Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma.

BACKGROUND: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. RESULTS: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. CONCLUSION: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.

Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel.

PURPOSE: To review and assign attribution for the causes of early deaths on two National Cancer Institute-sponsored cooperative group studies involving irinotecan and bolus fluorouracil (5-FU) and leucovorin (IFL). PATIENTS AND METHODS: The inpatient, outpatient, and research records of patients treated on Cancer and Leukemia Group B protocol C89803 and on North Center Cancer Treatment Group protocol N9741 were reviewed by a panel of five medical oncologists not directly involved with either study. Each death was categorized as treatment-induced, treatment-exacerbated, or treatment-unrelated. RESULTS: The records of 44 patients who experienced early deaths on C89803 (21 patients) or N9741 (23 patients) were reviewed. Patients treated with irinotecan plus bolus 5-FU/leucovorin had a three-fold higher rate of treatment-induced or treatment-exacerbated death than patients treated on the other arm(s) of the respective studies. For C89803, these rates were 2.5% (16 of 635) for IFL versus 0.8% (five of 628) for bolus weekly 5-FU and leucovorin. For N9741, these rates were 3.5% (10 of 289) for IFL, 1.1% (three of 277) for oxaliplatin plus bolus and infusional 5-FU and leucovorin, and 1.1% (three of 275) for oxaliplatin plus irinotecan. Multiple gastrointestinal toxicities that often occurred together were characterized into a gastrointestinal syndrome. Sudden, unexpected thromboembolic events were characterized as a vascular syndrome. The majority of deaths in both studies were attributable to one or both of these syndromes. CONCLUSION: Close clinical monitoring, early recognition of toxicities and toxicity syndromes, aggressive therapeutic intervention, and withholding therapy in the presence of unresolved drug-related toxicities is recommended for patients receiving IFL or other intensive chemotherapy regimens.

Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation.

PURPOSE: Lometrexol [(6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate] is the prototype folate antimetabolite that targets the de novo purine synthesis pathway. Early phase I trials were confounded by cumulative myelosuppression that prevented repetitive administration. Subsequent preclinical and clinical studies suggested that coadministration of folic acid might favorably modulate lometrexol toxicity without eliminating potential antitumor activity. We set out to determine if concurrent folic acid would allow administration of lometrexol on a weekly schedule, and, if so, to identify an appropriate dose combination for phase II trials. Pharmacokinetic and metabolism studies were undertaken in an attempt to improve our understanding of lometrexol pharmacodynamics. METHODS: Patients with advanced cancer received daily oral folic acid beginning 7 days before lometrexol and continuing for 7 days beyond the last lometrexol dose. Lometrexol was administered by short i.v. infusion weekly for 8 weeks. Scheduled lometrexol doses were omitted for toxicity of more than grade 2 present on the day of treatment, and dose-limiting toxicity was prospectively defined in terms of frequency of dose omission as well as the occurrence of severe toxic events. Plasma and whole blood total lometrexol contents (lometrexol plus lometrexol polyglutamates) were measured in samples taken just prior to each lometrexol dose. RESULTS: A total of 18 patients were treated at five lometrexol dose levels. The maximum tolerated dose was identified by frequent dose omission due to thrombocytopenia and mucositis. The recommended phase II dose combination is lometrexol 10.4 mg/m(2) per week i.v. with folic acid 3 mg/m(2) per day orally. One patient with melanoma experienced a partial response, and three patients, two with melanoma and one with renal cell carcinoma, experienced stable disease. Lometrexol was not detectable in any predose plasma sample tested. The total red blood cell content of lometrexol increased over several weeks and then appeared to plateau. CONCLUSIONS: Weekly administration of lometrexol is feasible and well-tolerated when coadministered with daily oral folic acid. The nature of the interaction between natural folates and lometrexol that renders this schedule feasible remains unclear. A definition of dose-limiting toxicity that incorporated attention to dose omissions allowed efficient identification of a recommended phase II dose that reflects the maximum feasible dose intensity for a weekly schedule. Lometrexol is a promising, anticancer agent.

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.

Phase II trial of oral etoposide in recurrent or refractory endometrial adenocarcinoma: a southwest oncology group study.

