Clinical phase I-II and pharmacokinetic study of high-dose thymidine given by continuous intravenous infusion.

High-dose thymidine (dThd) was given to 12 patients with advanced hematological and solid tumors. The dose schedule used was 75 g/sq m/day, given i.v. continuously for 5 days or more. Myelosuppression, especially leukopenia, was the dose-limiting toxicity. Nonhematological toxicities affected the gastrointestinal tract (nausea, vomiting, anorexia, diarrhea, and indigestion) and the central nervous system (somnolence, headache, visual illusions, and memory impairment). Patients who had received cumulative doses of dThd developed alopecia. Thymine crystals were noted in the urine after refrigeration. Tumor regression (less than partial remission) occurred in one patient with melanoma. Three of four patients with acute leukemia had a fall in peripheral white blood cell counts and blasts but no marrow improvement. Four patients with adenocarcinoma (three colon, one unknown primary) had stable disease. Pharmacokinetic studies revealed that, at a dThd dose of 75 g/sq m/day, millimolar concentrations of dThd and thymine can be achieved in the plasma. The half-life of dThd was approximately 100 min. One-third of the plasma concentrations was measurable in the cerebrospinal fluid. dThd was mainly excreted by the kidneys.

Phase I clinical and pharmacological study of 4'-(9-acridinylamino)-methanesulfon-m-anisidide using an intermittent biweekly schedule.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA, NSC 249992), an acridine derivative, was given to 28 patients with solid tumors and one patient with Hodgkin's disease in a Phase I clinical trial. The dose schedule used was a single dose given every 14 days for three doses. The amount given ranged from 10 to 120 mg/sq m/dose. Dose-limiting toxicity was moderate to severe leukopenia which occurred at and above 70 mg/sq m. Thrombocytopenia was infrequent and did not require transfusion. Nonhematological side effects were mild and included nausea, vomiting, local irritation, and fever. Antineoplastic activity was noted in liposarcoma, adenocarcinoma of unknown primary origin, and squamous carcinoma of unknown primary origin (one patient each). Pharmacokinetics studies were done in 19 patients. Total m-AMSA and free m-AMSA concentrations showed a biphasic distribution with an initial rapid phase of t1/2 = 10 to 15 min for both, and a second slow phase of t1/2 = 8 to 9 hr for total m-AMSA and 3 hr for free m-AMSA. Phase II studies with m-AMSA, in hematological cancers are warranted, since its most consistent effect is on leukocytes. The recommended dosages for solid-tumor Phase II studies are 70 mg/sq m for good-risk patients and 50 mg/sq m for poor-risk patients, given as a single dose every other week, or 120 mg/sq m for poor-risk patients for the single-dose every-3-week schedule.

Randomized trial of three combinations of cisplatin with vindesine and/or VP-16-213 in the treatment of advanced non-small-cell lung cancer.

One hundred sixty-seven evaluable patients with non-small-cell lung cancer were randomized to receive high-dose cisplatin and vindesine (PVD), or cisplatin and VP-16-213 (etoposide epipodophyllotoxin) (PVP), or cisplatin with VP-16-213 and vindesine (PVPVD). The patient distribution and characteristics were similar in all the treatment arms. The response rate differences (35% in PVD arm, 30% in PVP arm, and 22% in PVPVD arm) were not statistically significant (P = .33). Response durations were 43 weeks in the PVD arm, 20 weeks in the PVP arm, and 27 weeks in the PVPVD arm. Median survival was 29 weeks in the PVD and PVP arms and 28 weeks in the PVPVD arm. Median survival time of responding patients was 76 weeks in the PVD arm and 65 weeks in the PVP arm; 78% of patients were alive at 22+ to 87+ weeks follow-up in the PVPVD arm. Myelosuppression was similar in all three treatment arms. Significantly more azotemia occurred in the PVD arm than in the PVP and PVPVD arms (P = .002), and significantly more neuropathy in the PVD and PVPVD arms than in the PVP arm (P = .003 and .005). All the treatment arms have similar antitumor activity in non-small-cell lung cancer, but the PVP combination is slightly less toxic than the PVD and PVPVD treatment arms.

