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Results for “Maximum Tolerated Dose”

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At least 109 records · Page 6Linked to original sources

PubMed2005

Radioimmunotherapy of prostate cancer using 90Y- and 177Lu-labeled J591 monoclonal antibodies: effect of multiple treatments on myelotoxicity.

PURPOSE: Bone marrow is the dose-limiting organ in radioimmunotherapy. Fractionated dose regimens may decrease myelotoxicity and increase greater total administered dose. We have studied the effect of two or three treatments of 177Lu-J591 and 90Y-J591 monoclonal antibodies (mAb) on myelotoxicity. EXPERIMENTAL DESIGN: J591 is a deimmunized anti-PSMA mAb. Seven groups of patients with prostate cancer (n = 35) received 10 to 75 mCi/m2 of 177Lu-J591 and five additional groups (n = 28) received 5 to 20 mCi/m2 of 90Y-J591. Fifteen patients received two to three treatments of 177Lu-J591 (30, 45, or 60 mCi/m2) and four patients received two or three doses of 90Y-J591 (17.5 or 20 mCi/m2). Re-treatment consisted of patients receiving the same 177Lu or 90Y dose as their initial cycle. Time between treatments was 2 to 4 months. RESULTS: The single dose maximum tolerated dose was 70 mCi/m2 with 177Lu-J591 and 17.5 mCi/m2 with 90Y-J591. With a single dose of 177Lu, no severe toxicity was observed below 60 mCi/m2. With 177Lu, two doses of 45 or 60 mCi/m2, totaling 90 to 120 mCi/m2, proved to be quite toxic. Three doses of 30 mCi/m2 (total 90 mCi/m2), however, were well tolerated. With 90Y, four patients tolerated two to three doses of 17.5 or 20 mCi/m2. Thrombocytopenia increased at higher doses and after repeat treatments. At higher doses, the nadir was lower and the time to reach nadir was longer. Time for recovery of platelets seems related to the total dose. CONCLUSIONS: Multiple (two or three) administrations of 177Lu-J591 (30-60 mCi/m2) or 90Y-J591 (17.5 mCi/m2) over a 4- to 6-month period were tolerated by the patients with manageable thrombocytopenia. Although a single large dose may deliver optimal radiation dose to kill a larger fraction of tumor cells, fractionated therapy offers the advantage of lower myelotoxicity and prolonged tumor response. With 177Lu-J591, dose fractionation in combination with taxanes should be considered as an alternative approach to achieve optimal therapeutic efficacy in patients with prostate cancer.

Antibodies, Monoclonal↗

PubMed2001

Receptor-mediated radiotherapy with 90Y-DOTA-D-Phe1-Tyr3-octreotide.

A newly developed somatostatin radioligand, DOTA-[D-Phe1-Tyr3]-octreotide (DOTATOC), has been synthesised for therapeutic purposes, because of its stable and easy labelling with yttrium-90. The aim of this study was to determine the dosage, safety profile and therapeutic efficacy of 90Y-DOTATOC in patients with cancers expressing somatostatin receptors. We recruited 30 patients with histologically confirmed cancer. The main inclusion criterion was the presence of somatostatin receptors as documented by 111In-DOTATOC scintigraphy. 90Y-DOTATOC was injected intravenously using a horizontal protocol: patients received equivalent-activity doses in each of three cycles over 6 months. The first six patients received 1.11 GBq per cycle and the four successive groups of six patients received doses increasing in 0.37-GBq steps. Toxicity was evaluated according to WHO criteria. No patient had acute or delayed adverse reactions up to 2.59 GBq 90Y-DOTATOC per cycle (total 7.77 GBq). After a total dose of 3.33 GBq, one patient developed grade II renal toxicity 6 months later. The maximum tolerated dose per cycle has not yet been reached, although transient lymphocytopenia has been observed. Total injectable activity is limited by the fact that the maximum dose tolerated by the kidneys has been estimated at 20-25 Gy. Complete or partial tumour mass reduction occurred in 23% of patients; 64% had stable and 13% progressive disease. It is concluded that high activities of 90Y-DOTATOC can be administered with a low risk of myelotoxicity, although the cumulative radiation dose to the kidneys is a limiting factor and requires careful evaluation. Objective therapeutic responses have been observed.

