drug concentrations in plasma and (b) that the quantitative relationship between toxicity and drug exposure, as measured by plasma drug concentration times time (C x T), holds across species. If true, this hypothesis would suggest that dose escalations in humans could be safely based on measurement of drug levels in plasma, rather than on empirical escalation schemes. In addition to the collection of a larger retrospective data base to validate this hypothesis, practical results have already been achieved. In two studies sponsored by the National Cancer Institute (NCI), the escalation pattern was prospectively modified on the basis of measurements of drug levels in plasma. In addition, for three NCI-sponsored drugs, more careful matching of schedules between clinical and preclinical testing produced entry doses that were up to 25 times higher than doses used in standard procedures. Consequently, the phase I trials for each drug were completed with a savings of 12-24 months. As a result of work in both the United States and Europe, a substantial collection of data now demonstrates that coordination with preclinical pharmacology and toxicology studies can save both time and resources in early clinical trials without a loss of safety.

Phase I trial of 5-fluorouracil and recombinant α2a-interferon in patients with advanced colorectal carcinoma

Abstract: We have previously shown that the combination of 5-fluorouracil (5-FUra) and recombinant α- 2a -interferon (rIFN-α- 2a ) produced objective responses in 23 of 32 (63%) previously untreated patients with advanced colorectal carcinoma. Because in vitro data suggest that rIFN-α- 2a modulates the cytotoxic effects of 5FUra in a concentration-dependent manner, a phase I clinical trial was initiated to determine the maximum tolerated dose of rIFN-α 2a when administered in combination with 5FUra. A total of 27 patients with advanced colorectal carcinoma were enrolled. The median age was 64 years, and the median performance status was 1. A total of 18 patients had no prior chemotherapy and 19 no prior 5FUra. 5FUra was administered at 750 mg/m 2 /day by continuous i.v. infusion for 5 days, followed by weekly bolus therapy. rIFN-α 2a was administered at 6, 9, 12, 15, or 18 × 10 6 units s.c. beginning on day 1. The dose-limiting toxicity of this regimen was fatigue, resulting in a decrease in performance status, and this was the only toxicity that correlated with increasing dose of rIFN-α 2a . Eastern Cooperative Oncology Group grade 3–4 toxicities included leukopenia (6), thrombocytopenia (2), anemia (4), stomatitis (4), diarrhea (4), neurological (2), infection (2), and allergy (2). Three quarters of the patients required interruption of therapy or dose reductions of either 5FUra or rIFN-α 2a for toxicity. Among the patients with measurable disease who were previously untreated with 5FUra, 5 of 9 at the lowest dose levels achieved an objective response, including one pathological complete responder, whereas 0 of 9 at the three highest dose levels responded. Among patients previously treated with 5FUra, only 1 achieved an objective response. We conclude that the maximum tolerated dose of rIFN-α 2a , when administered with 5FUra as above, is 15–18 × 10 6 units; however, the efficacy of this regimen does not appear to be related to the dose intensity of rIFN-α 2a , and future regimens should employ a lower dose, intermittent schedule of rIFN-α 2a , which may be better tolerated.

A randomized phase II study of acivicin and 4'deoxydoxorubicin in patients with hepatocellular carcinoma in an Eastern Cooperative Oncology Group study.

Abstract: We analyzed 56 of 75 previously untreated patients with hepatocellular carcinoma who entered on a prospectively randomized trial of acivicin versus 4'deoxydoxorubicin (esorubicin). At least one episode of severe toxicity was documented in 23% of the patients on acivicin and 45% of those on 4'deoxydoxorubicin. Two patients responded to 4'deoxydoxorubicin. One response was partial, lasting 58 weeks, and one was complete, lasting more than 4 years. The 90% confidence interval for response is 1-20%. In view of a 45% rate of severe or worse toxicity with 4'deoxydoxorubicin, this drug cannot be recommended as treatment. There were no responses on acivicin.

Epirubicin in extensive small-cell lung cancer: a phase II study in previously untreated patients: a National Cancer Institute of Canada Clinical Trials Group Study.

