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Results for “Maximum Tolerated Dose”

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PubMed2002

Irinotecan and gemcitabine in patients with solid tumors: phase I trial.

Using a day 1 and 8, every-3-week schedule, our purpose was to determine the maximum tolerated dose of irinotecan (CPT-11, Camptosar) that can be administered immediately after gemcitabine (Gemzar) at a dose of 1,000 mg/m2 IV. In this phase I trial, the maximum tolerated dose was defined as the dose level immediately below the level in which two of the first three patients in any cohort, or at least two of six patients in any expanded cohort, experienced dose-limiting toxicity. Dose-limiting toxicity pertained only to toxicity during the first cycle of treatment. Escalation of irinotecan was planned in groups of three patients, with three additional patients added at the first indication of dose-limiting toxicity. A total of 19 patients have been enrolled. Grade 4 diarrhea was the dose-limiting toxicity at the irinotecan dose of 115 mg/m2. Hematologic toxicity was not dose limiting. Three patients required canceling of the day 8 dose due to grade 3 myelosuppression. Three patients, two with pancreatic cancer and one with metastatic carcinoma of unknown primary, had a partial response. The maximum tolerated dose of irinotecan in this combination was 100 mg/m2/dose. The dose-limiting toxicity was diarrhea. The maximum tolerated dose is the recommended starting dose for phase II studies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs.

OBJECTIVES: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs. STUDY DESIGN: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria. RESULTS: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs. CONCLUSIONS: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

Adult↗

PubMed1995

Update: the M.D. Anderson Cancer Center experience with paclitaxel in the management of breast carcinoma.

The first of three trials at M.D. Anderson Cancer Center investigating paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in metastatic breast cancer was a phase II study involving 25 patients (297 courses) previously treated with only one chemotherapy regimen; the patients received paclitaxel 250 mg/m2 infused over 24 hours without granulocyte colony-stimulating factor (G-CSF). Complete (12%) and partial responses (44%) led to median durations of response and survival of 9 and 21 months, respectively. The median paclitaxel dose was 200 mg/m2. Despite profound neutropenia (median granulocyte count of 0.3 cells x 10(9)/L for the first three courses), infection occurred in 42% of patients but only 6% of courses. In a phase I trial of paclitaxel 125 mg/m2 over 24 hours followed by doxorubicin 60 mg/m2 using G-CSF at 5 micrograms/kg days 5 through 19, dose-limiting mucositis with neutropenic fever occurred at the starting dose, so the maximum tolerated dose was one dose lower: paclitaxel 125 mg/m2 (over 24 hours) followed by doxorubicin 48 mg/m2 over 48 hours. Among 10 patients, there was one complete response and seven partial responses (overall response, 80%). Suspecting a schedule-dependent interaction between drugs, a phase I trial of the reverse sequence yielded a maximum tolerated dose, defined by neutropenic fever without mucositis, of doxorubicin 60 mg/m2 (over 48 hours) followed by paclitaxel 150 mg/m2 (over 24 hours) in 21 patients. A pharmacokinetic study in which the sequence of administration of paclitaxel over 24 hours and doxorubicin over 48 hours was alternated in courses 1 and 2 indicated that when paclitaxel by 24-hour infusion is given first, doxorubicin plasma levels at the end of infusion were an average 70% higher and doxorubicin clearance was reduced approximately 30% compared with the reverse sequence. Similarly, the incidence of grade 2 or 3 mucositis was 70% with the paclitaxel/doxorubicin sequence versus only 10% with the reverse sequence. We concluded that paclitaxel slows doxorubicin metabolism and that when used together in this schedule, doxorubicin should precede paclitaxel. In the third trial paclitaxel without G-CSF was administered to two groups of heavily pretreated patients: (1) those with only two prior chemotherapy regimens (inclusive of adjuvant therapy) received paclitaxel 175 mg/m2 over 24 hours and (2) those with three or more prior regimens received paclitaxel 150 mg/m2 over 24 hours. Response rates in both regimens were approximately 20%. We conclude that paclitaxel has significant antitumor activity in metastatic breast cancer, especially in patients with limited prior therapy, without need for G-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed2001

Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia.

Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity against malignant myeloid cells (ID(50), 1-2 mM). Higher doses induce apoptosis. Patients with myelodysplasia (n = 11) and acute myeloid leukemia (n = 16) were treated with PB as a 7-day continuous infusion repeated every 28 days in a Phase I dose escalation study. The maximum tolerated dose was 375 mg/kg/day; higher doses led to dose-limiting reversible neurocortical toxicity. At the maximum tolerated dose, PB was extremely well tolerated, with no significant toxicities; median steady-state plasma concentration at this dose was 0.29 +/- 0.16 mM. Although no patients achieved complete or partial remission, four patients achieved hematological improvement (neutrophils in three, platelet transfusion-independence in one). Other patients developed transient increases in neutrophils or platelets and decrements in circulating blasts. Monitoring of the percentage of clonal cells using centromere fluorescence in situ hybridization over the course of PB administration showed that hematopoiesis remained clonal. Hematological response was often associated with increases in both colony-forming units-granulocyte-macrophage and leukemic colony-forming units. PB administration was also associated with increases in fetal erythrocytes. These data document the safety of continuous infusion PB and provide preliminary evidence of clinical activity in patients with myeloid malignancies.

Acute Disease↗

PubMed2003

Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer.

PURPOSE: The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer. PATIENTS AND METHODS: Nineteen patients were treated. Gemcitabine 1,000 mg/m(2) was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m(2), escalated to a targeted dose of 50 mg/m(2) using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest. RESULTS: Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m(2) cisplatin dose level. Patients treated at 30 and 40 mg/m(2) cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis. CONCLUSION: Cisplatin at doses up to 40 mg/m(2) may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.

Aged↗

PubMed2006

Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity.

A comparative approach to the differences between systemic toxicity and developmental neurotoxicity of organophosphates is critical to determine the degree to which multiple mechanisms of toxicity carry across different members of this class of insecticides. We contrasted neuritic outgrowth and cholinergic synaptic development in neonatal rats given different organophosphates (chlorpyrifos, diazinon, parathion) at doses spanning the threshold for impaired growth and viability. Animals were treated daily on postnatal days 1-4 by subcutaneous injection so as to bypass differences in first-pass activation to the oxon or catabolism to inactive products. Evaluations occurred on day 5. Parathion (maximum tolerated dose, 0.1 mg/kg) was far more systemically toxic than was chlorpyrifos or diazinon (maximum tolerated dose, 1-5 mg/kg). Below the maximum tolerated dose, diazinon impaired neuritic outgrowth in the forebrain and brainstem, evidenced by a deficit in the ratio of membrane protein to total protein. Diazinon also decreased choline acetyltransferase activity, a cholinergic neuronal marker, whereas it did not affect hemicholinium-3 binding to the presynaptic choline transporter, an index of cholinergic neuronal activity. There was no m(subscript)2(/subscript)-muscarinic acetylcholine receptor down-regulation, as would have occurred with chronic cholinergic hyperstimulation. The same pattern was found previously for chlorpyrifos. In contrast, parathion did not elicit any of these changes at its maximum tolerated dose. These results indicate a complete dichotomy between the systemic toxicity of organophosphates and their propensity to elicit developmental neurotoxicity. For parathion, the threshold for lethality lies below that necessary for adverse effects on brain development, whereas the opposite is true for chlorpyrifos and diazinon.

Animals↗

PubMed2002

Pegylated liposomal doxorubicin with vinorelbine in metastatic breast carcinoma. A phase I-II clinical investigation.

A multicenter phase I-II trial was carried out with the aim of identifying the dose-limiting toxicity and the maximum tolerated dose of vinorelbine (VNR) in combination with pegylated liposomal doxorubicin at a dose of 20 mg/m(2) every 15 days in patients with metastatic breast carcinoma. In the phase I part of the trial, VNR was given at a dose of 20 mg/m(2) every 15 days to a group of 3 patients. In absence of unacceptable toxicity, VNR was escalated to 25, 30, and 35 mg/m(2) for subsequent groups of 3 patients, until the dose-limiting toxicity was reached. No case of palmar-plantar erythrodysesthesia was recorded in these patients. Grade 4 neutropenia, grade 3 thrombocytopenia, and grade 3 mucositis were the dose-limiting toxicities recorded in patients treated with VNR 35 mg/m(2). These side effects caused a substantial decrease in programmed dose intensity. Therefore 30 mg/m(2) was considered the maximum tolerated dose of VNR in combination with pegylated liposomal doxorubicin 20 mg/m(2), both given every 15 days. These dosages were employed for the treatment of further 18 patients included in phase II of the study. The overall response rate, calculated according to an intention to treat analysis, was 63% (95% CI: 44-80%), with 2 patients achieving a complete response. The median time to progression was 7.0 months or more (range 2-14 months). Median duration of objective responses was 8.4 months or more. The duration of the 2 complete responses was 9 and 14 months, respectively. Median duration of survival was 16.0 months or more (range from 4.0 to >or=24.0). Toxicity was generally mild and easily manageable. Neutropenia and mucositis were the most frequently recorded side effects. A case of palmar-plantar erythrodysesthesia was recorded in phase II of the study. In conclusion, the maximum tolerated dose of VNR in association with pegylated liposomal doxorubicin is 30 mg/m(2) on a bimonthly schedule. Moreover, the combination of VNR and pegylated liposomal doxorubicin is active against metastatic breast carcinoma and is associated with a good toxicity profile. Further studies with this combination regimen are warranted.