Combined chemoradiotherapy in limited-disease, inoperable non-small cell lung cancer.

Forty-three patients with limited-disease, inoperable non-small cell lung cancer received two intravenous courses of cyclophosphamide, Adriamycin, and cisplatin (CAP) chemotherapy over a 6-week period. This was followed by 5 weeks of combined chemoradiotherapy (CCRT) consisting of low weekly doses of CAP for 5 weeks plus 50 Gy continuous X ray therapy (XRT) to the primary tumor site. Chemotherapy was continued until disease progression occurred or until the total dose of Adriamycin reached 450 mg/m2, whichever came first. CCRT improved the response rate [complete response (CR) plus partial responses (PR)] from 25% after two courses of CAP alone to 65% after CCRT. Previous response to two courses of CAP influences response subsequent to CAP plus XRT. A pretherapy weight loss of 6% or greater had a significant adverse effect on both response and survival time. The median survival time for all patients was 50 weeks; patients whose disease responded to treatment survived significantly longer than patients with nonresponding disease. The median time until disease progression was 37 weeks. Twenty-seven patients relapsed. The first sites of relapse were local in 30% of the patients, distant in 56% of them, and both local and distant in 15%. Severe esophagitis occurred in 30% of the patients and was dose-limiting. The administration of CCRT resulted in an improved response rate compared with the rates reported in previous studies of chemotherapy or radiotherapy alone. Further improvement of the CCRT program is needed to increase long-term survival time and to decrease esophageal toxicity.

Timing of elective brain irradiation: a critical factor for brain metastasis-free survival in small cell lung cancer.

Risk factors for brain metastasis in small cell lung cancer were studied in 260 patients without brain metastasis at presentation who were treated on 5 protocols. The first three protocols offered elective brain irradiation (EBI) to all available patients after 2 or 3 courses of chemotherapy (early EBI), whereas the other two offered it after 5 or 6 courses of chemotherapy (late EBI). The overall incidence of brain metastasis was higher in the late EBI group than in the early EBI group (23.6% vs. 14.3%, p = 0.08), primarily due to higher incidence of brain metastasis developing before EBI in the former. There was a higher incidence of brain metastasis in patients without than in patients with bone marrow metastasis (21.4% vs. 6.8%, p = 0.04), in patients less than 60 years old than in patients 60 years or older (23.4% vs. 13.4%, p = 0.06), and in patients with than in patients without bone metastasis (30.2% vs. 16.8%, p = 0.07). Major risk factors for short brain metastasis-free survival were bone metastasis (p = 0.008), late EBI (p = 0.03), and failure to achieve complete remission after induction chemotherapy (p = 0.001) or as a best response (p = 0.0001). The early EBI group had a longer brain metastasis-free survival than the late EBI group, even among patients with bone metastasis (p = 0.02) or bone marrow metastasis (p = 0.05) and those who achieved complete remission after induction chemotherapy (p = 0.06) or as a best response (p = 0.05). These results indicate that timing of EBI is a critical factor in brain metastasis in patients with small cell lung cancer. There was no difference in overall survival between the two groups, however, even among patients who achieved complete remission as a best response.

Esophageal complications from combined chemoradiotherapy (cyclophosphamide + Adriamycin + cisplatin + XRT) in the treatment of non-small cell lung cancer.