Adult↗

PubMed2001

[Renal protection with amifostine during intraoperative peritoneal chemohyperthermia (IPCH) with cisplatin (CDDP) for peritoneal carcinosis. Phase 1 study].

BACKGROUND: An innovative approach to peritoneal neoplasm therapy is based on the surgical exeresis of visceral neoplasms, peritonectomy and lastly perfusion of the abdominal cavity with cytostatic drugs in hypothermia (1PCH). Cisplatin (CDDP) is one of the most frequently used drugs for peritoneal perfusion owing to its excellent synergy with hypothermia, reduced ability to penetrate the peritoneal- plasma barrier and its demonstrated efficacy against the majority of neoplasms causing peritoneal carcinosis. A major restriction is that CDDP causes renal toxicity. In order to minimise the risk of renal damage, the authors studied the use of amifostin to protect the renal system. A phase-1 study was performed to find the dose of amifostin that guarantees effective renal protection without causing hypotension. METHODS: A total of 67 cytoreductions were performed at our centre associated with abdominal cavity perfusion using cytostatic compounds in hyperthermia (1PCH) with CDDP for peritoneal carcinosis. Among the first 9 patients undergoing IPCH without nephroprotection, Grade 2 (WHO) renal toxicity was observed in 4 cases (44%) and Grade IV-WHO toxicity in one patient (11%) leading to hemodialysis and death. Arnifastin was then administered to 18 patients. The administration protocol was as follows: cytoreduction, im. administration of amifostin 910 mg/m2 in 15 minutes, execution of IPCH. All patients treated using this dose presented hypotension with systolic arterial pressure <70 mmHg and amifostin administration was consequently suspended. Amifostin was then administered to a further 18 patients divided into groups of three. The dose used for the first triplet was 400 mg/m2; we then increased the dose by 50 mg/m2 in each subsequent triplet. The maximum dose tolerated was 50 mg/m2 less than the initial dose that caused systolic pressure to fall below 70 mmHg. RESULTS: Patients treated with doses = or <500 mg/m2 did not present hypotension and it was therefore possible to administer the entire dose. Patients treated with 600 mg/m2 of amifostin all presented hypotension <70 mg Hg, leading to the suspension of the drug. A new triplet of patients was treated at a dose of 550 mg/m2 and none showed hypotension. Taking 550 mg/m2 as the maximum tolerable dose, a further 22 patients then received amifostin infusion with 550 mg/m2 prior to IPCH. Creatinemia was assayed daily for two weeks and creatinine clearance was measured twice a week to evaluate the efficacy of nephroprotection. None of the patients treated with amifostin during the study died from causes correlated to renal failure: 1 patient died from TEP and 1 from septic shock. No patient treated with a dose of 550 mg/m2 developed arterial hypotension. None of the 18 patients in the dose-finding study presented postoperative creatinemia >1.6 (WHO grade 1 toxicity). In the group of 22 patients treated later, 2 cases (9%) presented creatinemia >1.6 (1.8 and 2.1) for a few days; both had undergone severe debulking and one of the patients subsequently underwent resection and anastomosis of the left renal artery invaded by the neoplasm. CONCLUSIONS: Some patients undergoing cytoreduction+IPCH without the use of amifostin developed severe renal toxicity; acute renal failure occurred in 1 patient requiring hemodialysis and was the main cause of death. None of the 28 patients treated with amifostin 550 mg/m2 developed hypotension or renal insufficiency; only 2 cases showed a slight transient increase in renal function markers. Amifostin appears to be an effective drug for protecting renal emunctory from the toxic effects of CDDP used in cytoreduction+IPCH in patients with peritoneal carcinosis. The dose of 550 mg/m2 used in this study does not cause hypotension and is recommended for this type of clinical use.