Adult↗

PubMed2002

A Phase I study of bizelesin (NSC 615291) in patients with advanced solid tumors.

PURPOSE: To evaluate the toxicities, characterize the pharmacokinetics, and determine the maximum-tolerated dose of bizelesin administered once every 4 weeks. PATIENTS AND METHODS: Patients with advanced solid tumors received escalating doses of bizelesin as an i.v. push every 4 weeks. Pharmacokinetic studies were performed with the first treatment cycle. RESULTS: Nineteen eligible patients received a total of 54 courses of bizelesin at doses ranging from 0.1 to 1 microg/m(2). Dose-limiting toxicity of neutropenia was seen in 2 of 4 patients treated at the 1 microg/m(2) dose level. Nonhematological toxicity was generally mild with maximum toxicity being <or= grade 2 per National Cancer Institute Common Toxicity Criteria. No objective responses were seen in the 19 eligible patients. An L1210 bioassay was used to determine bizelesin plasma levels. The terminal elimination half-life was 140 min at the recommended Phase II dose. The area under the concentration time curve increased in proportion to administered dose, and the clearance remained constant over the dose range studied. Correlation analysis demonstrated relationships between dose and area under the concentration with cycle 1 hematological parameters, including absolute neutrophil and leukocyte nadirs. CONCLUSION: Bizelesin administered every 4 weeks as an i.v. push is well tolerated with dose-limiting toxicity of neutropenia. The maximum-tolerated dose (and recommended Phase II dose) is 0.8 microg/m(2) administered once every 4 weeks.

Adult↗

PubMed1993

Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor.

BACKGROUND: Topotecan has been shown in previous studies to be a specific inhibitor of topoisomerase I, a nuclear enzyme required for DNA replication and transcription. PURPOSE: Our objectives in this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxic effects, and recommended phase II dose of topotecan and to define the pharmacokinetics of topotecan in humans. METHODS: Forty-three patients with advanced, incurable solid tumors were treated. Doses ranged from 0.5 to 2.0 mg/m2 daily for five days [corrected], with treatment cycles repeated initially every 28 days. Following the identification of the standard maximum tolerated dose, further dose escalations were attempted by following topotecan cycles with recombinant granulocyte colony-stimulating factor (rG-CSF). RESULTS: The maximum tolerated dose without rG-CSF for patients without prior cytotoxic therapy was 1.75 mg/m2 daily. The maximum tolerated dose for previously treated patients was 1.50 mg/m2 daily. The dose-limiting toxic effect was myelosuppression, with granulocytopenia being most commonly observed. Use of rG-CSF did not permit topotecan dose intensification, since thrombocytopenia and fatigue rapidly emerged as dose-limiting toxic effects. Plasma half-lives of topotecan (lactone form) were approximately 10 and 100 minutes for distribution and elimination phases, respectively. CONCLUSIONS: The doses of topotecan recommended for use in phase II clinical trials in solid tumors are 1.5 and 1.25 mg/m2 daily in previously untreated and previously treated patients, respectively. Based on observed rates of recovery from myelosuppression, treatment should be possible on a 21-day cycle. Dose intensification was not possible with the use of rG-CSF; however, rG-CSF may be a useful addition to the regimens of those few patients who experience either prolonged granulocytopenia or neutropenic sepsis or those who are not able to receive their second treatment cycle by day 21.

Adult↗

PubMed1999

Weekly administration of docetaxel (Taxotere): summary of clinical data.

