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  • 1
    Electronic Resource
    Electronic Resource
    Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 493-496 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21–77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (〈65 or 〉65 years) versus dose delivered [〈 the maximum tolerated dose (MTD) vs ≥ the MTD] or toxicity (〈 grade 3 vs ≥ grade 3). Of 344 patients, 81 (23.5%) were 〉65 years old, 34 (9.9%) were ≥70 years old, and 5 (1.5%) were ≥75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged ≥75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686507
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  • 2
    Electronic Resource
    Electronic Resource
    Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 493-496 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21–77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (〈65 or 〉65 years) versus dose delivered [〈 the maximum tolerated dose (MTD) vs ≥ the MTD] or toxicity (〈 grade 3 vs ≥ grade 3). Of 344 patients, 81 (23.5%) were 〉65 years old, 34 (9.9%) were ≥70 years old, and 5 (1.5%) were ≥75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged ≥75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686507
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  • 3
    Electronic Resource
    Electronic Resource
    Combined-modality treatment for stage IIIa (N2) non-small cell lung cancer: A National Cancer Institute Intergroup study (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. S71 
    Details
    ISSN: 1432-0843
    Keywords: Key words Combined-modality treatment ; Stage III A ; NSCLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Induction chemotherapy plus radiotherapy followed by surgery, evaluated in a number of phase II studies, is an effective treatment for patients with stage III A non-small cell lung cancer (NSCLC). The ongoing phase III National Cancer Institute Intergroup study is evaluating concurrent chemotherapy (cisplatin + etoposide)/radiotherapy followed by either surgery or additional radiotherapy followed by 2 additional cycles of chemotherapy in patients with stage III A disease. This study will help define the role of surgery and radiotherapy as part of the multimodality therapy of locoregional advanced NSCLC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800051083
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  • 4
    Electronic Resource
    Electronic Resource
    A phase I trial of trimetrexate glucuronate (NSC 352122) given every 3 weeks: clinical pharmacology and pharmacodynamics (1989)
    Springer
    Cancer chemotherapy and pharmacology 24 (1989), S. 314-320 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Trimetrexate glucuronate (TMTX), a non-classic folate antagonist, has been evaluated clinically on several schedules. We studied TMTX given as an i.v. bolus over 5–30 min every 3 weeks in 44 patients with advanced solid tumors; it was given at doses ranging from 20 to 275 mg/m2. The maximal tolerated dose (MTD) on this schedule is 220 mg/m2, which we also recommend as a starting dose for phase II studies in patients without extensive prior therapy. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for non-toxic patients. The principal dose-limiting toxicity was myelosuppression, although in some patients a flu-like syndrome precluded dose escalation. Significant rash and mucositis also frequently occurred in toxic patients. TMTX plasma concentrations were measured after the first dose and the data were fit by two-or three-compartment mammillary pharmacokinetic models. The TMTX clearance rate was 36.5±21 ml/min per m2 and did not change with dose; non-linearities with increasing dose were apparent in the steady-state volume of distribution (VSS) and in the terminal disposition half-life (t 1/2). The difference between pre-treatment and nadir leucocyte counts was correlated with TMTX dose (r=0.58; P=0.0006) and with the area under the concentration vs time curve (AUC) (r=0.41; P=0.02). Pre-treatment plasma albumin concentrations correlated weakly with the nadir white blood count (r=-0.36; P=0.047). Optimal schedules for the administration of TMTX have not been established and phase II trials using both bolus and daily x5 schedules are under way.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00304765
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  • 5
    Electronic Resource
    Electronic Resource
    Assessment of N-methylformamide (NMF) administered orally on a three times weekly schedule: a phase I study (1989)
    Springer
    Investigational new drugs 7 (1989), S. 317-325 
    Details
    ISSN: 1573-0646
    Keywords: N-methylformamide ; oral ; phase I ; toxicity ; reassessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This phase I study was conducted to reevaluate the dose-limiting toxicities, maximum tolerated (MTD) and recommended phase II doses of oral NMF administered on a three times weekly schedule for 4 out of every 6 weeks. This schedule was based on the observation that prolonged administration of NMF was associated with the most efficacious antitumor activity in preclinical studies. Phase II trials that employed a starting dose of 800 mg/m2, determined in a previous phase I trial, were suspended because of frequent and severe toxicities. In the current study, a symptom complex characterized by nausea, vomiting, and malaise was the dose-limiting toxicity of oral NMF administered on this schedule. Other toxicities included hepatic enzyme elevations, mild myelosuppression, and worsening of preexistent toxic peripheral neuropathies. Of interest, three patients who were asymptomatic prior to treatment, rapidly developed symptoms of increased intracranial