Abstract: The Clinical Trials Group of the National Cancer Institute of Canada (NCIC) studied single-agent epirubicin in 40 previously untreated patients with extensive small-cell lung cancer (SCLC). The starting dose of epirubicin was 100 (eight patients) or 120 (32 patients) mg/m2 administered intravenously every 3 weeks. Twenty patients (50%) achieved an objective response (95% confidence limits, 33% to 66%) and three of the 20 had complete responses (CRs). The median survival of all 40 patients was 8.3 months (35.4 weeks). Myelosuppression, mild or moderate nausea and vomiting, and hair loss were commonly seen. There was one chemotherapy-related death. This drug is active and well tolerated in SCLC and the use of it as first-line therapy did not appear to compromise survival in this group of patients.

Phase II study of amonafide: results of treatment and lessons learned from the study of an investigational agent in previously untreated patients with extensive small-cell lung cancer.

Abstract: Thirteen previously untreated patients with extensive small-cell lung cancer (SCLC) were treated with the investigational agent amonafide in a dose of 300 mg/m2 intravenously (IV) over 1 hour daily for 5 consecutive days. No responses were seen in 12 eligible patients. Myelosuppression was only occasionally seen. Other toxicities included diaphoresis, chest pain, local irritation at the injection site, arthralgias, nausea and vomiting, and neuromuscular problems. There were two early deaths, both attributable to tumor progression with resultant obstruction of a vital structure. Ten patients crossed over to alternate active therapy (etoposide [VP-16]-cisplatin) and five responded. The median survival time (MST) of the whole group of treated patients was 31 weeks. In future trials of investigational new drugs in previously untreated SCLC, we recommend that patients with the following characteristics be excluded: Eastern Cooperative Oncology Group (ECOG) performance status 2, 3, and 4; superior vena cava (SV...

Evaluation of the continuous infusion of etoposide plus cisplatin in metastatic breast cancer. A collaborative North Central Cancer Treatment Group/Mayo Clinic phase II study.

Abstract: A prospective clinical trial was done to evaluate the efficacy and toxicity of cisplatin plus etoposide (VP-16) in patients with breast cancer who failed one previous chemotherapy regimen for advanced disease or relapsed within 12 months of adjuvant chemotherapy. Partial responses occurred in 11 of 44 evaluable patients (25%; 95% confidence interval (CI), 13% to 40%). The median time to disease progression in responding patients was 4 months (range, 3 to 6+ months), whereas the median time to disease progression and survival for all patients who were treated were 3 and 7 months, respectively. There was marked toxicity related to this protocol treatment including pancytopenia, gastrointestinal upset, and renal insufficiency. Two treatment-related deaths occurred; one from sepsis and one from renal failure. Thus, this regimen, as second-line chemotherapy for women with metastatic breast cancer, resulted in moderate, short-term, antitumor activity at the expense of marked toxicity.

Intra-arterial hepatic chemotherapy with pirarubicin : preclinical and clinical studies

Abstract: Intra-arterial hepatic chemotherapy (IAHC) with adriamycin (ADM) has not increased its therapeutic index. For our preclinical studies, we selected pirarubicin (THP), an ADM derivative with faster cellular uptake. In rabbits with VX2 tumor in the liver we compared plasmatic and cellular pharmacokinetics of ADM and THP after i.v. and IAH therapy. For ADM, there were no differences in plasma and heart concentrations, with only a slight increase in tumoral levels after IAH compared to i.v. administration; on the other hand, with IAH THP, there was important reduction in systemic exposure with a major increase in tumoral drug distribution. In the phase I study, involving nine patients with implanted catheters, the starting dose of THP was 30 mg/m2 with a 10 mg/m2 intrapatient escalation every 3 weeks in the absence of toxicity. Pharmacokinetics were compared for i.v. and IAH administration in seven patients. The limiting toxicity was neutropenia and the maximal tolerated dose (MTD) ranged from 50 to 110 mg/m2. Moderate nausea-vomiting (grade 1-2) and alopecia (grade 1) occurred at the MTD. No arterial occlusion, gastroduodenal ulcer, hepatitis, or sclerosing cholangitis were seen. In the phase II study, in colorectal cancer patients (CRC) with metastasis confined to the liver, patients were enrolled until June 1990. THP (40 min infusion every 3 weeks) was initiated at 60 mg/m2 with 10 mg/m2 increment until grade 2 hematotoxicity. The median MTD was 85 mg/m2 (range of 60-120 mg/m2), and the median number of cycles was 7 (range of 2-11) with cumulated doses from 180 to 1,030 mg/m2. Grade 2-4 neutropenia was reached in 15 patients. Other toxicities included two arterial occlusions, one episode of gastritis, but no hepatic toxicity and no heart failure. Antitumor effect (in 18 patients) included 1 CR, 5 PR, 3 MR, 6 NC, and 3 PD. The median survival was 18+ months and 1-year survival was 73% +/- 12%. Seven patients had extrahepatic progression at this time. In conclusion, besides 5-FU or Fudr, THP is active in IAHC (probably in relation with high local extraction) on CRC liver metastases usually unresponsive to ADM. It can be given in an outpatient setting with minimal toxicity.