Esophageal complications from combined chemoradiotherapy (CCRT) were analyzed in 55 patients with limited non-small cell lung cancer. CCRT consisted of chemotherapy (cyclophosphamide, doxorubicin (Adriamycin), and cisplatin: CAP) and chest irradiation (5000 rad in 25 fractions/5 weeks). Forty-five patients received two courses of CAP, followed by five weekly courses of low dose CAP and irradiation followed by maintenance courses of CAP (Group 1). Ten patients received concomitant CCRT from the onset of treatment (Group 2). Esophagitis occurred in 80% of all patients. Severe esophagitis occurred in 27% of patients of Group 1 and 40% of patients of Group 2. Esophageal stricture or fistula developed in 1 of 45 (2%) patients in Group 1, and 3 of 10 (30%) patients in Group 2 (p less than 0.025). Weekly low-dose chemotherapy administered concomitantly with chest irradiation (R) at the onset of treatment significantly increases esophageal complications. A review of the literature suggests that CCRT may be used safely with split courses of R. The duration between onset of chemotherapy either before or after R should be greater than one week.

Clinical trials with diglycoaldehyde (NSC-118994): review and reasons for withdrawal from clinical trial.

All Phase II studies with diglycoaldehyde with leukemia and solid tumors have been reviewed. The dose schedules employed ranged from 1.5 to 2.0 g/m2/day for 3 to 5 days. The most common side effects have been gastrointestinal (nausea and vomiting), which occurred in 22% of the patients. Renal toxicity (rise in BUN, creatinine, and urinary proteins) was seem in 17% of the patients treated. Other infrequent toxicities include hypocalcemia (9%) and local complications such as phlebitis. Leukopenia, thrombocytopenia, positive Coombs' test and impairment in coagulation profile were also reported. In contrast to the hints of therapeutic efficacy described during Phase I trials, in phase II trials no activity was noted among 96 patients with solid tumors and only minimal antileukemic action among 49 other patients. These disappointing Phase II trials coupled with prominent toxicities have prompted the decision to terminate further clinical testing. This report summarizes all clinical observations as an example of circumstances which curtail clinical testing of anticancer drugs.

Phase I study of thymidine (dThd) and cisplatin (DDP) given in combination.

Twenty-three patients with a variety of solid tumors were given thymidine (dThd) at a single dose of 30 g/m2 along with cisplatin (DDP) at escalating doses ranging from 25 to 120 mg/m2. The dThd was administered first, and then after 50% of the total dThd dose had been infused over 1 h, the remaining 50% was given simultaneously with DDP at a separate intravenous site over the next 2 h. Treatment was repeated at 3-week intervals. Gastrointestinal toxicity was dose-limiting and dose-related with increasing dosages of DDP. Central nervous system manifestations occurred in 17% of the patients. Mild myelosuppression was observed only at DDP doses of greater than or equal to 75 mg/m2. Thrombocytopenia was more severe than leukopenia. The maximum tolerated doses on this schedule were 30 g/m2 of dThd and 100 mg/m2 of DDP.

Phase II pilot study with cisplatin, etoposide, and continuous-infusion 5-fluorouracil in metastatic non-small cell lung cancer.

A pilot study was conducted using a combination of cisplatin (70 mg/m2 i.v., day 1), etoposide (60 mg/m2 i.v., days 1 through 5), continuous-infusion 5-fluorouracil (800 mg/m2 i.v., days 1 through 5), and allopurinol (600 mg p.o., days 1 through 7). Treatment was repeated every 3-4 weeks. Ten patients with metastatic non-small cell lung cancer were treated. Significant toxicities were observed, including electrocardiographic changes simulating acute myocardial infarction in three patients. There was no objective response, therefore the study was closed early according to its design.

Phase II clinical evaluation of dihydroxyanthracenedione in patients with advanced lung cancer.

A phase II clinical study of dihydroxyanthracenedione ( DHAD ) was conducted in 50 patients with advanced lung cancers. DHAD was administered intravenously on a 5-day schedule repeated every 4 weeks. Most patients had adenocarcinoma (46%), and had received previous chemotherapy (66%) and radiation therapy (50%). Among 41 evaluable patients, there were four partial remissions, eight disease stabilizations and 29 disease progressions. Remissions were more common among previously untreated patients (20% vs. 4%), particularly in patients with adenocarcinoma and large cell carcinomas of whom 3/10 (30%) responded. Responses lasted 9+, 9, 7, and 3 months, respectively. Cardiac toxicity was not observed. Other toxicities were tolerable. DHAD is a potentially useful agent for the therapy of adenocarcinoma and large cell lung cancers.