pressure after starting NMF; and, computerized tomographic brain scans revealed metastatic tumors with significant peritumoral edema. NMF was well tolerated at 600 mg/m2, however, an abrupt increase in toxicity resulted when the dose was increased to 700 mg/m2. Although NMF peak plasma concentrations (Cmax) and areas under the plasma disappearance curves (AUC) differed between the 600 and 700 mg/m2 dose levels, these differences were not striking, and similar NMF plasma concentrations and exposures were well tolerated during intravenous trials. Based on this study, the recommended phase II dose for oral NMF administered three times weekly for 4 of 6 weeks was 600 mg/m2. Cmaxs and AUCs at this dose were significantly lower than those that were demonstrated to induce cytotoxicity, and differentiating, chemosensitizing, and radiosensitizing effects in preclinical studies suggesting that further clinical evaluations of NMF may not be warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173761
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  • 6
    Electronic Resource
    Electronic Resource
    Phase II study of n-methylformamide (NSC 3051) and spirogermanium (NSC 192965) in the treatment of advanced small cell lung cancer (1990)
    Springer
    Investigational new drugs 8 (1990), S. 183-185 
    Details
    ISSN: 1573-0646
    Keywords: n-methylformamide ; spirogermanium ; small cell lung cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00177255
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  • 7
    Electronic Resource
    Electronic Resource
    Phase II Studies (1990)
    Springer
    Investigational new drugs 8 (1990), S. 289-294 
    Details
    ISSN: 1573-0646
    Keywords: menogaril ; phase II ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eighteen women with metastatic breast cancer previously untreated with chemotherapy were entered on a phase II trial of intravenous menogaril, a new anthracycline derivative. Treatment was given at 140 mg/m2 on days 1 and 8 of each 28 day cycle. The most common toxicities were leukopenia in all patients and burning and phlebitis at infusion sites in 72%. Serial assessment of cardiac function by resting and stress gated blood pool scans showed temporary decrements in ejection fraction in only 2 patients (11%). The response rate to the therapy was 19% [95% CI 0–38%] including 1 complete and 2 partial responses. The median time to relapse among responders was 6.5 months. Mean survival in all patients entered was 15.8 months from date of entry. Menogaril at this dose and schedule has modest activity as first line therapy for metastatic breast cancer but also has significant marrow and local toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171839
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  • 8
    Electronic Resource
    Electronic Resource
    Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer (1997)
    Springer
    Investigational new drugs 15 (1997), S. 129-138 
    Details
    ISSN: 1573-0646
    Keywords: paclitaxel ; carboplatin ; phase I ; lung cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m2 followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m2, which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m2 as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005821125290
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  • 9
    Electronic Resource
    Electronic Resource
    A phase II study of Didemnin B (NSC 325319) in advanced malignant melanoma: an Eastern Cooperative Oncology Group study (PB687) (1998)
    Springer
    Investigational new drugs 16 (1998), S. 259-263 
    Details
    ISSN: 1573-0646
    Keywords: Didemnin B ; malignant melanoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Purpose: Didemnin B is a novel marine natural product cyclic depsipeptide containing unusual amino acid moieties. This agent demonstrates promising preclinical antitumor activity, including activity against B16 melanoma and against melanoma isolates in the human tumor stem cell assay. Methods: We conducted a phase II study of Didemnin B, given in Cremophor, at a starting dose of 4.2 mg/m2/IV q 28 days. Patients with measurable metastatic or advanced malignant melanoma were eligible. All patients were previously untreated with chemotherapy and had performance status 0 or 1. Doses were escalated to 4.9 and 5.6 mg/m2 in cycles 2 and 3, respectively. Results: Nineteen patients were entered and treated with a median of one cycle per patient. Eight of these patients went off study for toxicity including 7 with anaphylactoid reactions in the first or second cycle. One patient went off study after 3 cycles with severe myopathy, a newly described toxicity. Two were not evaluable for response and five were considered stable, including one patient with a transient PR of soft tissue disease in the first cycle. Another patient had stable disease for twelve cycles before progressing and one went off study electively after 3 cycles, for a total of 7 patients with stable disease. One patient with a measurable partial remission (PR) and went off study after three cycles due to severe myopathy, a then newly-described toxicity. No hematologic toxicity was seen. Nausea and vomiting were controlled with anti-emetics. Conclusions: This study was indeterminate with respect to the activity of Didemnin B in melanoma. Signs of activity were seen, particularly in soft tissue masses, though a large number of patients could not be evaluated fully for activity due to the occurrence of anaphylactoid reactions. This study does not preclude a clinically important level of activity for Didemnin B.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006110431250
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