Phase II study of homoharringtonine in patients with recurrent primary malignant central nervous system tumors.

Abstract: A phase 11 trial of Homoharringtonine (HHT) was performed in 15 patients with recurrent or progressive malignant glioma. The drug was administered at a initial dose of 4 mg/m2/day by continuous 5 day intravenous infusion (3 mg/m2/day x 5 days for heavily pretreated patients). Courses were repeated every 3–4 weeks upon recovery from toxicity. No objective antitumor regressions occurred. Two patients had no change in their CT brain scans for 2–3 months and one patient had stable disease for 6 months. Toxicity was tolerable and included myelosuppression and occasionally mild hypotension. Chemosensitivity testing with HHT and several other chemotherapy drugs was performed in glioma cell lines, including cell lines derived from these patients. The results suggest that HHT is an inactive drug in malignant glioma using this dose schedule.

A phase II study of ifosfamide and cisplatin chemotherapy for metastatic or relapsed carcinoma of the cervix.

Abstract: A total of 44 women received a combination of ifosfamide (1.5 g/m2 daily x5) and cisplatin (50 mg/m2 on day 1 only) as first-line chemotherapy for recurrent or metastatic carcinoma of the cervix. In all, 12/42 (38%) evaluable patients responded, with the median duration of response being 7 months. Bone marrow and gastrointestinal toxicity were frequently severe. There were 3 septic death. Although cisplatin plus ifosfamide is an active combination against this disease, these results suggest that it is no more so than either drug used alone.

Phase II study of recombinant human interferon-gamma in metastatic renal cell carcinoma.

Abstract: The efficacy of a low-dose regimen of human recombinant interferon-gamma was studied in 40 patients with metastatic or locally advanced renal cell carcinoma. Patients received 100 micrograms/m2/day as an infusion over 4 h. The intention was to find an active but tolerable regimen as a basis for future combination treatments with other cytokines or cytotoxic drugs. Activity of this low-dose schedule had been reported. In the absence of rapid progression, treatment was given for at least 3 months, and in case of stable disease it was continued for prolonged periods in order not to miss late remissions. Toxicity was generally mild, with fever and constitutional symptoms predominating. Therapeutic efficacy was low with only one partial remission. Three patients had stable disease over 6, 9, and 15 months. This low-dose schedule cannot be recommended for the treatment of renal cell cancer.

Phase II study of 4′-Epi-Doxorubicin in patients with untreated, extensive small Cell Lung Cancer

Abstract: The purpose of the study was to investigate the antitumour activity and toxicity of high dose (120 mg m-2) single agent epirubicin therapy in untreated extensive small cell lung cancer patients Out of 80 patients entered, 71 were evaluable for both antitumour activity and toxicity, 4 only for toxicity and 5 were lost for follow-up The drug possessed a high antitumour activity, the overall response rate was 479% (34/71) with 4 complete remissions (CR) and 30 partial remissions (PR) The median remission duration was 35 months Particular drug activity was observed in the primary tumours, lymph nodes and pleural metastases Toxicity (leukopenia, anaemia, vomiting, reversible rhythmic cardiac disorder, stomatitis) was mild, alopecia was registered less than in adriamycin medication One fatal congestive heart failure occurred The actual mean survival time calculated on the basis of the data gained from 64 patients was 70 months (range 2–22) The high antitumour activity and no increase in toxicity justify the incorporation of high dose epirubicin into combination therapy

Tumor necrosis factor in advanced colorectal cancer: a phase II study. A trial of the phase I/II study group of the Association for Medical Oncology of the German Cancer Society.