Sequential administration of thymidine, 5-fluorouracil, and PALA. A phase I-II study.

Twenty-seven patients with colorectal adenocarcinoma, (12) non-small cell bronchogenic carcinoma, (11) gastric adenocarcinoma (3), and adenocarcinoma of unknown primary lesion (1) were treated with the combination of thymidine (TdR), 5-fluorouracil (FU), and N-phosphonacetyl-L-aspartic acid (PALA). PALA 1 g/m2 was given over 1 hour on day 1, followed on day 2 by 30 g of TdR given over 3 hours. FU, 150-300 mg/m2, was administered sequentially over 1 hour immediately following TdR infusion. There were no responses seen using this dose schedule. Gastrointestinal and central nervous system toxicities were dose-limiting. Myelosuppression was seen at all dose levels and was not dose related. Fever and infection occurred in 16% and 3% of the courses. The maximum tolerated dosages on this schedule were PALA, 1 g/m2; TdR, 30 g; and FU, 250 mg/m2. Pharmacologic studies done revealed the following half-lives: TdR, 1.6 hours; thymine, 5.0 hours; FU, 6.8 hours; and FUDR, 3.7 hours. The significant prolongation of the half-life of FU with this drug combination implies that the tumor tissues may be exposed longer to the anticancer action of FU.

Clinical trials with the hexitol derivatives in the U.S.

Three hexitol derivatives, dibromomannitol (DBM), dibromodulcitol (DBD), and dianhydrogalactitol (DAG), originally investigated in Hungary, have been evaluated as anticancer agents in the United States. Their principal mechanism of action is attributed to alkylation via actual or derived epoxide groups. Their preclinical spectrum includes activity against murine leukemias and against the murine ependymoblastoma, which is particularly noteworthy for DAG. Dibromomannitol trials were targeted to chronic myelogenous leukemia but no advantage over busulfan therapy was demonstrable. Dibromodulcitol and DAG were sequentially evaluated for their usefulness against a wide variety of tumors. The activity of DBD against breast cancer has stimulated several continuing trials in this disease. On the other hand, DAG was disappointing in breast cancer and in several other malignancies, but some activity has been noted against lung cancer. Both DBD and DAG are being investigated for possible usefulness in the management of patients with intracranial neoplasms. The present clinical experience does not allow firm judgment on the advantage of one analogue over another. Such comparative analysis does point out the desirable direction of future studies as well as the limitations of current preclinical systems for the selection of analogues.

A clinical trial of pyrazofurin in combination with 5-azacytidine in acute adult nonlymphocytic leukemia.

Twenty adult patients with relapsed acute nonlymphocytic leukemia were given intravenously the combination of pyrazofurin (PF) 7.5-30 mg/m2 x 1 on day 1 plus 5-azacytidine (AZA) 150-250 mg/m2/d in three divided doses for 5 days. Four patients are early deaths secondary to infection or hemorrhage and are invaluable for response. Three patients achieved a response (two patients had a CR, the third patient had a CR, relapsed, and then a PR). Duration of response was short (41-94 days). Hematologic toxicity was universal and similar at al dose ranges studied. The median pretreatment WBC and platelet counts were 500 and 32,000/microliter, respectively, and the nadirs were 500 and 15,000/microliter. Recovery only occurred in those patients who achieved a response. Nonhematologic toxicity consisted of skin rash (100% of the courses), mucositis (60%), myalgia (93%), nausea and vomiting (83%), and hypotension (47%). In conclusion, although there is interesting preclinical data to suggest that the combination of PF and AZA has synergistic cytotoxicity on leukemic cells, this human clinical trial demonstrates that the combination has significantly more nonhematologic toxicity than AZA alone and no therapeutic advantage over treatment with AZA alone.