Docetaxel (Taxotere; Rhône-Poulence Rorer, Antony, France) is a highly efficacious antineoplastic agent; however, its administration every 3 weeks produces substantial myelosuppression. Based on recent observations that the administration of paclitaxel on a weekly schedule minimizes myelosuppression, investigation of weekly docetaxel has been initiated. A recently completed phase I study of weekly docetaxel demonstrates markedly decreased myelosuppression with this schedule. The maximum tolerated dose was 43 mg/m2/wk; with this dose, myelosuppression was mild and the dose-limiting toxicity was fatigue/asthenia. Other nonhematologic toxicities were uncommon when doses of less than 40 mg/m2/wk were administered. Edema was not observed, in spite of an abbreviated dexamethasone schedule (8 mg every 12 hours for three doses, beginning 12 hours before docetaxel). A 50% response rate using docetaxel 35 to 40 mg/m2/wk has been achieved in patients with metastatic breast cancer. When used concurrently with radiation therapy, weekly scheduling allowed a maximization of docetaxel dosing, with the maximum tolerated dose being 20 mg/m2/wk. It is likely that this novel schedule of docetaxel will allow the drug to be used with decreased toxicity and will facilitate its incorporation into active combination regimens. Further investigation of this novel schedule of administration is warranted.

Antineoplastic Agents, Phytogenic↗

PubMed1990

Phase I clinical and pharmacological study of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II).

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP) is a liposome dependent cisplatin analogue since the liposome carrier is required for its i.v. administration and for its biological activity. A Phase I study of liposome entrapped NDDP (L-NDDP) was performed using a single i.v. injection every 4 weeks. L-NDDP was prepared and characterized at M. D. Anderson Cancer Center. The maximum tolerated dose of L-NDDP was 312.5 mg/m2. The dose-limiting toxicity was myelosuppression, affecting all three blood cell lineages. The granulocyte nadir occurred on days 14-18, and the platelet nadir consistently earlier (days 11-12). The median day of recovery of blood cell counts was day 21 (range, 18-32). Other toxicities included grade 2 nausea and vomiting, fever consisting of a single temperature spike in most patients, grade 1 diarrhea after 60% of courses, and grade 1-2 malaise lasting for 5-10 days after the infusion in 73% of courses. Transient alanine aminotransferase elevations without clinical relevance were common. No signs of renal dysfunction or ototoxicity were observed. One patient with a preexisting peripheral neuropathy showed some progression of the neuropathy after a cumulative dose of 1605 mg/m2. Except for fever and transient liver dysfunction, no liposome related side effects were observed in spite of the high doses of lipid administered. The blood clearance of L-NDDP fits a two-compartment model at lower doses and a single-compartment model at the maximum tolerated dose, suggesting that saturation of the reticuloendothelial organs occurs at the maximum tolerated dose. Two minimal responses were observed. L-NDDP has a toxicity profile similar to that of carboplatin. Phase II studies to address the issue of how the therapeutic index of platinum compounds is affected by liposome entrapment are being planned.

Antineoplastic Agents↗

PubMed1996

Preliminary report on a phase I study of ifosfamide and vinorelbine (navelbine) in advanced non-small cell lung cancer.

Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a semisynthetic vinca alkaloid, and ifosfamide have each shown activity as a single agent and in various combination-chemotherapy regimens against non-small cell lung cancer. Vinorelbine usually has been given on a once-weekly schedule. We designed a phase I study adding escalating doses of vinorelbine on a novel schedule of 3 consecutive days to ifosfamide in a dose-intensive regimen with granulocyte colony-stimulating factor. The goals were to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine and to document the toxicity profile and the overall response and survival rates observed. Eligibility criteria included histologically or cytologically documented stage IIIB or stage IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 15 mg/m2) on days 1, 2, and 3 and ifosfamide at 2 g/m2 and decreased to 1.6 g/m2 on days 1, 2, and 3. Granulocyte colony-stimulating factor was administered subcutaneously at 5 micrograms/kg on days 5 through 11 in all patients. Cycles were repeated every 21 days. Forty-two patients were treated. The median age was 58 years (age range, 34 to 75 years); 41 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in two of three patients at the initial dose level of ifosfamide 2 g/m2 and vinorelbine 15 mg/m2. Ifosfamide was therefore decreased to 1.6 g/m2, and vinorelbine was subsequently escalated, with a maximum administered dose of 35 mg/m2. The recommended phase II dose was ifosfamide 1.6 g/m2 on days 1, 2, and 3 with vinorelbine 30 mg/m2 on days 1, 2, and 3, given with granulocyte colony-stimulating factor support, on a 21-day cycle. At the recommended phase II dose myelosuppression remained the most common toxic effect, with grade 3 or 4 neutropenia of brief duration occurring in 20 patients. Final analysis has not yet been completed, but responses have been observed at several dose levels. The maximum tolerated dose of vinorelbine given on days 1, 2, and 3 is 30 mg/m2 when given with ifosfamide at 1.6 g/m2 on days 1, 2, and 3 and granulocyte colony-stimulating factor support. Myelosuppression is the dose-limiting toxic effect. Future analyses of the data will report the overall response and survival rates in these patients.

