Phase II trial of trimetrexate for unresectable or metastatic non-small cell bronchogenic carcinoma

Summary We treated 34 chemotherapy-naive patients with stage IIIb or IV non-small cell lung cancer with trimetrexate 150–200 mg/m² intravenously over 30 minutes every two weeks. Six of 31 evaluable patients (19%) achieved a partial response. The major toxic effects from this regimen were myelosuppression, nausea/vomiting, and skin rash. We conclude that this well-tolerated schedule of trimetrexate has significant activity as a single agent against non-small cell lung cancer.     

Phase II study of tiazofurin (NSC 286193) in the treatment of advanced small cell bronchogenic carcinoma

Summary Fourteen evaluable patients with small cell bronchogenic carcinoma received tiazofurin, an inhibitor of inosine monophosphate dehydrogenase, that progressed after one combination chemotherapy. No objective remission was observed at the dosage of 800 mg/m² for 5 consecutive days. Toxicity was moderate.     

A phase II trial of ilmofosine in non-small cell bronchogenic carcinoma

Summary We have conducted a study of ilmofosine (1-hexadecylthio; 2-methoxyethyl-rac-glycero-3-phosphocho-line) in non-small cell bronchogenic carcinoma, using a schedule of continuous infusion for 5 days and a dose of 300 mg/m²/day. Toxicities were gastrointestinal (nausea, vomiting, diarrhea), fatigue and liver function abnormalities. These were severe and resulted in the removal of some patients from study. No consistent pattern of bone marrow suppression was seen. No tumor regressions occurred in 14 evaluable patients including 5 with no prior therapy. We conclude that ilmofosine is inactive in this tumor at this dose and schedule.     

Phase II trial of spirogermanium in advanced non-small cell lung cancer

Summary A phase II trial of spirogermanium was conducted in advanced previously untreated non-small cell lung cancer patients. The drug was given by intravenous infusion 3 times per week for 2 weeks, twice per week for the next 2 weeks, and then weekly. Starting dose was 125 mg/m², and dose escalation of 25 mg/m² per week was required in the absence of toxicity to a maximum dose of 200 mg/m² per infusion. Fifteen eligible patients were treated, and no objective responses were seen. Primary toxicity was neurologic and reversible after withdrawal of the drug. We conclude that spirogermanium is not active against non-small cell lung cancer in the dosage used in this study.     

Phase I study and pharmacokinetics of caracemide (NSC-253272) administered as a short infusion

Summary A Phase I study of caracemide evaluating a short intravenous infusion repeated every 21 days is presented. Patients were entered at 85 mg/m² with subsequent escalation levels of 170, 425, 595, and 795 mg/m². Mild to moderate nausea and vomiting occurred at all dose levels. An apparent allergic reaction was observed at the 425 mg/m² level. A burning pain originating in the mucosal areas of the head and neck, progressing to the chest and abdomen, was noted at the 425 mg/m² level. Because of this observation, the infusion time was extended to 4 h. At the 795 mg/m², this toxicity precluded completion of the 4 h infusion. Pharmacokinetic evaluation disclosed blood levels of 0.74–2.31 g/ml at the 425 mg/m² during the 0.5 h infusion. At the same dose for a 4 h infusion time, blood levels were 0.15–0.18 g/ml. At 595 mg/m² administered as a 4 h infusion, blood levels increased to 0.33 ± 0.14 g/ml. The drug was cleared rapidly from the blood compartment with a half-life of 2.5 min and a total body clearance of 11.5 1/min/m². No partial or complete response was observed. However, an advanced colon carcinoma patient experienced subjective pain relief with a decrease in carcinoembryonic antigen. The dose-limiting toxicity of caracemide using the 4 h infusion was an intolerable burning pain with a maximum tolerated dose of 795 mg/m². Further characterization of this dose-limiting toxicity is required prior to further clinical evaluation of caracemide.     

Phase I–II study of pibenzimol hydrochloride (NSC 322921) in advanced pancreatic carcinoma

Pibenzimol is a fluorescent molecule known to bind to double stranded DNA. It also induces prolongation of the G₂ phase of the cell cycle, inhibition of DNA replication and cessation of the growth of some cells in late S phase after DNA content has been doubled. It has been shown to increase the life span of mice bearing intraperitoneally implanted L1210 and P388 leukemia. These factors coupled with the affinity of pibenzimol for pancreatic tissue led us to conduct a phase I–II trial of pibenzimol hydrochloride in patients with advanced pancreatic cancer. Twenty-six patients were treated with a five day continuous infusion of pibenzimol at a dose ranging from 6–28 mg/m²/d. There were no treatment related deaths. Major toxicity was hyperglycemia which was self-limited. No objective responses were noted.     