Amifostine↗

PubMed1989

Evaluation of antitumor activity in a human breast tumor/nude mouse model with a special emphasis on treatment dose.

Eight lines of human breast tumors implanted in nude mice were treated with various antitumor agents at two different doses, maximum tolerated doses (MTD) and rational doses (RD) that were pharmacokinetically equivalent to the clinical doses; the response rates to both doses were compared. With MTD, the response rates to mitomycin C and vinblastine were 100%, and those to other agents including cyclophosphamide, nimustine (a water-soluble nitrosourea), vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 5-fluorouracil (5-FU), and methotrexate were 30%-50%, indicating high responsiveness to the former two agents. In contrast, when the RD were used, the response rates to the majority of these agents were 25%-40%, and those to vincristine and nimustine were 13% and 0%, respectively. These results agree with the reported clinical results compared with those with MTD, suggesting the importance of the use of clinically equivalent doses in the evaluation of antitumor efficacy in a human tumor/nude mouse system.

Animals↗

PubMed1989

Polypeptides controlling hematopoietic blood cell development and activation. II. Clinical results.

Colony-stimulating factors (CSFs) have entered the clinical arena. Several investigators have explored, in first clinical phase I studies, different routes of administration to define the optimum biological dose, maximum tolerated dose, toxicity, and pharmacokinetics of these reagents. It has been demonstrated that recombinant human (rh) granulocyte-macrophage CSF (GM-CSF) and granulocyte CSF (G-CSF) can be safely administered over a broad dose range to increase number of circulating granulocytes in man. More recently, GM-CSF and G-CSF have been involved in phase Ib/II studies to assess the granulopoietic responses of patients with granulocytopenia due to various underlying disease states including myelodysplastic syndrome, aplastic anemia, cyclic neutropenia, Kostmann's syndrome, and the acquired immuno-deficiency syndrome. Both factors were also investigated with respect to their potential to prevent chemotherapy induced granulocytopenia or to accelerate recovery from that condition. The short-term effects of rh GM-CSF after autologous bone marrow transplantation for various solid tumors and lymphoid malignancies were assessed as well. In this article we will focus on recent results that have emerged from in vivo studies utilizing CSFs.

Bone Marrow↗

PubMed2006

Opiate pharmacology of intrathecal granulomas.

BACKGROUND: Chronic intrathecal morphine infusion produces intradural granulomas. The authors examined a variety of opioids infused intrathecal for analgesic activity and toxicity. METHODS: Two sets of experiments were undertaken in dogs with chronic intrathecal catheters: (1) Six-hour intrathecal infusions were used to determine the full analgesic dose and the maximum tolerated dose. (2) To establish toxicity, the maximum tolerated dose was given for up to 28 days by continuous intrathecal infusion. Drugs examined were morphine sulfate, hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), naloxone, or saline. RESULTS ANALGESIA AND TOLERABILITY: Six-hour intrathecal infusion of agonists resulted in a time-dependent increase in thermal escape latency. At higher concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity occurred. The concentrations, in mg/ml, for full analgesic dose/maximum tolerated dose were as follows: morphine, 0.9/12.0; hydromorphone, 1.0/3.0; D/L-methadone, 2.8/3; L-methadone, 1.0/> 1.0; fentanyl, 0.3/2.0; DAMGO, 0.1/> 2.0; D-methadone, > 1/> 1; naloxone, > 10/> 10. SPINAL PATHOLOGY: Chronic intrathecal infusion of the maximum tolerated dose revealed 100% intradural granuloma formation after morphine, hydromorphone, L-methadone, and naloxone. DAMGO induced a mass in only a single animal (one of three). D/L- and D-methadone produced intradural granulomas but were also associated with parenchymal necrosis. Saline and fentanyl animals displayed no granulomas. CONCLUSIONS: Intrathecal opiate-induced granulomas are not strictly dependent on opioid receptor activation. Therefore, opiates at equianalgesic doses present different risks for granuloma formation. Importantly, D/L- and D-methadone also resulted in parenchymal necrosis, an affect associated with the N-methyl-D-aspartate antagonist action of the D-isomer.