Abstract: In a phase II study, the efficacy and toxicity of human recombinant tumor necrosis factor (rh TNF-alpha) were evaluated in patients with advanced colorectal carcinoma. Rh TNF-alpha was given as short term infusion at a dose of 3 × 105 U/m2 on three successive days. Treatment was repeated after a two week interval. The response was evaluated after four treatment cycles. In 15 patients entering the study, we found one partial response, one stable disease, 9 progressive diseases, and four patients who where not evaluable for tumorremission. There were numerous side effects of the treatment, mainly fever, chills, loss of appetite, leukopenia, and hepatotoxicity. In this regimen, rh TNF-alpha does not suggest a therapeutic advantage for treatment of advanced colorectal carcinoma.

Megestrol acetate: phase II study of a single daily administration in advanced breast cancer.

Abstract: A new formulation of megestrol acetate, a semisynthetic oral progestin used in the hormonal treatment of breast cancer, allows the administration of 160 mg of the drug in a single daily dose. Sixty-nine postmenopausal patients with advanced breast cancer have been treated with this regimen: five patients received megestrol acetate as first-line treatment of their metastatic disease, while all the others had been previously treated with one or more regimens of chemotherapy and/or hormone therapy. The median duration of the treatment for evaluable patients was 3 months (range 1–13+). Among 65 evaluable patients 2 complete responses and 12 partial responses (objective response rate 21.5%; 95% confidence limits 12.31%–33.49%) were observed. Median duration of response was 7 months (range 2–12+). Responses were observed both in visceral and in non-visceral sites of disease. Twenty-nine patients obtained a stabilization of disease (44.7%), and twenty-two progressed (33.8%). Median duration of stabilization was 4 months (range 3–13+). Median survival for all patients from the start of megestrol acetate was 9 months (range 1–22+). The most common side effect of therapy was weight gain, occurring in 36% of patients. Megestrol acetate on a single-daily-dose schedule can be considered as an interesting hormonal treatment for advanced breast cancer, especially in the clinical instance of patients who, after having obtained a remission or stabilization of disease with tamoxifen, need further palliative treatment.

Clinical Pharmacokinetics in the Drug Regulatory Process

Abstract: The task of the authorities is to ensure that marketed drug products are safe and effective when used as intended. To determine that this is the case the authority requires substantial information on the chemical, pharmaceutical, toxicological, pharmacological and clinical pharmacological properties of the drug. Knowledge about the human pharmacokinetics of a drug and the application of pharmacokinetic principles is necessary to understand fully the features of the drug and the interindividual differences in therapeutic and toxic effects

Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1.

Abstract: Successful treatment of advanced cancer of the prostate which no longer responds to hormonal manipulation continues to be a difficult task. The present study describes the results of treatment of the first fourteen patients in Phase II clinical trials with Antineoplaston AS2-1 (AS) and low-dose diethylstilbestrol (DES). The study involved thirteen patients diagnosed with stage IV and one patient with stage II adenocarcinoma of the prostate. The ages of the patients were between 54 and 88. The previous therapy included prostatectomy, orchiectomy, radiation therapy and treatment with DES, LHRH agonist (LH), flutamide (FL), aminoglutethimide and immunotherapy. After initial response to such treatments, the disease continued to progress. The majority of patients showed progression of the disease after treatment with LH and FL. The current treatment program consisted of administration of AS and DES. The treatment was given orally daily. The majority of patients received from 97 to 130 mg/kg/24 h of AS and from 0.01 to 0.02 mg/kg/24 h of DES. The treatment was administered from 64 to 425 days and was free from significant side effects due to AS. The dose of DES was lower than usual, and only some patients experienced mild side effects typical for DES. Only two patients showed progression of the disease. Complete remission was obtained in two patients and partial remission in three patients. Stabilization of the disease with objective improvement was determined in seven patients. The first patient enrolled in the program has been in complete remission for 17 months and off the treatment for 16 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Design and Analysis of Clinical Trials for Anti-Infective Drug Products