Oral etoposide has activity in a wide variety of tumors and is well tolerated. Therefore, the efficacy of oral etoposide was assessed as a treatment of metastatic endometrial cancer. To be eligible for this group-wide Southwest Oncology Group trial, patients had to have histologically proven metastatic or recurrent endometrial carcinoma; no previous cytotoxic therapy; and adequate renal, hepatic, and hematologic function, and they had to have given informed consent. Therapy consisted of oral etoposide, 50 mg daily on days 1-21 on a 28-day schedule. Therapy was continued in the absence of toxicity or disease progression. Forty-four eligible women, with a median age of 68 years (range 38-84 years) were treated. Radiotherapy had been delivered to 33 and hormomal therapy to 21. The median duration of therapy was 69 days (range 7-510 days). The treatment was well tolerated. Only one patient had grade 4 neutropenia, and a second had grade 4 anemia. Three patients had grade 3 nausea. One complete and five partial responses (14%) were observed. An additional four patients had unconfirmed responses. Tumor regressions were noted in nodes, bone, and visceral organs. While oral etoposide has only a modest level of activity when used in chemonaive patients, the minimal toxicity of this drug makes it a candidate for use in combination chemotherapy.

Phase Ib trial of bryostatin 1 in patients with refractory malignancies.

A Phase Ib trial of bryostatin 1, a macrocyclic lactone and protein kinase C (PKC) activator, was conducted in patients with refractory nonhematological malignancies with the primary goal of determining whether down-regulation of peripheral blood mononuclear cell (PBMNC) PKC activity could be achieved in vivo in humans. Patients (four patients/cohort) received bryostatin 1 (25 microg/m2) as a 1-h infusion weekly three times every 4 weeks, but to study the schedule dependence of pharmacokinetics and pharmacodynamics, the first dose was administered according to one of three schedules: (a) a 1-h infusion; (b) a 24-h infusion; or (c) a split course (12.5 microg/m2 as a 30-min infusion) on days 1 and 4. Conventional toxicities (grades I-III) included myalgias, fever, anemia, fatigue, phlebitis, and headache; in addition, two patients in cohort 3 experienced transient elevations in liver function tests, although these patients had preexisting liver metastases. No objective clinical responses were encountered. Effects on PBMNC PKC activity were heterogeneous. Several patients in cohorts 1 and 2 experienced significant declines in activity (approximately 50%) that were sustained in some cases for periods of > or = 72 h. Comparison of 72-h with baseline values for all three patient cohorts combined revealed a trend toward PKC down-regulation (P = 0.06; signed rank test). For each schedule, plasma bryostatin 1 levels were below the level of detection of a platelet aggregation-based bioassay (3-4 nm). Bryostatin 1 administration failed to produce consistent alterations in lymphocyte immunophenotypic profiles, interleukin 2-induced proliferation, or cytotoxicity, although two of three samples from patients in cohort 3 did show significant posttreatment increases in proliferation. Moreover, in some patients, bryostatin 1 treatment increased lymphokine-activated killer cell activity. These findings indicate that bryostatin 1 doses of 25 microg/m2 can induce in vivo PBMNC PKC down-regulation in at least a subset of patients and raise the possibility that higher bryostatin 1 doses may be more effective in achieving this effect.

Evaluation of multimodality treatment of locoregional esophageal carcinoma by Southwest Oncology Group 9060.

BACKGROUND: Continuous infusion 5-fluorouracil (CI5-FU) has been utilized concurrently with radiotherapy to improve tumor control. In this pilot trial, cisplatin, CI5FU, and radiotherapy were utilized for the treatment of locoregional esophageal carcinoma. It was postulated that the combination would be well tolerated and associated with high response rate and survival duration. METHODS: Thirty-two eligible patients with locoregional squamous cell carcinoma and adenocarcinoma of the esophagus received a regimen consisting of the following: radiotherapy, 50 Gray (Gy) (30 Gy anteroposterior/posteroanterior regional with 20 Gy AP/LPO/RPO boost) over 5 weeks, with CI5-FU 250 mg/m2/d for the duration of radiotherapy and cisplatin 25 mg/m2/day on Days 1-3 during Weeks 1 and 4 of the radiotherapy cycle. Upon completion of radiotherapy, two additional course, of cisplatin 75 mg/m2 on Days 1 and 29 and CI5-FU 300 mg/m2/day on Days 1-21 and 29-50 were delivered. Following imaging and endoscopic reassessment, patients with no evidence of disease received more chemotherapy. Surgery was suggested only for patients with residual local disease. RESULTS: Complete response was demonstrated in 44% of patients, clinically in 12 patients, and during surgery in 2 others. The median survival was 20 months, and the 1-year survival rate was 59%. Toxicity was severe, comprised of esophagitis, infection, and gastrointestinal complications. Dose delays and reductions occurred in the majority of patients. Four early deaths were noted. CONCLUSIONS: The regimen that was the focus of this trial has been active in the treatment of esophageal carcinoma. However, compared with existing regimens, its complexity and toxicity preclude its future use without modifications.

Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks.

CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.

A pilot trial of continuous infusion 5-fluorouracil with levamisole for adjuvant therapy of colon cancer.

The relatively high response rate demonstrated with the use of continuous infusion 5-Fluorouracil (CIFU) 200 to 300 mg/m2 per day in disseminated colon cancer is the rationale behind a NCI-sponsored intergroup trial (INT 0153) for postoperative adjuvant therapy of stage III colon cancer. Because CIFU necessitates a significant reduction in the dose of the modulator leucovorin compared with bolus 5-FU, a pilot study of continuous infusion 5-FU in several doses with levamisole was conducted to determine any unexpected toxicity of this combination, and to assess completion rates of levamisole was conducted to determine any unexpected toxicity of this combination, and to assess completion rates of this dose intensive schedule. CIFU, scheduled as two 12-week cycles, was administered at 250 mg/m2 per day. Pending toxicity at the initial dose, CIFU was to be escalated (300 mg/m2) or de-escalated (200 mg/m2). All but one patient entered on this trial completed 24 weeks of adjuvant CIFU+levamisole. Eight patients (57%) completed 24 weeks of therapy with the 2-week scheduled break. One of these 8 patients required a dose reduction without interrupting the schedule. Six patients had toxicity from the CIFU, which obliged us to interrupt the schedule. Limiting toxicities were stomatitis and hand-foot syndrome. No dose-limiting hematologic toxicity was encountered. Three patients (21%) had catheter problems that required replacement. These data suggest that up to 30% of patients started on this regimen may require dose reduction, shorter infusion courses with rest breaks, or both to complete 24 weeks of adjuvant treatment in order to achieve desired dose intensity.

Phase I clinical trial of pyrazoloacridine NSC366140 (PD115934).

The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the pre-clinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.

Phase I study of monoclonal antibody-ricin A chain immunoconjugate Xomazyme-791 in patients with metastatic colon cancer.

The immunoconjugate XMMCO-791/RTA consists of ricin A chain bound to a murine monoclonal antibody MoAb 791T. This monoclonal antibody (MoAb) binds to a glycoprotein of 72 kD, which is expressed on human colorectal carcinoma, ovarian carcinoma, and osteogenic sarcoma. XMMCO-791/RTA was tested in a Phase I trial with proposed dose escalation steps of 0.02, 0.04, 0.15, and 0.2 mg/kg per day. Twelve patients with metastatic colorectal carcinoma were treated at 0.02, 0.03, and 0.04 mg/kg per day dose levels administered over 1 hour on days 1-5. Study-related toxicities were hypotension (6 patients); greater than 10% weight gain (6 patients); peripheral edema (9 patients); fever (4 patients); confusion (3 patients); diarrhea (3 patients); proteinuria, as identified by dipstick (3 patients), greater than 0.6 mg/dl decrease in serum albumin (11 patients); greater than 25% decrease in oncotic pressure (10 patients), and a decrease in ionized calcium (8 patients). Six patients received a second course of treatment. HAMA levels developed in 9 patients and titers increased with number of courses administered. Decreased overall toxicity, in comparison to the first course, was noted, but one patient had an allergic-type response (hypotension, crushing chest pain, diaphoresis) after the test dose of the second course (HAMA level > 10,000 IgG). Life-threatening toxicity in the form of fluid shift, resulting in noncardiac pulmonary edema and third-spacing occurred after course 1 in 1 of 3 patients at the 0.04 mg/kg per day level. No further dose escalation was attempted and no antitumor activity was seen.

A phase II trial of piroxantrone in advanced ovarian carcinoma after failure of platinum-based chemotherapy: Southwest Oncology Group Study 8904.

