Biomedical subjects
G R Weiss
Publications and source records attributed to G R Weiss.
Phase I clinical and pharmacokinetic trial of Brequinar sodium (DuP 785; NSC 368390).
Brequinar sodium is a 4-quinolinecarboxylic acid analogue that inhibits dihydroorotate dehydrogenase and subsequent de novo pyrimidine biosynthesis. It has shown dose-dependent antineoplastic activity against several mouse and human tumor models. This trial evaluated Brequinar given as a single daily i.v. bolus over a 5-day period repeated every 28 days. One hundred seven courses of treatment at dosages ranging from 36 to 300 mg/m2/day x 5 were administered to 45 patients (31 male and 14 female) with refractory solid tumors; median age was 58 years (range 30-74); median Southwest Oncology Group performance status was 1 (range, 0-3). Thirty patients had prior cytotoxic chemotherapy. Dose-limiting toxicities were thrombocytopenia and a severe desquamative maculopapular dermatitis. Two of 5 good risk patients at 300 mg/m2 and 3 of 6 poor risk patients at 170 mg/m2 developed a platelet count less than 25 x 10(3)/microliters. Two of 5 good risk patients at 300 mg/m2 and 1 of 6 poor risk patients at 170 mg/m2 developed a severe desquamative dermatitis. Moderate to severe mucositis was usually associated with the thrombocytopenia and/or the dermatitis. Nonhematological drug-related toxicities included nausea and vomiting, malaise, anorexia, diarrhea, phlebitis, reversible transaminase elevation, and mucositis. Other hematological toxicities were anemia, granulocytopenia, and leukopenia. There were no drug-related deaths. There were no objective tumor responses. Plasma and urine levels of Brequinar were quantified by high pressure liquid chromatography in 28 patients. Plasma levels and areas under the curve increased proportionally with increased dose. Brequinar had a harmonic mean terminal t1/2 of 8.1 +/- 3.6 h with a model-independent determined apparent volume of distribution at steady state of 9.0 +/- 2.9 liters/m2 and a total body clearance of 19.2 +/- 7.7 ml/min/m2. Renal excretion was a minor route of elimination for Brequinar. The maximally tolerated dose of Brequinar on a daily x 5 i.v. schedule was 250 mg/m2 for good risk patients. For the daily x 5 i.v. schedule, the recommended dose of Brequinar for phase II evaluation is 250 mg/m2 for good risk patients and 135 mg/m2 for poor risk patients.
Phase I trial of echinomycin (NSC 526417), a bifunctional intercalating agent, administered by 24-hour continuous infusion.
Echinomycin was administered to 43 patients with advanced cancer in escalating doses ranging from 60 to 2128 mcg/m2. The dose-limiting toxicity of echinomycin administered as a 24-h continuous infusion every 28 days was nausea and vomiting beginning at the end of the 24 h infusion and lasting from 3 to 8 days. Other toxicities included sporadic thrombocytopenia and biochemical evidence of liver dysfunction characterized by elevations in SGOT. Peripheral vein phlebitis was noted in 100% of patients, and watery diarrhea of 24-48-h duration was noted in 7% of patients. The maximally tolerated dose of echinomycin was 2128 mcg/m2. The recommended dose for phase II trials utilizing the 24-h continuous infusion schedule is 1600 mcg/m2 repeated every 28 days with pretreatment antiemetics.
A phase I clinical and pharmacological study of weekly intravenous infusions of piritrexim (BW301U).
Thirty-eight patients with advanced resistant cancers were enrolled on this study of piritrexim (PTX; BW 301U) administered intravenously weekly for 4 weeks. Of 50 courses of treatment begun, 39 evaluable 4-week courses of the drug were completed by this group of patients. Dosages ranged from 44 to 530 mg/m2/week. One patient at each dosage level received an initial weekly dose of PTX in oral form accompanied by pharmacokinetic blood sampling after the oral dose and also after a subsequent intravenous dose. Toxicities included mild nausea and vomiting, and moderate to severe peripheral vein phlebitis. Anemia and thrombocytopenia were the dominant hematological toxicities. One patient with pulmonary metastases from malignant fibrous histiocytoma experienced a 12-week partial response to PTX treatment at a dosage of 400 mg/m2/week. Pharmacokinetic analysis of plasma for PTX concentrations was accomplished utilizing a competitive protein binding assay. The estimated total body clearance ranged from 136 to 173 ml/min/1.73 m2. Mean terminal half-life after intravenous administration was 5.61 +/- 2.38 h (S.D.), and after oral administration was 5.72 +/- 2.04 h. Mean systemic bioavailability after oral administration was 75 +/- 56%.