Abstract: T H E Food and Drug Adminis t ra t ion (FDA) process for approval of new drugs for marketing is a multidisciplinary ap­ proach involving review input from physi­ c ians , pha rmaco log i s t s , toxicologis ts , chemists, microbiologists, statisticians, and others. Our goal is to review results of preclinical and clinical studies to deter­ mine whether substantial evidence has been presented to serve as the basis of ap­ proval of the new drug product. Section 505 (d) of the January 1975, Federal FD & C Act defines substantial evidence as evi­ dence consisting of adequate and wellcontrolled investigations, including clini­ cal investigations, by experts qualified by scientific training and experience to evalu­ ate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it pur­ ports or is represented to have under the conditions of use prescribed, recommend-

Phase II Study of Pirarubicin in Metastatic Breast Cancer

Abstract: Pirarubicin is a more lipophilic derivative of doxorubicin, with a higher uptake rate of cells, lower cardiotoxicity and better antitumor efficacy in preclinical models. Thirty-four patients with metastatic breast cancer were treated in a multicenter phase II study with pirarubicin (THP) using a dosage of 75 mg/m2/every 3 weeks. The patients had a median age of 56 years (range 41-73) and a performance status of WHO grade 0-2. Patients pretreated with anthracyclines, or who were older than 75 years and without sufficient bone marrow reserve were excluded. The 32 evaluable patients received a median number of 4 cycles (range 2-8). The myelosuppression was dose-limiting and led to infections (grades 1 and 2) in 5 patients. Twenty-eight patients developed leukocytopenia grade 3 and 4 toxicity and 7 patients experienced thrombocytopenia grade 1 and 2. The drug was subjectively well tolerated and nausea, vomiting and alopecia were mild. One complete remission with a duration of 15.4 months (67 weeks) and 7 partial remissions with a median duration of 9.3 months (40 weeks) were achieved, which resulted in an overall response rate of 25%. Twenty-one patients were stable for 17 weeks (median) under the treatment with pirarubicin.

Phase II study of tallysomycin S10b in patients with advanced colorectal cancer.

Abstract: A total of 16 patients with histologically confirmed colorectal cancer were entered into this phase II trial, designed to evaluate the efficacy and safety of tallysomycin S10b. The compound was given i. v. weekly at a dose of 2.5 mg/m2 by push injection. Pulmonary toxicity was the most significant side effect; it was observed in three patients and required treatment discontinuation in one. Skin lesions occurred in three patients. Other side effects were mild and their relationship to drug administration was ill-defined. No responses were observed in this group of patients, most of whom had received prior therapy.

Phase II study of 4'-epi-doxorubicin in patients with untreated, extensive small cell lung cancer. South-East European Oncology Group (SEEOG).

Abstract: The purpose of the study was to investigate the antitumour activity and toxicity of high dose (120 mg m-2) single agent epirubicin therapy in untreated extensive small cell lung cancer patients. Out of 80 patients entered, 71 were evaluable for both antitumour activity and toxicity, 4 only for toxicity and 5 were lost for follow-up. The drug possessed a high antitumour activity, the overall response rate was 47.9% (34/71) with 4 complete remissions (CR) and 30 partial remissions (PR). The median remission duration was 3.5 months. Particular drug activity was observed in the primary tumours, lymph nodes and pleural metastases. Toxicity (leukopenia, anaemia, vomiting, reversible rhythmic cardiac disorder, stomatitis) was mild, alopecia was registered less than in adriamycin medication. One fatal congestive heart failure occurred. The actual mean survival time calculated on the basis of the data gained from 64 patients was 7.0 months (range 2-22). The high antitumour activity and no increase in toxicity justify the incorporation of high dose epirubicin into combination therapy.

Phase II study of N-methylformamide (N-MF) (NSC 3051) in patients with advanced squamous cancer of the cervix. A Gynecologic Oncology Group study.

Abstract: Twenty patients with advanced measurable, squamous carcinoma of the cervix were treated with 25 courses of N-MF at doses ranging from 600–800 mg/m2, intravenously, daily for 5 days every 28 days. Nineteen patients are evaluable for toxicity and 17 for response. All patients had prior radiation and had received one prior chemotherapy regimen while only 10 patients had had prior surgery. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1, or 2. No responses were seen. Hematologic adverse effects were extremely rare as predicted by early clinical trials. One unusual toxicity was a syndrome consisting of pain, anorexia, lethargy, and declining performance status (pain/lethargy syndrome) that was reversible with discontinuation of the drug. This adverse effect was a reason for discontinuation of N-MF in two patients. As reported in previous studies with this drug, hepatic toxicity was also common, usually reversible, and also a cause for discontinuation of the drug. The lack of clinical activity and the unpleasant adverse effects in this population of patients with previously treated cervix cancer makes it unlikely that this drug will play any significant role in treatment.