A phase II trial of the new anthrapyrazole piroxantrone was conducted by the Southwest Oncology Group in advanced ovarian carcinoma. The objective were to evaluate its response rate and toxicity in patients who had disease persistence, progression, or recurrence either during or after platinum-containing chemotherapy. A two-stage statistical design targeted accrual to 15 eligible patients if no responses were observed. The piroxantrone starting dose was 120 mg/m2, with the provision to escalate to 150 and 180 mg/m2. There were 16 eligible patients, all of whom had received either one (12 patients) or two (4 patients) prior platinum-containing regimens; one patient had received doxorubicin. Fourteen of the 16 patients were enrolled either at the time of disease persistence/progression during initial chemotherapy or with recurrence or progression within 6 months of the previous platinum-based remain. One to 5 cycles of piroxantrone were given. Dose escalation was feasible in 7 patients but was prevented in the other 9 by neutropenia. Maximum toxicity for all cycles was none or grade 1 in 2 patients; grade 2, 5; grade 3, 8; and grade 4, 1. All but one of the grade 3 or 4 events was from myelosuppression; there were no adverse cardiac events. No responses were observed. Thus, piroxantrone appears inactive in patients with persistent, progressive, or recurrent ovarian cancer who recently had received a platinum-based regimen.

Adjuvant continuous infusion 5-FU, whole-abdominal radiation, and tumor bed boost in high-risk stage III colon carcinoma: a Southwest Oncology Group Pilot study.

PURPOSE: Results of a combined modality adjuvant pilot program of low-dose continuous-infusion 5-fluorouracil, whole-abdominal radiation, and tumor bed boost in patients with colon cancer with involved nodes and serosal involvement are presented. METHODS AND MATERIALS: Forty-one eligible patients with completely resected T3N1-2M0 colon cancer (modified Astler-Coller C2) were treated with 5-fluorouracil (5-FU) at a dose of 200 mg/m2/day by continuous infusion and 30 Gy of concomitant whole-abdominal radiation in 1 Gy fractions. An additional 16 Gy boost to the tumor bed was administered in 1.6 Gy fractions. After completion of combined modality treatment and a 21-day rest period, patients received 4 days of 5-FU at a dose of 1000 mg/m2 by continuous infusion every 28 days for nine cycles. RESULTS: Five-year disease-free and overall survival estimates were 58 and 67%, respectively, for all T3N1-2 patients. Five-year disease-free and overall survival estimates for the 19 patients with four or fewer nodes were both 61%. Five-year disease-free survival and overall survival estimates for the 20 patients with more than four involved nodes were 55% and 74%, respectively (the exact number of involved nodes were unknown for two patients). Disease-free and overall survival estimates for patients treated with 5-FU and radiation compare favorably to the 5-FU plus levamisole arm of the intergroup adjuvant colon study (Int 0035/SWOG 8591) in patients with more than four positive nodes where the 5-year disease-free and overall survival estimates were 35% and 39%, respectively. Disease-free and overall survival estimates for patients with four or fewer nodes in the 5-FU plus levamisole arm of the intergroup study were 64 and 68%, which is not markedly different from results obtained with radiation and 5-FU in the current study. There were no treatment-related fatalities. Seventeen percent of patients had severe and 7% had life-threatening toxicity of any kind. One patient had an acute partial bowel obstruction and two patients had chronic low grade enteritis. CONCLUSION: Continuous infusion 5-FU and whole-abdominal radiation with tumor bed boost should be further investigated in a larger trial of T3N1-2 colon cancer.

Chemoradiotherapy of esophageal carcinoma.

BACKGROUND: Chemoradiotherapy has demonstrated efficacy in esophageal cancer but rarely is curative. To improve local control and decrease metastases, a 7-month regimen was used with standard-dose radiotherapy (RT), cisplatin (DDP), and continuous infusion (CI) 5-fluorouracil (5-FU) in patients with locoregional squamous/adenocarcinoma of the esophagus. METHODS: Initial treatment consisted of RT to the esophagus (4000-5000 cGy) for 5-6 weeks, CI 5-FU (300 mg/m2/day) concurrent with RT, and DDP (25 mg/m2/day x 3) for Days 1-3 and 21-23. Two monthly cycles of DDP (75 mg/m2 Day 1) and 5-FU (300 mg/m2 x 21 days) followed. Patients were restaged with endoscopy and computed tomography scan. Patients without evidence of residual disease received three more cycles of chemotherapy (CT); those with persistent tumor underwent esophagectomy or additional CT/RT, and those with disease progression were offered alternative CT. RESULTS: From December 1987 to September 1991, 18 men and 8 women, including 2 with adenocarcinoma, were eligible for inclusion in the study. All were evaluable for toxicity and response. The median age was 61.5 years (range, 50-80 years), the median pretreatment weight loss was 9 lbs, and the median serum albumin level was 4.3 mg%. Therapy was toxic; 19 patients were hospitalized for treatment-related esophagitis, thrombosis, or infection. Grade III and IV leucopenia were seen in 12 patients and 1 patient, respectively. One patient had Grade IV thrombocytopenia. Of 26 patients, 17 (65%) had no tumor on restaging. Five patients had recurrences in the esophagus (1), liver (3), and lung (2). Three patients had second neoplasms. The median survival was 24 months. CONCLUSION: This treatment regimen provides high frequency of local tumor resolution, but with significant toxicity.