Review of interleukin-2 alone and interleukin-2/LAK clinical trials in metastatic malignant melanoma.
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A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma.
Thirty-six patients with metastatic melanoma were entered into a study of the therapeutic efficacy of adoptive immunotherapy with high-dose interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells. Thirty-two patients who received all components of the therapy are evaluable for response, and all patients are evaluable for toxicity. Sites of disease included lung, liver, subcutaneous nodules, and intra-abdominal metastases. One complete response (CR) and five partial responses (PRs) resulted from treatment (19% response rate). The median response duration was 5 months, with the durable CR continuing at 31+ months and one durable PR continuing for 13 months. Sites of response included lung, liver, subcutaneous nodules, and lymph nodes. Response, response duration, or site of response did not correlate with the total dose of IL-2 administered, rebound lymphocytosis, or the number of LAK cells infused. Toxicity included hypotension, fluid retention with a "capillary leak syndrome" in most patients, and transient multiorgan dysfunction that resolved promptly after the completion of therapy. Adverse cardiac events occurred in 16% of patients, with one myocardial infarction leading to a death. This study confirms the activity of the initial IL-2/LAK cell regimen in metastatic melanoma reported by Rosenberg et al, supporting the concept of adoptive immunotherapy as an important new treatment approach for this disease.
Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines.
The National Cancer Institute (NCI) Extramural IL2/LAK Working Group treated 93 patients with 114 cycles of high-dose intravenous (IV) interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells in three phase II trials. Thirty-six patients had metastatic melanoma, 35 had metastatic renal cell cancer, and 22 had colorectal cancer. All patients had a Karnofsky performance status greater than or equal to 80% and normal laboratory tests and organ function, and had received no more than one prior form of immunotherapy or chemotherapy. Objective responders were eligible to receive up to two additional courses of therapy at 12-week intervals. The most frequent toxicities were a capillary leak syndrome resulting in marked extravascular fluid shifts, and hypotension requiring treatment with large volumes of IV fluids and vasopressor agents. Laboratory and clinical evidence of hepatic and renal dysfunction were virtually universal. Intensive care-level support was routinely provided and the toxicity observations confirmed the need for this level of care. The life-threatening toxicities were cardiac and pulmonary. Five of the 27 patients who experienced significant respiratory compromise required intubation and mechanical ventilatory support. Twenty patients developed cardiac arrhythmias, the majority of which were supraventricular. There was a single episode of ventricular tachycardia requiring cardioversion. Four patients had transient cardiac ischemia, and an additional four had myocardial infarctions, one of which was fatal. With these exceptions, all toxicities were rapidly reversible. The occurrence of only a single therapy-related death and a very low incidence of other irreversible or life-threatening events is comparable to the level of toxicities often observed in other phase II trials. Although the intensity of this regimen limits this approach to a subset of cancer patients with excellent performance status and adequate organ function, because of the frequency and apparent durability of complete responses, this treatment warrants further investigation.
Phase I clinical investigation of amonafide.
Amonafide (benzisoquinolinedione, NSC 308847) is a new synthetic imide antineoplastic agent with DNA intercalative properties that has been evaluated in a phase I clinical trial. The drug was administered as a single intravenous (IV) infusion over 30 to 120 minutes repeated every 28 days. Ninety-five courses of therapy at doses ranging from 18 to 1,104 mg/m2 were administered to 38 patients with refractory solid tumors. Granulocytopenia was dose limiting. Leukopenia was seen in 13 of 31 courses at doses of 690 mg/m2 or greater. Life-threatening granulocytopenia (less than or equal to 250 microliters) was noted in 1/6 patients treated at 800 mg/m2, 1/8 patients treated at 918 mg/m2, and 2/5 patients treated at 1,104 mg/m2. No definite relationship between myelotoxicity and prior treatment status was noted. Rate-of-infusion dependent, nonhematologic toxicities included diaphoresis, flushing, dizziness, and tinnitus, all of which were ameliorated by increasing the duration of drug infusion to 120 minutes. In addition, nausea and vomiting (grades 1 and 2) were seen in 29/56 courses at doses greater than or equal to 519 mg/m2, but were easily controlled by phenothiazine antiemetics. Amonafide plasma and urine concentrations were determined by high-pressure liquid chromatography (HPLC). Plasma concentrations declined biexponetially with a terminal harmonic mean terminal half-life (t 1/2) of 5.5 h. The mean apparent volume of distribution at steady-state and total body clearance were 532 L/m2 and 84 L/h/m2, respectively. Less than 5% of the total dose of amonafide was excreted unchanged in the urine. Antitumor activity has been noted in one patient with non-small-cell lung cancer (one complete response exceeding 29 months duration) and in one patient with prostatic cancer (complete pain relief and improvement in bone scan for 9 months). The recommended dose for phase II trials with this schedule of amonafide is 918 mg/m2 with dose escalation to amonafide is 918 mg/m2 with dose escalation to myelotoxicity.