Biochemical pharmacology of N-acetyl-N-(methylcarbamoyloxy)-N'-methylurea (caracemide; NSC-253272)

Preclinical pharmacologic studies of caracemide [N-acetyl-N-(methylcarbamoyloxy)-N'-methylurea; CAR] have demonstrated a marked instability of this compound in the presence of either phosphate buffer (pH 7.4) or human plasma. Using [1-14C-acetyl]CAR and [3H-methylcarbamoyloxy]CAR, three CAR degradation products were identified: product A, N-(methylcarbamoyloxy)acetamide; product B: N-(methylcarbamoyloxy)-N'-methylurea; and product C: N-hydroxy-N'-methylurea. CAR degradation in human plasma was demonstrated by high-performance liquid chromatography (HPLC) to occur in a time- and temperature-dependent manner. A 30-min incubation (37 degrees) of CAR (10(-4) M) with human plasma resulted in degradation of more than 55% of parent compound; at 1 hr, more than 75% of original CAR was degraded. Incubation of [1-14C-acetyl]CAR with rat brain homogenate resulted in the formation of 14CO2. This reaction was partially inhibited by coincubation with physostigmine (10(-3) M). CAR inhibited acetylcholinesterase activity in neuroblastoma cells with an IC50 of 14 microM. In mechanism of action studies, CAR was found to inhibit ribonucleotide reductase activity but only at nine times the IC50 of hydroxyurea. In contrast to hydroxyurea, CAR was found to be non-cell-cycle phase-specific and non-cross-resistant with two CHO cell lines resistant to hydroxyurea. These data demonstrate the instability of CAR; moreover, they suggest that its mechanism of cytotoxicity is distinctly different from that of hydroxyurea and that the neurotoxicity associated with CAR administration may be caused in part by inhibition of acetylcholinesterase activity.     

Phase II study of n-methylformamide (NSC 3051) and spirogermanium (NSC 192965) in the treatment of advanced small cell lung cancer

Summary Fifty-four evaluable patients with SCLC previously treated with chemotherapy received either N-methylformamide or spirogermanium. There was one partial response to N-methylformamide. The median survival times for patients treated with N-MF and spirogermanium were 11.7 and 12.6 weeks respectively. Five patients treated with N-MF experienced severe toxicity while four patients treated with spirogermanium experienced severe and life-threatening toxicity.Other participating institutions include: Case Western Reserve University, Cleveland, OH (CA 14548); Chicago Medical School, Chicago, IL (CA 14144); Fox Chase Cancer Center, Philadelpha, PA (CA 18281); Hawaii Medical Association, Honolulu, HI; Mayo Clinic, Rochester, MN (CA 13650); Medical College of Ohio, Toledo, OH; New York University Medical Center, New York, NY (CA 16395); Northwestern University Medical Center, Chicago, IL (CA 17145); Hospital of the University of Pennsylvania, Philadelphia, PA (CA 15488); University of Pittsburgh, Pittsburgh, PA (CA 18653); Roswell Park Memorial Institute, Buffalo, NY (CA 12296); Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL (CA 25988); Natalie Warren Bryant Cancer Center, Tulsa, OK; Vermont Regional Cancer Center, Burlington, VT; University of Wisconsin Clinical Cancer Center, Madison, WI (CA 21076).Dr. Ettinger is an American Cancer Society, Maryland Division, Professor of Clinical Oncology.     

Phase II trial of irofulven (6-hydroxymethylacylfulvene) for patients with advanced renal cell carcinoma

The aim of this study was to determine the antitumor activityof irofulven (6-hydroxymethylacylfulvene) in patients withadvanced renal cell carcinoma (RCC). Eligible patients hadadvanced renal cell carcinoma with bidimensionally measurabledisease, a Karnofsky performance status of at least 70, lifeexpectancy of greater than three months, no prior treatmentwith chemotherapy, and no evidence of brain metastases.Irofulven was administered at a dose of 11 mg/m² by 5-minintravenous infusion, on 5 consecutive days. Cycles wererepeated every 28 days. Thirteen patients were enrolled inthis study and 12 were evaluable for response. Of the twelveevaluable patients, no major responses were achieved. Eightpatients had stable disease as best response. Toxicityincluded myelosuppression and gastrointestinal side effects.At the dose and schedule used in this trial, irofulven did notproduce clinical response in RCC.     