Analgesics, Opioid↗

PubMed2006

A phase 1 study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 7 days every 21 days in pediatric patients with solid tumors.

PURPOSE: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days. EXPERIMENTAL DESIGN: Patients who were </=18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m(2)/d (n = 3) and was escalated to 130 mg/m(2)/d (n = 6), 165 mg/m(2)/d (n = 6), 200 mg/m(2)/d (n = 6), and 250 mg/m(2)/d (n = 2) in cohorts of three to six patients. The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle. RESULTS: Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m(2)/d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m(2)/d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed. CONCLUSION: ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m(2)/d administered orally, daily for 7 days every 21 days. This dose is >40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.

Administration, Oral↗

PubMed2004

Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT).

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide (average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mg m(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mg m(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mg m(-2). The half-lives of both MAG-CPT and released CPT were prolonged (>6 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.

Acrylamides↗

PubMedDate not supplied

AIDS Clinical Trials Group Study 094: a phase I/II trial of ABV chemotherapy with zidovudine and recombinant human GM-CSF in AIDS-related Kaposi's sarcoma.

PURPOSE: To define the maximum tolerated dose of doxorubicin when combined with fixed doses of bleomycin, vincristine, zidovudine, and recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) in patients with advanced AIDS-related Kaposi's sarcoma. PATIENTS AND METHODS: Twenty male patients were treated with zidovudine at doses of either 100 or 200 mg by mouth every 4 hours, and cytotoxic chemotherapy with bleomycin 10 U/m2 and vincristine 1.4 mg/m2 by vein every 2 weeks. Four successive cohorts received fixed doses of doxorubicin given intravenously every 2 weeks: two cohorts each received 10 mg/m2 (levels 1, 2) or 20 mg/m2 (levels 3, 4). The first cohort received rhGM-CSF at a dose of 10 micrograms/ kg, given subcutaneously on days 2 through 11 (level 1). Due to toxicity, the dose of rhGM-CSF was reduced to 5 micrograms/kg (levels 2, 3) and then to 2.5 micrograms/kg (level 4). RESULTS: The dose-limiting toxicity was severe neutropenia, occurring in 10 patients. Severe neutropenic episodes occurred after a median of three cycles of chemotherapy, with the nadir occurring after 14 days (median). Moderate neutropenia occurred in 14% of all cycles administered. Constitutional toxicities of moderate or greater severity occurred in four patients. Five of 10 patients at a doxorubicin dose of 20 mg/m2 (levels 3 and 4) experienced severe neutropenia. Thus, doxorubicin at 10 mg/m2, with BV (bleomycin, vincristine chemotherapy), zidovudine (100 mg five times daily), and rhGM-CSF (5 micrograms/kg/day), was defined as the maximum tolerated dose. CONCLUSIONS: The maximum tolerated dose of doxorubicin is 10 mg/ m2 every 2 weeks when given in combination with BV chemotherapy, zidovudine, and rhGM-CSF. While the addition of rhGM-CSF at doses of 2.5 to 5 micrograms/kg decreased the duration of neutropenia, it did not prevent the occurrence of severe neutropenia from combined myelotoxic therapy.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Phase I clinical and pharmacokinetic study of flavopiridol in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors. PATIENTS AND METHODS: Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3. RESULTS: Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 micromol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2). CONCLUSION: The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.

Adolescent↗

PubMed1990

Phase I trial of 5-fluorouracil, leucovorin, and cisplatin in combination.