Response rates--an evolution.

The documented frequency of response of cancers to common chemotherapy agents and combinations appears to have decreased over the decades. Multiple reasons exist for this decline including: changes in eligibility and evaluability criteria; changes in the type of patients entered onto trial; and, altered criteria for response and methods for response assessment. The disinclination to publish negative results also permits a bias in a favor of overestimating a drug's efficacy. Circumspection now is advised in assessing data from older trials.

Hepatoma/merbarone. A Southwest Oncology Group study.

Sixteen eligible patients with hepatocellular carcinoma, previously untreated, received merbarone 1000 mg/m2/d for five consecutive days every 21 days. No complete or partial response to treatment was obtained. Seven patients had grade 4 granulocytopenia. One patient died with renal failure. Merbarone in this dose and schedule was ineffective in the treatment of hepatocellular carcinoma.

GM-CSF, carboplatin, doxorubicin: a phase I study.

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m2, administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1-21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m2, 325 mg/m2 and 400 mg/m2. At carboplatin 400 mg/m2 and doxorubicin 60 mg/m2, thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m2, doxorubicin 60 mg/m2, and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.

Randomized clinical trial of mitomycin-C with or without pretreatment with WR-2721 in patients with advanced colorectal cancer.

The use of mitomycin for metastatic colorectal cancer has been limited by mitomycin's myelosuppressive potential. The objective of this randomized study was to determine whether WR-2721 would decrease the hematologic toxicity of mitomycin in patients with colorectal cancer resistant to fluorouracil-based therapy. Ninety-seven patients with refractory colorectal cancer were randomized to receive either mitomycin 20 mg/m2 only or the same dose of mitomycin after pretreatment with WR-2721, 910 mg/m2. The principal toxicity in both groups was thrombocytopenia. The platelet nadirs were lower in patients receiving single-agent mitomycin (P = 0.026). Surprisingly, no clinical complete or partial responses were noted in either group, and survival was not different between the two groups. Thus, while WR-2721 decreased the thrombocytopenia associated with mitomycin therapy, mitomycin was ineffective in the treatment of refractory colorectal carcinoma.

Amonafide treatment of refractory esophageal cancer. A Southwest Oncology Group study.

Amonafide, a synthetic benzisoquinolinedione, was evaluated for treatment of squamous esophageal cancer. Eleven men and 5 women were eligible with a median performance status of 1 and median age of 63 years. Six had no prior treatment. All patients had measurable disease. Therapy consisted of amonafide 300 mg/m2d days 1-5 every 21 days. Thirty-five courses of therapy were delivered. The median number of courses received was two. Sixteen patients are evaluable for toxicity. Thirteen are evaluable for response. Toxicity was severe. Seven patients were hospitalized for toxicity. Six patients had grade IV granulocytopenia; two, grade IV thrombocytopenia. Angioedema developed in one patient; severe exfoliative dermatitis in another. A single partial response, with the decrease in size a supraclavicular node, was noted in a previously untreated patient. Amonafide, in this dose and schedule, is associated with occasionally severe toxicity precluding its likely use in squamous cell esophageal carcinoma.

Difluorodeoxycytidine (dFdC)--gemcitabine: a phase I study.

Difluorodeoxycytidine (dFdC) demonstrated broad spectrum activity in preclinical models. A phase 1 study utilizing twice weekly injections was conducted in 50 eligible and evaluable patients. Twenty-nine patients received drug by 30 minute infusion at doses of 5-90 mg/m2 and 22, by 5 minute bolus at 30-150 mg/m2. The primary dose limiting toxicities were marrow suppression and flu-like symptomatology. Thrombocytopenia was dose limiting at 75 mg/m2 on the infusion schedule and 150 mg/m2 on the 5 minute schedule. Flu-like symptoms with fever, rigors and malaise occurred the day of injection in many patients. One patient with renal cell carcinoma attained a partial response. Evaluation of the drug's efficacy and schedule dependency continue.