Phase II study of lonidamine in patients with metastatic breast cancer. An Eastern Cooperative Oncology Group study.

Abstract: The Eastern Cooperative Oncology Group conducted a phase II study of lonidamine in patients with metastatic breast cancer. The drug was given orally to a maximum daily dose of 340 mg/m2. Forty-two patients were entered on study. One partial response was observed; there were no life-threatening toxicities. The results of this study are compared to two similar phase II trials.

Chemotherapy with tauromustine in advanced non-small cell lung cancer. A trial of the Phase II Study Group of the Association for Medical Oncology of the German Cancer Society.

Abstract: Tauromustine (TCNU) is a newly developed nitrosourea compound. As a result of molecular modification, TCNU is more hydrophilic than BCNU and CCNU. In experimental data there was a high therapeutic index, especially in Walker 256 carcinosarcoma in rats, and in phase I trials antitumor activity was observed in NSCLC (10/33 remissions). There was also activity in melanoma, breast cancer, pleurameso-theliomas and ovarian cancer. To determine the effectiveness, duration of response and toxicity of TCNU the following phase II trial was performed. Patients received 130 mg/m2 TCNU every 35 days orally. Twenty-five patients were treated; 22 were evaluable. The female/male ratio was 18/4, 1 patient was stage III, 21 patients stage IV, the mean age was 62.3 years (range 32–70). Between 1 and 4 courses (mean 1.9) were administered. Histology was as follows: 6 squamous cell, 11 adeno-carcinoma, 2 large cell and 3 polymorph cell carcinomas. No objective response (CR + PR) was observed; 6/18 patients had stable disease, 7/18 progression and 5/18 early progression. The median survival time is 4.9 months. The most severe side effect was thrombocytopenia (WHO grade 3 + 4, 4/22 patients). TCNU administered at this dose and schedule does not show substantial antitumor activity in patients with NSCLC. The fact that no objective tumor remission was observed suggests that the true response rate is

Pirarubicin (4'-o-tetrahydropyranil-adriamycin) for treatment of advanced breast cancer. A Clinical Phase II study.

Abstract: In a phase II study, 77 patients with metastatic breast cancer were treated with pirarubicin, 70 mg/m2 iv every 3 weeks. Most of them had received prior hormonal (n = 39) and/or chemotherapeutic drug treatment for advanced disease, including anthracycline-containing regimens in 17. After a median of 5.5 treatment cycles (range 1–14), objective tumor response was seen in 22/71 (31%) evaluable patients (4CR, 18 PR). Stable disease occurred in 34 (48%) patients, whereas the tumor progressed in 15 (21%). Significant hematologic toxicity (WHO grade III–IV) requiring interval and/or dose adjustments was observed in 41 (58%) patients. Other treatment-related side effects were generally mild, and included alopecia in 52 (73%), nausea and/or emesis in 50 (70%), and stomatitis and diarrhea in 3 patients each. There was no treatment-related death, nor was there any evidence of cardiac toxicity thus far. In summary, the early results of this trial suggest that pirarubicin is an active and rather well tolerated drug in pretreated patients with advanced breast cancer.

Phase II evaluation of esorubicin (4'deoxydoxorubicin) in pancreatic adenocarcinoma: a Southwest Oncology Group study.