The ongoing evaluation of combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin in several tumors prompted a phase I clinical trial of cisplatin with 5-FU modulated by leucovorin. A total of 26 patients were treated with varying doses of 5-FU by continuous i.v. infusion for 5 days; 200 mg/m2 leucovorin was given by daily bolus injection for 5 days; and 20 mg/m2 cisplatin was infused over 2 h on each day of treatment. Courses were repeated every 21-28 days. The starting dose of 5-FU was 300 mg/m2. Poor-risk patients (extensive prior radiation, performance status of 2 or worse) did not tolerate the initial dose; the maximum tolerated dose of 5-FU in this group was 200 mg/m2 daily. Good-risk patients tolerated 300 mg/m2, but a majority had excessive toxicity at higher doses. The dose-limiting toxicity was gastrointestinal (mucositis/diarrhea) and/or myelosuppression; additional side effects included were nausea and vomiting (less than or equal to grade 2) and ataxia (one patient). Among 13 patients with colorectal cancer, 4 partial responses were observed. The marked reduction in the tolerable dose of 5-FU occasioned by the addition of modulating doses of leucovorin is noteworthy. The responses observed support further investigation of this regimen in phase II trials.

Aged↗

PubMed2006

A phase I study of myo-inositol for lung cancer chemoprevention.

INTRODUCTION: A phase I, open-label, multiple dose, dose-escalation clinical study was conducted to assess the safety, tolerability, maximum tolerated dose, and potential chemopreventive effect of myo-inositol in smokers with bronchial dysplasia. MATERIALS AND METHODS: Smokers between 40 and 74 years of age with >or= 30 pack-years of smoking history and one or more sites of bronchial dysplasia were enrolled. A dose escalation study ranging from 12 to 30 g/d of myo-inositol for a month was first conducted in 16 subjects to determine the maximum tolerated dose. Ten new subjects were then enrolled to take the maximum tolerated dose for 3 months. The potential chemopreventive effect of myo-inositol was estimated by repeat autofluorescence bronchoscopy and biopsy. RESULTS: The maximum tolerated dose was found to be 18 g/d. Side effects, when present, were mild and mainly gastrointestinal in nature. Using the regression rate of the placebo subjects from a recently completed clinical trial with the same inclusion/exclusion criteria as a comparison, a significant increase in the rate of regression of preexisting dysplastic lesions was observed (91% versus 48%; P = 0.014). A statistically significant reduction in the systolic and diastolic blood pressures by an average of 10 mm Hg was observed after taking 18 g/d of myo-inositol for a month or more. CONCLUSION: myo-Inositol in a daily dose of 18 g p.o. for 3 months is safe and well tolerated. The potential chemopreventive effect as well as other health benefits such as reduction in blood pressure should be investigated further.

Adult↗

PubMed1995

A phase I study of etoposide phosphate administered as a daily 30-minute infusion for 5 days.

PURPOSE: To determine the maximum tolerated dose, toxicities, kinetics, and disposition of etoposide phosphate when administered as a daily 30-minute infusion for 5 days. PATIENTS AND METHODS: Twenty-eight patients were enrolled in this phase I dose-escalation trial. Cohorts of patients received etoposide phosphate in etoposide equivalent doses of 50, 75, 100 and 125 mg/m2 intravenously for 30 minutes each day for 5 days. Pharmacokinetic sampling of both blood and urine was performed and concentrations of etoposide and etoposide phosphate were determined on day 1 of study for each patient and on day 4 of study for three patients receiving the 100 mg/m2 dose. RESULTS: The dose-limiting toxicity was reversible myelosuppression as evidenced by leukopenia and neutropenia. Toxicities seen were comparable to those expected from etoposide administration. With this schedule, the 100 mg/m2 dose was the maximum tolerated dose. Nonhematologic toxicities were generally mild. Two patients had major responses and three others had minor responses. Pharmacokinetic analyses revealed rapid (< 15 minutes) extensive conversion of etoposide phosphate to etoposide. Peak plasma etoposide concentrations and etoposide areas under the curve were proportional to the dose of etoposide phosphate administered. Etoposide kinetics were similar to those expected after a comparable dose of etoposide. CONCLUSIONS: Etoposide phosphate is a water-soluble pro-drug of etoposide that is rapidly converted to etoposide in vivo with a toxicity profile similar to etoposide. Etoposide generated from etoposide phosphate exhibits linear kinetics over a dose range of 50 to 125 mg/m2. When administered as a daily 30-minute infusion for 5 days, the dose-limiting toxicity is myelosuppression and 100 mg/m2 daily is the maximum tolerated dose.