Phase II trial of topotecan in patients with advanced renal cell carcinoma

Summary Fifteen patients with advanced renal cell carcinoma were treated on a phase II trial with topotecan. None of the fourteen evaluable patients achieved a complete or partial response. Myelosuppression was the most common toxicity. Eighty percent (12 of 15) of patients experienced grade III or IV neutropenia and/or anemia. Topotecan is not efficacious in the treatment of advanced renal cell carcinoma.     

Release of methyl isocyanate from the antitumor agent caracemide (NSC-253272)

In recent phase 1 clinical trials, caracemide [N-acetyl-N-(methylcarbamoyloxy)-N-methylurea; NSC-253272] has demonstrated a marked potential to produce severe central nervous system (CNS) toxicity. Recent in vitro studies of this antitumor agent have presented indirect evidence indicating that methyl isocyanate is a likely metabolite which results from incubation of caracemide with either phosphate buffer or human plasma [4]. This report presents evidence that methyl isocyanate is formed from caracemide in a concentration- and time-dependent manner. These data implicate the caracemide-mediated formation of methyl isocyanate as at least a plausible explanation for the CNS toxicity exhibited by this drug.     

Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer

Background Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. Methods Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0–2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m² twice daily was administered orally on days 1–7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). Results Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2–17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1–3 nausea/vomiting, and grade 1–2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 ± 1.66 μg/ml (7.40 ± 4.25 μM; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 ± 0.16 μg/ml and 0.05 ± 0.07 μg/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 ± 0.18 μg/ml, with no correlation between salivary and plasma drug levels. Conclusions Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure.     

A phase II trial of gallium nitrate (NSC #15200) in advanced or recurrent squamous cell carcinoma of the cervix

Twenty-four evaluable patients with advanced, persistent or recurrent squamous cell carcinoma of the cervix were treated with 750 mg/m² of gallium nitrate (NCS # 15200) every three weeks. No patient had prior cytotoxic chemotherapy. Two patients had a partial response (8.3%), ten patients had stable disease (41.7%), and twelve (50%) had increasing disease. The 95% upper confidence bound for response is 24.0%. The major toxicities were nausea, vomiting and anemia. Gallium nitrate has minimal activity in patients with previously untreated squamous cell carcinoma of the cervix.Address for offprints: GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107, USAThe following are participating institutions: University of Alabama at Birmingham (CA 12484), The Oregon Health Sciences Center University*, University of California Medical Center at Los Angeles (CA 13630), University of North Carolina School of Medicine (CA 23073), Bowman Gray School of Medicine of Wake Forest University (CA 21946), The Albany Medical College of Union University (CA 27469), University of Pittsburgh School of Medicine*, Eastern Virginia Medical School (CA 40296), State University of New York at Stony Brook* and Pennsylvania Hospital*. * = Unfunded     

Phase II trial of daily oral etoposide in patients with advanced non-small cell lung cancer

Forty-six previously untreated patients with advanced non-small cell lung cancer (NSCLC) were entered into a Hoosier Oncology Group phase II trial of daily oral etoposide 50 mg/m²/d. The dose limiting toxicity was granulocytopenia. The non-hematologic toxicity was mild, with only 19% of patients developing Grade 3 or 4 leukopenia. Two partial responses of 10 and 16 weeks duration were seen in 43 evaluable patients, for an overall response rate of 4%. We conclude that daily oral etoposide has minimal activity in advanced NSCLC, and does not improve response rates over conventional 1–5 day intravenous etoposide administration.from the Hoosier Oncology Group, the Walther Cancer Institute, Indianapolis, IN; Department of Medicine, Indiana University, Indianapolis, IN, USADr. Einhorn is the Walther American Cancer Society Professor of Clinical Oncology.     

Phase Ⅱ trial of gemcitabine plus cisplatin in patients with advanced non-small cell lung cancer

Aim:

To investigate the pharmacodynamics and pharmacokinetics of gemcitabine (dFdC) administered on d 1 and 5 plus cisplatin administered on d 1 in chemonaive patients with stage IIIB or IV non-small cell lung cancer (NSCLC).