Phase I and clinical pharmacology trial of crisnatol (BWA770U mesylate) using a monthly single-dose schedule.
Crisnatol is a novel lipophilic arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models which functions as a DNA intercalator. In this Phase I trial, a 6-h infusion of the drug was administered i.v. in 700 to 1500 ml of 5% dextrose in water every 28 days. Eighty-five courses at doses of 7.5 to 516 mg/m2 were administered to 43 patients with refractory solid tumors. Reversible neurological toxicity was dose limiting at 516 mg/m2 and was manifested as somnolence, dizziness, blurred vision, unsteady gait, and alpha-slowing on electroencephalogram at the end of infusion. All neurological signs and symptoms were reversible. No hematological toxicity was observed. Other toxicities included phlebitis, mild to moderate nausea and vomiting, reversible sinus node arrest in one patient, and hypertension. Crisnatol plasma concentrations were determined by high-pressure liquid chromatography. After infusion, plasma concentrations declined biexponentially with a terminal t1/2 of 2.9 h. Using a two-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 58.8 liters/m2 and 18.3 liters/h/m2, respectively, indicative of extensive tissue distribution and rapid hepatic clearance. Peak plasma levels occurred at the end of infusion and correlated with the onset of neurological toxicity. The recommended Phase II dose for this schedule is 388 mg/m2.
Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. A phase II clinical trial.
STUDY OBJECTIVE: To confirm the antitumor efficacy of treatment with interleukin-2 and lymphokine-activated killer cells in patients with metastatic renal cancer. DESIGN: Nonrandomized, phase II clinical trial. SETTING: Tertiary care units in university medical centers. PATIENTS: Consecutive trial of 35 patients with metastatic or unresectable renal cell cancer who have bidimensionally measurable disease, performance status 0 or 1, and normal function of all vital organs. Thirty-two patients completed interleukin-2 priming and received at least one lymphokine-activated killer cell infusion. Three patients were removed from the study and did not receive infusion of cells secondary to rapid tumor progression or toxicity. INTERVENTIONS: Patients initially received recombinant interleukin-2, 100,000 units/kg body weight every 8 hours, on days 1 to 5 in a priming phase to stimulate lymphokine-activated killer cell precursors and effector activity in vivo. Leukapheresis was done on days 8 to 12 and lymphocytes were cultured in vitro with interleukin-2 for 3 to 4 days to amplify lymphokine-activated killer cell activity. Finally, interleukin-2, 100,000 units/kg every 8 hours, was infused with cultured cells on days 12 to 16. All doses of interleukin-2 and lymphokine-activated killer cells were administered in intensive care units. MEASUREMENTS AND MAIN RESULTS: The mean number of doses of interleukin-2 administered during the priming phase was 12.9 +/- 0.4; the mean number of lymphokine-activated killer cells reinfused was 7.0 +/- 0.6 X 10(10); and the mean number of interleukin-2 doses administered during the last phase was 10.2 +/- 0.6. The overall objective response rate was 16%; two patients had complete responses and three patients had partial responses with greater than 50% reduction of all measurable tumor. The complete responders remain disease-free at 12 and 9 months. Two partial responders have not had tumor regrowth at 16 and 15 months. The third partial responder relapsed at 4 months. Toxicity was severe but generally of short duration and manageable. There were no treatment-related deaths. Hypotension, weight gain, anemia, and elevations of serum creatinine levels and liver enzymes were common. Two patients required intubation; one patient had a myocardial infarction. CONCLUSIONS: This phase II study confirms the antitumor activity of interleukin-2 and lymphokine-activated killer cell therapy in patients with metastatic or unresectable renal cell cancer. Response rates, especially complete remission rates, are comparable or better than rates achieved with other forms of therapy.
Use of in vitro dose response effects to select antineoplastics for high-dose or regional administration regimens.