Adult↗

PubMed1995

A phase I/II trial of combination paclitaxel and carboplatin in advanced or metastatic non-small cell lung cancer: preliminary results of an ongoing study.

Because of paclitaxel's (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) high single-agent activity in non-small cell lung cancer we developed a study to determine the maximum tolerated dose and a dose suitable for outpatient phase II/III trials of paclitaxel combined with a fixed dose of carboplatin (area under the concentration-time curve of 6, Calvert formula). From October 1993 to November 1994, 41 patients were entered into this trial, including six at dose level I (paclitaxel 150 mg/m2), six at dose level 2 (paclitaxel 175 mg/m2), II at dose level 3 (paclitaxel 200 mg/m2), 13 at dose level 4 (paclitaxel 225 mg/m2), and five at dose level 5 (paclitaxel 250 mg/m2). Patient characteristics included 27 men and 14 women with a median age of 64 years (age range, 46 to 81 years). The median Southwest Oncology Group performance status was I (range, 0 to 2). Nineteen patients had unresectable stage III and 22 had stage IV non-small cell lung cancer. Forty-one patients and 167 treatment courses were evaluable for toxicity. Hematologic toxicity was generally mild to moderate, not related to paclitaxel dose, and never dose limiting. Thrombocytopenia was remarkably mild, with only one episode of grade 3 toxicity (no grade 4). Arthralgias and cumulative sensory neuropathy were dose related and dose limiting. The maximum tolerated dose was defined at the 250 mg/m2 dose level with three of five patients achieving grade 3 (severe toxicity. The 225 mg/m2 dose level appears to be well tolerated, but accrual at this dose level is ongoing. This appears to be a highly active regimen, with objective responses in 20 (two complete responses and 18 partial responses) of 32 patients with objectively measurable disease for an overall response rate of 62.5%.

Aged↗

PubMed1995

A phase I study of intraperitoneal interferon-alpha 2b and intravenous cis-platinum plus cyclophosphamide chemotherapy in patients with untreated stage III epithelial ovarian cancer: a Gynecologic Oncology Group pilot study.

Previous clinical investigations using interferons (IFNs) have shown activity against epithelial ovarian cancer. The objective of this study was to determine the maximum tolerated dose of intraperitoneal (ip) IFN-alpha 2b which could be administered in combination with intravenous (iv) cis-platinum plus cyclophosphamide chemotherapy. After comprehensive surgical staging and maximal cytoreduction, previously untreated patients with primary ovarian adenocarcinoma were entered at one of five IFN dose levels. IFN-alpha 2b (5-30 x 10(6) units) was administered ip on Day 1 (+/- Day 8). cis-Platinum (75 mg/m2) plus cyclophosphamide (750 mg/m2) were administered iv on Day 2 with prophylactic hydration and anti-emetics. Courses were repeated every 3 weeks for 8 cycles. Adverse effects were recorded using standard Gynecologic Oncology Group toxicity scales. Fifteen patients with mean age 56 years (range 43-73) were entered and received a combined total of 100 treatment cycles. Catheter-related complications occurred in 8 patients, and in three cases lead to catheter removal and discontinuation of ip therapy. Two patients experienced grade 2-3 nephrotoxicity and 1 experienced grade 2 peripheral neuropathy. There was a single episode of chemical peritonitis. Myelosuppression was the dose-limiting toxicity with grade 3-4 leukopenia complicating 6, 5, 12, 11, and 17 cycles at dose levels 1-5, respectively. No patient completed planned treatment without interruption or dose reduction. Planned cis-platinum dose intensity was most compromised at the fifth IFN-alpha 2b dose level. The maximum tolerated dose of IFN-alpha 2b was determined to be 20 x 10(6) units repeated on Days 1 and 8 of this 21-day cis-platinum plus cyclophosphamide chemotherapy cycle.

Adenocarcinoma↗

PubMedDate not supplied

A phase I clinical and pharmacological profile of dacarbazine with autologous bone marrow transplantation in patients with solid tumors.