Abstract: Esorubicin (4′ deoxydoxorubicin) is a new analogue of the anthracycline, doxorubicin. This compound lacks the hydroxyl group at 4′ position on the amino sugar of the anthracycline. Phase II study was designed to determine the clinical response rate and to define the qualitative and quantitative toxicities of esorubicin in patients with adenocarcinoma of the pancreas. Fifty-eight patients with inoperable adenocarcinoma of the pancreas were entered on the study, 47 were evaluable for response, and 57 were evaluable for toxicity. The dose of esorubicin was 30 mg/m2 for good risk patients and 25 mg/m2 for poor risk patients every 21 days and administered IV push through a side arm of a running IV. Diphenhydramine, 50 mg is administered IM prior to the administration of the drug to block local venous reaction. Subsequent doses of esorubicin were modified according to granulocyte and platelet nadirs and the drug was not administered until recovery of platelets (> 100,000/ul) and wbc (> 3000/ul). Three partial responses, 20 stable, and 31 with increased disease were observed. Forty-seven had severe granulocytopenia (< 250), and two patients had severe thrombocytopenia (< 25,000). One patient experienced a decrease in left ventricular ejection fraction with a total dose of 180 mg/m2. The dose of esorubicin in this study demonstrated that the drug has minimal activity in adenocarcinoma of the pancreas but the toxicity is tolerable. Search should continue for single agents with activity in this disease.

A-phase II study of intravenous 6-thioguanine (NSC-752) in multiple myeloma. A Southwest Oncology Group study.

Abstract: Thirty-three patients with relapsing or refractory multiple myeloma were treated with 6-Thioguanine (6TG) at a dose of lg/M2, with therapy given over four hours every three weeks. The major toxicity seen was myelotoxicity; thrombocytopenia was more commonly noted than neutropenia. One patient achieved a PR, two were clinically improved. 6TG in this short infusion schedule proved to be myelotoxic, but demonstrated little activity in previously treated myeloma patients.

Association of bolus tetrahydropyranyl adriamycin and 120 hours continuous 5-fluorouracil infusion in patients with metastatic breast cancer.

Abstract: 4'-O-Tetrahydropyranyl adriamycin (THP adriamycin) is a new anthracycline active as a single drug in advanced breast cancer. We have undertaken a phase II study as first-line treatment for metastatic disease with THP adriamycin day 1 = 40 mg/m2 i.v. bolus and 5-fluorouracil day 1 to day 5 = 750 mg/m2 as a continuous i.v. infusion. The dose of THP adriamycin was further escalated up to the maximal tolerated dose defined as grade 3 granulopenia for each patient. Thirty-nine patients were included, 37 being so far evaluable for toxicity and for efficacy. The mean number of cycles given was 5 (range: 2-12). The overall response rate (CR + PR) was 54% (95% CI: 37.9-70.1) and the CR rate 8%. Sites of response were as follows: lung 6/9, liver 11/18, breast 4/8, nodes 7/14, skin 3/8, bone 2/8. Neutropenia with grade 3 + 4 nadir values was observed in 70.2% of the patients according to the objective of the study. No severe thrombopenia or anemia occurred. Stomatitis grade 3 was seen in 27% and grade 4 in 3% of the patients. Alopecia grade 2 was seen in 18% and grade 3 in 9%. No other toxicity was observed. We conclude that this association is effective in metastatic breast cancer, giving few alopecia. A high response rate in liver metastases warrants further evaluation.

VM-26 in colorectal carcinoma: a Southwest Oncology Group study.

Abstract: In this multi-institutional phase II study, VM-26 or Teniposide was administered to forty-two patients with advanced colorectal cancer. Patients were initially treated at 60 mg/M2 daily for 5 days with dose adjustments depending on toxicity. One complete response and one partial response were observed lasting six and four months respectively. Leukopenia was severe in 40% of patients. No drug related deaths were seen. In this Southwest Oncology Group (SWOG) study, VM-26 appeared to have minimal benefit in advanced colorectal cancer.

[Clinical results of UFT enteric-coated granule therapy under cooperative study (phase II study). Tokyo Cancer Chemotherapy Cooperative Study Group].

Abstract: We have carried out the Phase II study by oral administration of UFT enteric-coated granules (UE) against various malignant tumors. Out of 45 patients entered in the study, 40 patients were evaluable: 36 patients among them had measurable lesions. PR (partial response) were obtained in two (11.1%) out of 18 patients with gastric cancer and one (50.0 %) out of 2 patients with lung cancer. Total response rate was 8.3%. Side effects by UE were slight; that is, anorexia (13.3%), nausea and vomiting (8.9%), generalized malaise (8.9%) and so forth. UE, as a long-term therapy, can be considered a useful drug against cancers with less side effects.