Adult↗

PubMed2001

Application of preclinical data to initiate the modified continual reassessment method for maximum tolerated dose-finding trials.

This study was conducted to evaluate whether the allometric approach can be used to predict maximum tolerated dose (MTD) in humans from animal data. Twenty-five anticancer drugs were taken from the literature and used in this analysis. The results of the study indicate that MTD can be predicted with reasonable accuracy using interspecies scaling. The predicted MTD can then be applied to the modified continual reassessment method retrospectively for the selection of initial and subsequent doses of anticancer drugs in the patient population. This approach can save time and avoid many unnecessary steps to attain MTD in humans if it could be applied prospectively.

Animals↗

PubMed2002

Hematologic toxicity in radioimmunotherapy: dose-response relationships for I-131 labeled antibody therapy.

UNLABELLED: Bone marrow toxicity is generally dose-limiting for radioimmunotherapy (RIT) with beta-emitting radionuclides. Treatment may be prescribed on the basis of administered activity or absorbed dose. An optimal definition of maximum tolerated dose will enable the clinical benefits of RIT to be maximized. METHODS: We examined data from six clinical studies of RIT with various 131-I labeled antibodies and antibody fragments that treated a total of 114 patients. We also examined a sub-set of 36 patients with minimal prior chemotherapy who were treated with 131I-labeled intact murine IgG at a single institution. For both these groups the ability of absorbed dose-based methods to predict bone marrow tolerance was compared with that of activity-based methods. RESULTS: Marrow toxicity was more accurately predicted by absorbed dose than by activity in the general case where a variety of different antibodies and antibody fragments were used. For the more homogeneous smaller group, well defined "dose-response" relationships were observed for both absorbed dose and administered activity. However, absorbed dose-based definitions of maximally tolerated dose yielded a better stratification of patients than activity-based definitions (including per meter squared) such that fewer patients had major toxicity when treated below "tolerance", and fewer patients had minor toxicity when treated above "tolerance". CONCLUSIONS: Absorbed dose-based definitions of maximum tolerated dose and escalation variables are optimal for 131I-labeled antibody therapy. The ability of pre-therapy dosimetry studies to predict the behavior of therapeutic administrations must be validated for prospective clinical applications.

Blood Platelets↗

PubMed2004

Rationale and clinical validation of epidermal growth factor receptor as a target in the treatment of head and neck cancer.

Recurrent/metastatic head and neck cancer is an area of high, unmet treatment need. There is a strong rationale for targeting the epidermal growth factor receptor (EGFR) in head and neck cancer as most of these tumors express high levels of EGFR relative to normal tissue, with high expression correlating with poor patient outcome. This rationale has been validated in extensive preclinical studies. Two small molecules with EGFR inhibitory activity, gefitinib ('Iressa', ZD1839) and erlotinib ('Tarceva', OSI-774), and a humanized monoclonal antibody against the EGFR extracellular domain, cetuximab ('Erbitux', C225), are in clinical trials for advanced head and neck cancer. The initial results of these trials are promising. Gefitinib and erlotinib show activity as monotherapy in patients with recurrent or metastatic head and neck cancer, and have an acceptable safety profile compared with conventional chemotherapy. Gefitinib, which can be given at doses below the maximum tolerated dose, is associated with slightly lower rates of adverse events than erlotinib, which is dosed at the maximum tolerated dose. Combinations of cetuximab with radiotherapy or platinum-based chemotherapy have also shown activity in phase I/II studies. Both gefitinib and cetuximab have entered phase III studies. The results of these trials, which will mature over the next few years, will help determine the optimal use of EGFR agents in head and neck cancers.