Dacarbazine (DTIC) is a chemotherapy drug which has antitumor activity at standard doses, exhibits a steep dose-response effect in vitro, and is associated with relatively few non-hematologic toxicities. These characteristics suggest a potential role for this drug in bone marrow transplant preparative regimens. To pursue this hypothesis, 16 patients with refractory solid tumors were enrolled in a phase I study of single agent DTIC to determine the dose of DTIC requiring bone marrow reinfusion and to define the dose-limiting toxicity and maximum tolerated dose when given with autologous bone marrow rescue. Pharmacokinetics were evaluated at the 4394 mg/m2 dose level. The marrow requiring dose was 2000 mg/m2 when given as a single intravenous (i.v.) infusion. The extramyeloid dose-limiting toxicity of DTIC was hypotension, with the maximum tolerated dose of DTIC being 3380 mg/m2 when given with bone marrow transplantation (BMT). Other toxicities were transient and tolerable. At 4394 mg/m2 of DTIC, plasma concentrations declined biexponentially with a terminal half-life of 3 hours. The mean clearance was 10.6 L/hr/m2 with a volume of distribution at steady state of 37.5 L/m2 and a mean maximum plasma concentration of 150 mcg/ml. One patient with melanoma developed a partial response of short duration after receiving 2600 mg/m2 of DTIC. Dacarbazine can be significantly dose escalated with an acceptable toxicity profile, when given with BMT. Future trials should focus on the addition of this drug to current BMT preparative regimens used for the treatment of patients with lymphoma.

Adult↗

PubMed1987

Adenosine-provoked angina pectoris-like pain--time characteristics, influence of autonomic blockade and naloxone.

In a study to characterize the time characteristics and the influence of blockade of beta, cholinergic and opioid receptors on the chest pain induced by adenosine, this agent was given as a bolus into a peripheral vein of six healthy volunteers (4 men) 24-45 years of age. On the first day the maximum tolerable dose was determined in each case. On the second day three doses of adenosine (1/3, 2/3, and a full maximum tolerable dose) and three doses of placebo were given as single blind doses in randomized order. Thereafter metoprolol (10 mg to males, 8 mg to females), followed by 1 mg atropine and then 0.4 mg naloxone were given intravenously. After each agent the test procedure was repeated. Heart rate and atrio-ventricular blocks were recorded by electrocardiography and respiration by dynamic spirometry. One minute after each dose of adenosine, the chest pain was scored. The maximum tolerable dose of adenosine was 8.0-15.9 mg. All subjects experienced angina pectoris-like pain. Following injection, onset of respiratory stimulation, AV-block and chest pain occurred after 14 +/- 4.0, 19 +/- 5.4 and 21 +/- 6.4 s, the differences being highly significant. Maximal respiratory stimulation occurred after 18 +/- 4.6, not statistically different from the onset of AV-block which in its turn occurred earlier (P less than 0.005) than the time for maximal central chest pain, 29 +/- 7.8 seconds. Metoprolol induced a 20% slowing of heart rate. After atropine there was a 30% faster heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed2006

Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.

Animals↗

PubMed2006

Designing dose-escalation trials with late-onset toxicities using the time-to-event continual reassessment method.

PURPOSE: The standard design for phase I trials of combined chemotherapy and radiation, which enters either three or six patients per dose level, has little statistical basis and is subject to opening and closing because of delayed toxicities that disrupt patient accrual. We compared the operating characteristics of this standard design and the time-to-event continual reassessment method (TITE-CRM) for dose-escalation trials of combination chemotherapy and radiation. METHODS: The operating characteristics were determined by Monte Carlo simulation of 60,000 phase I trials. RESULTS: Compared with the standard trial design, in studies with delayed toxicity (ie, where four or more patients are expected to enter onto the study during a single previously enrolled patient's observation for toxicity), TITE-CRM trials are significantly shorter when toxicity observation times are long, treat more patients at or above the maximum-tolerated dose, identify the maximum-tolerated dose (MTD) more accurately, and provide phase II information, but do not expose patients to significant additional risk. Estimation precision and overdose control of TITE-CRM increase as the design assumptions more closely resemble the true state of nature, but are reduced if, for instance, the toxicity of treatment has been grossly underestimated. CONCLUSION: Compared with the standard design, if there is any prior knowledge concerning the toxicity profile of a treatment, TITE-CRM can leverage it to produce more accurate estimates of the MTD and does not expose patients to significant excess risk, but requires timely communication between clinical investigators, data managers, and study statisticians.

Algorithms↗