Phase I-II clinical trial of thymidine, 5-FU, and PALA given in combination.

Twenty-eight patients with advanced adenocarcinoma were treated with a combination of thymidine, 5-FU, and PALA. PALA (1 g/m2) was given on the first day, followed on the second day with 30 g of thymidine and 150-300 mg/m2 of 5-FU given simultaneously through two iv sites. Responses were seen in two of 17 patients (12%) with colorectal adenocarcinoma. One response was complete and one was partial. The gastrointestinal tract and CNS were the sites of dose-limiting toxic effects. Myelosuppression was observed only at 5-FU doses of 250 and 300 mg/m2.

Squamous cell carcinoma of the thymus: a case report of rapid response to cyclophosphamide, doxorubicin, cisplatin, and prednisone.

A woman with unresectable squamous cell carcinoma of the thymus was treated with combination chemotherapy consisting of cyclophosphamide, adriamycin, cisplatin, and prednisone. Rapid tumor response and hyperuricemia occurred within 10 days after the first course of chemotherapy. Mediastinal irradiation was given after two courses of chemotherapy. Chemotherapy was continued until the total dose of adriamycin reached 450 mg/m2. The patient is alive and well in remission more than 111 weeks after therapy was begun and more than 63 weeks after treatment was discontinued. Further study of this chemotherapeutic regimen in squamous cell carcinoma of the thymus is needed. Monitoring of serum uric acid levels may be required.

Phase I trial of pentamethylmelamine in patients with previously treated malignancies.

Pentamethylmelamine (PMM), a demethylated soluble analog of hexamethylmelamine, was given to 35 patients with solid tumors in a phase I clinical trial. Thirty patients were given single doses ranging from 80 to 2000 mg/m2 in a 2-hour infusion every 3 weeks. Once a maximum tolerated dose was defined for this schedule, an additional five new patients plus four patients who had already received PMM were treated on a multiple-dose schedule of PMM given three times a week every Monday, Wednesday, and Friday (M-W-F) for 4 weeks. Dose-limiting toxic effects for the single-dose schedule were in the central nervous system and gastrointestinal tract, manifested by nausea (60%), vomiting (49%), somnolence (37%), depression (6%), and headache (6%). Other toxic effects observed on this schedule included anorexia (34%), diarrhea (7%), and diaphoresis (21%). The toxic effects were first observed in mild form at 400 mg/m2/dose and became progressively more severe and prolonged with each dose escalation; they were considered intolerable at the 2000-mg/m2 dose level in all patients treated. The nine patients receiving the multiple-dose schedule were given PMM at a dose of 1000 mg/m2 three times a week (M-W-F). This level produced dose-limited nausea and vomiting in all patients so that no patient completed greater than 3 weeks of treatment on this schedule. One patient developed PMM-related visual hallucinations. PMM produced no hematologic, hepatic, renal, allergic, or acute side effects; no alopecia was observed. Minor tumor regressions of 1 month's duration were seen in two patients, one with pleural mesothelioma and one with a parotid gland tumor. The recommended doses for solid tumor phase II studies are 1500 mg/m2 given as a 2-hour infusion every 3 weeks and 1000 mg/m2 given three times a week (M-W-F), repeated at 3-week intervals.

Use of carcinoembryonic antigen in small cell lung cancer. Prognostic value and relation to the clinical course 1.

Carcinoembryonic antigen (CEA) was measured in 147 patients at diagnosis of small cell lung cancer; 17% of patients with limited disease and 51% with extensive disease had an abnormal CEA level (greater than 10 ng/ml). The median level was higher in extensive than in limited disease (11 ng/ml and 5.8 ng/ml, respectively; P less than 0.001). Multivariate analysis showed CEA level greater than or equal to 50 ng/ml to be an adverse prognostic factor (P = 0.02); median survival at this level was shorter than at less than 50 ng/ml (7 and 46 weeks, respectively; P = 0.002). No consistent directional changes of follow-up CEA values were observed in patients with initially normal CEA levels, but normalization of levels occurred in complete responders. We recommend that CEA be measured in this disease at diagnosis as an additional prognostic factor and that patients with abnormal initial CEA levels have follow-up measurements to aid in evaluating response.