Antibodies, Monoclonal↗

PubMedDate not supplied

Phase I trial of concomitant hyperfractionated radiotherapy with docetaxel and cisplatin for locally advanced head and neck cancer.

BACKGROUND: This study was conducted to determine the maximum tolerated dose of docetaxel when administered concomitantly with radical hyperfractionated radiotherapy and cisplatin in patients with locally advanced head and neck cancer. PATIENTS AND METHODS: Patients with stage III-IV tumors received radical radiotherapy of 74.4 Gy given in two daily fractions of 1.2 Gy for 6 weeks. Cisplatin was given once weekly on day 1 at a constant dose of 15 mg/m2. The starting dose of docetaxel was 10 mg/m2 once weekly on day 3, with planned escalation steps of 5 mg/m2. Main endpoints of the study were the maximum tolerated dose of docetaxel, acute toxicities, and the preliminary efficacy results. RESULTS: Twenty-five patients were enrolled. Median follow-up was 15 months (range: 4-40 months). Two of three patients presented with dose-limiting toxicities at the 15-mg/m2 dose of docetaxel (one patient presented with multiple grade 3-4 toxicities requiring hospitalization for management and another presented with multiple toxicities including life-threatening bronchoaspiration). Thus, the weekly docetaxel dose of 10 mg/m2 was considered the maximum tolerated dose. Nineteen patients were then treated with the maximum tolerated dose and no dose-limiting toxicities were observed. Radiotherapy was completed in all patients except one (median dose: 74.4; range: 73.2-74.4), and at least 80% of the scheduled cisplatin and docetaxel doses were given in 92% of the patients. Acute toxicities were dominated by grade 3 mucositis (92%) and grade 3-4 dysphagia (68%). The 2.5 year actuarial local control rate was 87.5%, and the disease-free survival rate was 75%. At the time of last follow-up, 23 patients were alive and two had died from cancer. No distant metastases were observed. DISCUSSION: In patients with locally advanced head and neck cancer, this study determined the maximum tolerated dose of docetaxel to be 10 mg/m2 administered once weekly when given concurrently with 74.4 Gy hyperfractionated radiotherapy and a weekly 15-mg/m2 dose of cisplatin. The toxicity profile and the encouraging results suggest that this new combination merits further investigation in a multi-institutional phase II trial.

Aged↗

PubMed2005

Matrix metalloproteinase-activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity.

Matrix metalloproteinase (MMP)-activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals, MMP-selective conjugates were given to mice with HT1080 xenografts and the distribution of doxorubicin was determined. These studies showed that MMP-selective conjugates were preferentially metabolized in HT1080 xenografts, relative to heart and plasma, leading to 10-fold increases in the tumor/heart ratio of doxorubicin. The doxorubicin deposited by a MMP-selective prodrug, compound 6, was more effective than doxorubicin at reducing HT1080 xenograft growth. In particular, compound 6 cured 8 of 10 mice with HT1080 xenografts at doses below the maximum tolerated dose, whereas doxorubicin cured 2 of 20 mice at its maximum tolerated dose. Compound 6 was less toxic than doxorubicin at this efficacious dose because mice treated with compound 6 had no detectable changes in body weight or reticulocytes, a marker for marrow toxicity. Hence, MMP-activated doxorubicin prodrugs have a much higher therapeutic index than doxorubicin using HT1080 xenografts as a preclinical model.

Animals↗