Methods:

In each combination cycle, gemcitabine was administered at a dose of 1250 mg/m² as a 30 min intravenous (iv) infusion on d 1 and 5 followed by cisplatin at a dose of 75 mg/m² as a 3 h iv infusion on d 1 every 3 weeks. There was an interval of 1 h between the two infusions. Clinical response and toxicity of the regimen were observed. Furthermore, the plasma concentrations of gemcitabine (dFdC) and its metabolite (dFdU) at different time points were detected during the first cycle of infusion. Pharmacokinetic software (PKS) was used to estimate the pharmacokinetic parameters of gemcitabine and its metabolite dFdU.

Results:

A total of 28 patients was enrolled in the study. The median age was 54 years (range 27–75 years), and most patients were in good clinical condition. Twenty-seven patients received two or more treatment cycles. The overall clinical response rate was 33.3%. The median overall survival time was 13 months. The estimated median time to tumor progression (TTP) was 6.2 months, and the 1-year survival rate was 55.6%. Toxicities were tolerated. The main toxicity was myelosuppression; 35.7% of patients had grade 3/4 hematologic toxicities and 28.6% had grade 3/4 non-hematologic toxicities, which were commonly gastrointestinal responses. The pharmacokinetic parameters of dFdC and dFdU were not different between pre- and post-administration of gemcitabine on d 1 and 5. dFdU was minimal (0.729±0.637 μg/mL) before gemcitabine was infused on d 5, and gemcitabine was not present.

Conclusion:

The regimen is active and well tolerated in chemonaive patients with advanced NSCLC. After gemcitabine was administered on d 1 and 5, the pharmacokinetic parameters of dFdC and dFdU showed no difference from those before the infusion, and dFdU was minimal before gemcitabine was administered on d 5.     

Phase II trial of fenretinide in advanced renal carcinoma

Summary Purpose: Fenretinide, a synthetic form of retinoid, induced apoptosis even in chemotherapy resistant cell lines. A phase II study was hence conducted to evaluate toxicity and efficacy of fenretinide in metastatic renal cancer. Methods: Eligibility included unresectable or metastatic renal cell carcinoma (RCC), adequate organ function and Zubrod performance status 2. Prior immunotherapy and a maximum of one prior chemotherapy regimen were allowed. Fenretinide was administered at a dose of 900 mg/m² twice daily orally for 7 days in a 21-day cycle. Toxicity was assessed at the start of each cycle, and response every 2 cycles. Results: Nineteen eligible patients enrolled of which fifteen had visceral/bone metastases. Seventeen patients had prior nephrectomy and 11 had prior immunotherapy. 76 cycles of therapy were delivered. Therapy was very well tolerated with few severe toxicities consisting of thrombosis in 1 individual and grade 3 fatigue, nausea and diarrhea in 1 patient. 5 patients had grade 2 nyctalopia and 3 patients had transient grade 2 visual toxicity. No objective responses were noted. Stable disease was seen in seven of nineteen cases (37%, 90% C.I. 0.21–0.59). Median time to progression was 1.5 months and median duration of stable disease was 5.8 months (90% C.I. 3.0–8.4). Median survival was 10 months. Tumor fenretinide levels were obtained in three patients and were in the lower end of the therapeutic range. Conclusion: Fenretinide was well tolerated but demonstrated minimal activity that was consistent with results of intratumoral drug measurements. Strategies are needed that will increase systemic and tumor levels of fenretinide.Supported in part by NCI Cancer Center Support Grant CA-22453.     

Phase II trial of fazarabine in advanced colorectal carcinoma

A total of 15 patients with measurable advanced colorectal adenocarcinoma were prospectively treated with fazarabine (Ara-AC), reconstituted in dimethyl sulfoxide, and administered at a starting dose of 48 mg/m2/day as a continuous intravenous infusion for three days. The dose was repeated every 21 days and dose escalations or reductions were made on the basis of toxicities encountered in the preceding course. No patient achieved either a complete or partial response. Major toxicities encountered were granulocytopenia, thrombocytopenia, nausea, vomiting, anemia, and headache. All toxicities were reversible upon discontinuation of the drug and no life-threatening toxicities occurred. These data indicate that further clinical trials in colorectal carcinoma with this agent and schedule of administration are not warranted.