Weekly doxorubicin versus doxorubicin every 3 weeks in cyclophosphamide, doxorubicin, and cisplatin chemotherapy for non-small cell lung cancer.

A prospective randomized study was done to determine the effect of different doxorubicin (Adriamycin [ADR], Adria Laboratories, Columbus, OH) administration (schedules every week versus every 3 weeks) on the productivity of a cyclophosphamide, ADR, cisplatin (CAP) chemotherapy regimen for patients with non-small cell lung cancer (NSCLC). Electrocardiograms, multigated cardiac scans, echocardiograms, and endomyocardial biopsies were done serially for cardiac monitoring. Of 102 patients, 47 ahd inoperable limited disease (LD), 47 had extensive disease (ED), and eight had no evidence of disease. In the last group chemotherapy was given adjuvantly. Fifty-one patients were entered into each treatment arm. The groups were formed according to extent of disease and were comparable in terms of patient characteristics. In these groups, the overall response rates using both schedules in LD patients were similar: in patients without chest irradiation previously, there was a response of 35% with ADR weekly, and 31% with ADR triweekly; in LD patients with chest irradiation previously, the response was 20% with ADR weekly, and 25% with ADR triweekly; and in ED patients, 16% with ADR weekly, and 11% with ADR triweekly. There was no significant difference in survival between the two treatment groups. However, results for all responders suggested a longer duration of response with weekly than with triweekly ADR (complete plus partial response: 35.8 versus 11.4 weeks, P = 0.06; minor response: 34 versus 11.5 weeks, P = 0.003, respectively). Results also suggested that weekly ADR was less cardiotoxic than triweekly ADR: 29% of patients in the former group had no changes or only minor changes in endomyocardial biopsy results, whereas all patients in the latter group had at least grade 0.5 changes at a similar dosage. The median doses of weekly ADR were higher at the same endomyocardial biopsy-defined toxicity levels. No correlation was found between toxic effects defined by endomyocardial biopsy results and those defined by noninvasive monitoring techniques, although the number of patients assessed was small. Weekly ADR produced less granulocytopenia and a lower incidence of fever (6% versus 16%, P less than 0.001) than did triweekly ADR. Alopecia, nausea, vomiting, and diarrhea were significantly less for weekly ADR than triweekly Adr (P less than 0.0005, less than 0.0005, and less than 0.005, respectively). These data suggest that weekly ADR can achieve the same therapeutic results as the standard triweekly regimen with less cardiotoxicity, myelotoxicity, alopecia, diarrhea, nausea, and vomiting in patients with NSCLC.

VM-26, a new anticancer drug with effectiveness in malignant lymphoma: an Eastern Cooperative Oncology Group Study (EST 1474).

Thirty-six patients with stage III and IV Hodgkin's disease and non-Hodgkin's lymphoma, who had become refractory to conventional chemotherapy, were treated with VM-26. Complete remissions were documented in two patients with diffuse histiocytic lymphoma. Six patients (four with non-Hodgkin's lymphomas and two with Hodgkin's disease) had partial remissions. The overall response rate was 22% (eight of 36 patients). Hematologic toxicity was the most frequent dose-limiting toxicity. Nonhematologic toxic effects were mild and acceptable. This study demonstrates that VM-26 can produce tumor responses in refractory lymphomas. The Eastern Cooperative Oncology Group is currently planning two new phase II studies to incorporate VM-26 with other active new agents, one involving hexamethylmelamine and the other involving cis-dichlorodiammineplatinum(II).