Several preclinical and clinical studies have documented that dose or dose intensity of chemotherapeutic agents are important factors for response of patients' tumors. This finding has prompted empiric trials of certain chemotherapeutic agents in high-dose or regional administration treatment regimens. The present study was performed to identify agents that would be particularly good candidates for high-dose or regional administration regimens against particular types of tumors. Using a human tumor cloning technique, we constructed dose in vitro response lines for ten different chemotherapeutic agents against seven different histologic types of malignancies. Slopes of the lines indicated the agents with the greatest increases of in vitro response per increment in dose of the agent. Tumors against which the agents gave the steepest dose response lines included lymphoma, head and neck cancer, ovarian cancer, and small-cell lung cancer, while the dose response lines for non-small-cell lung cancer, breast cancer, and colon cancer were quite flat. Suggestions for clinical trials based on these findings include the use of high-dose melphalan for patients with lymphoma, head and neck, and ovarian cancer; the use of mitoxantrone in high-dose regimens for patients with breast cancer; high-dose cisplatin regimens for patients with small-cell lung cancer; high-dose bleomycin regimens for patients with non-small-cell lung and head and neck cancer; and regional perfusion of liver metastases from colorectal cancer with cisplatin. Prospective testing of high-dose or regional administration regimens suggested by this new model should indicate its use for prediction of the best agent to use in high-dose regimens against a particular tumor type.
Pharmacologic analysis of the ip administration of fludarabine phosphate in the swine.
Fludarabine phosphate, an investigational water-soluble adenosine analog, was administered ip to five miniature swine at doses of 10, 16, and 25 mg/m2. Blood and peritoneal fluid samples were collected for 4 hours following drug administration and were submitted to high-performance liquid chromatographic analysis for the concentrations of the dephosphorylated derivative, 2-fluoro-ara-A. Peak peritoneal fluid concentrations of 2-fluoro-ara-A ranged from 7.72 to 18.01 micrograms/ml at the doses tested; peritoneal fluid areas-under-the-curve (AUCs) ranged from 19.23 to 47.33 micrograms X hour/ml. The peak serum concentrations of 2-fluoro-ara-A ranged from 0.15 to 0.46 micrograms/ml; serum AUCs ranged from 0.51 to 1.2 micrograms X hour/ml. The ip administration of fludarabine phosphate results in a 28-62-fold peak peritoneal concentration advantage over peak serum concentrations and a 20-53-fold advantage for peritoneal over serum AUCs. Comparison of data generated in this swine study to data from pilot studies of the ip administration of fludarabine phosphate in humans will be of interest.
Phase II study of fludarabine phosphate for the treatment of advanced non-small cell carcinoma of the lung: a Southwest Oncology Group Study.
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Second-line chemotherapy for ovarian cancer.
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A phase I and pharmacokinetic comparison of hepatic arterial and peripheral vein infusions of bisantrene for liver cancer.
Bisantrene (NSC-337766) was administered to five patients with cancer of the liver (one case of hepatocellular carcinoma, two of metastatic carcinoma of unknown primary, two of metastatic colorectal carcinoma). Under fluoroscopic guidance, percutaneous hepatic venous catheters were placed in five patients and percutaneous hepatic arterial catheters in four. A fifth patient's hepatic arterial catheter was implanted at laparotomy. Hepatic plasma flow was estimated by the Fick principle using peripheral vein indocyanine green infusion. On the first day of treatment, patients received a 2- or 4 h hepatic arterial infusion of bisantrene (130 mg/m2); peripheral venous, hepatic arterial, and hepatic venous timed blood samples were drawn during and for 18 h after drug infusion. On the second day of treatment, 2- or 4 h peripheral vein infusion of bisantrene (130 mg/m2) was followed by the same blood sampling schedule. Patients were followed weekly for toxicity. Four patients received only one course of treatment, while a fifth received two courses. All patients experienced leukopenia (median nadir 2400/mm3; range 1400-2700/mm3). Two patients developed fever after drug infusion. No antitumor responses were observed. Plasma bisantrene concentrations were measured by HPLC. Pharmacokinetic analyses are reported for four patients. The hepatic extraction ratio ranged from 15% to 49%, hepatic plasma clearances were 0.029-0.353 1/min/m2; peripheral vein areas under the concentration-time curve during hepatic arterial infusion ranged from 35% to 50% of peripheral vein areas under the curve during peripheral vein infusion. We conclude that hepatic arterial bisantrene infusion offers only modest pharmacokinetic advantage to the target organ or to the systemic circulation over peripheral vein infusion.
Pulmonary complications of peritoneal access catheters.
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