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Biomedical subjects

M M Kligerman

Publications and source records attributed to M M Kligerman.

At least 37 records · Page 2Linked to original sources
PubMed1986

WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial.

WR-2721 S-2-(3-aminopropylamino) ethyl phosphorothioic acid, is an organic thiophosphate compound that in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Preliminary data from our controlled phase I trial of WR-2721 and cyclophosphamide suggested that WR-2721 protected against cyclophosphamide-induced granulocytopenia. Since variable drug doses and infusion rates were used in these early studies, we initiated a controlled phase II trial using constant drug doses to establish more precisely WR-2721's level of protection. Initially, 21 patients received 1,500 mg/m2 of cyclophosphamide alone and were retreated 4 weeks later after hematologic recovery was complete with 740 mg/m2 of WR-2721 before the same dose of cyclophosphamide. With WR-2721 pretreatment, 19 of 21 (90%) patients had improved WBC and granulocyte counts. The mean WBC increased from 1,760/mL with cyclophosphamide alone to 2,500/mL with WR-2721 pretreatment (P less than .0005). The mean granulocyte count increased from 541/mL on cyclophosphamide to 1,247/mL with WR-2721 and cyclophosphamide (P less than .0005). Following cyclophosphamide administration alone, neutropenic fevers developed in three patients. No patient experienced a febrile episode following WR-2721 and cyclophosphamide administration. Platelet nadirs below 100,000/mL were only noted in two patients treated with cyclophosphamide alone. Objective partial responses were observed in four of 19 (21%) patients with measurable or evaluable disease. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced hematologic toxicity.

Aged↗
PubMed1986

Final report of the phase I trial of single-dose WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid].

Two hundred one patients were entered in a single-dose phase I trial of WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid]. Major toxic effects included emesis and hypotension. The observed minor toxic effects were somnolence and sneezing. Two infusion schedules were tested: long-infusion time, which fixed the rate, but varied total time; and short-infusion time, which varied the rate, but fixed the time to 15 minutes. Emesis was significantly influenced by infusion time; the long schedule caused a 57% incidence whereas the short schedule caused only a 28% incidence. Within the long-infusion group, higher-dose patients and women were more likely to vomit. Although only 15% of the entire group had hypotension, the long-infusion schedule had a hypotension incidence of 23%; the short schedule had an incidence of only 3% (P less than 0.0005). Within the long-infusion group, dose and tumor site significantly influenced the incidence of hypotension. No factors were associated with these toxic effects in the short-infusion schedule. However, certain toxic effects were too infrequent to detect significant differences. For future trials we recommend 740 mg/m2 infused in 15 minutes. With this schedule, vomiting was seen in 25% of infusions and hypotension was seen in only one of 68 infusions. To date, no delayed toxic effects have been detected in any organ system, and the trial resulted in no toxic deaths.

Adult↗
PubMed1985

Localization and protection of kidneys in radiation treatment planning using computed tomography.

Irradiation treatment portals of the upper abdomen must limit the dose to the kidneys. Sparing one-third of the parenchyma of each kidney will prevent late clinical sequelae. One hundred CT scans of the abdomen were studied to evaluate using the vertebrae as landmark for treatment planning. In lateral fields, using the anterior border of the vertebral column as a landmark for the posterior high isodose line will limit treatment to less than 60% (mean 22%) of a single kidney. Placing the edge of an anterior/posterior field 2 cm lateral to the vertebral column will limit the dose to less than 44% of a single kidney (mean 11%).

Adult↗
PubMed1984

Toxicity of WR-2721 administered in single and multiple doses.

Two hundred forty-three patients have received WR-2721 in Phase I-II studies. Separate studies were conducted in which patients with advanced malignancies received WR-2721 before single or multiple doses of radiotherapy or in single doses prior to cyclophosphamide, nitrogen mustard or cis-platinum. Single doses were escalated from 25 to 1330 mg/m2. An Acceptable Tolerated Dose (ATD) of 740 mg/m2 infused in 15 minutes has been established and is currently used in Phase II studies. Significant persistent hypotension (greater than 20 torr systolic) as a dose-limiting toxicity has occurred in 5% of patients in the single dose study. Fifty-five patients have been entered in the multiple dose trial. Dose levels of 340 mg/m2, four times a week for three weeks, and 250 mg/m2, four times a week for six weeks have been reached. There were five idiosynchratic reactions (fever, chills, rash, hypotension), one of which was severe. Some patients withdrew from the multiple dose study because of vomiting after each injection, or fear. No deaths nor any long-term untoward effects were observed. There is no suggestion of tumor protection.

Amifostine↗
PubMed1984

Phase I controlled trials of WR-2721 and cyclophosphamide.

WR-2721 is an organic thiophosphate compound which in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Controlled Phase I trials of WR-2721 and cyclophosphamide were initiated to determine if WR-2721 protected against cyclophosphamide's hematologic toxicity. Fifteen patients received WR-2721 (450-1100 mg/m2) prior to cyclophosphamide (1200-1800 mg/m2) and were subsequently retreated 4 weeks later with the same cyclophosphamide dose alone. With WR-2721 pretreatment, 11/15 (73%) patients had improved WBC counts. The mean WBC increased from 1800/mm3 on cyclophosphamide alone to 2700/mm3 with WR-2721 + cyclophosphamide (p = 0.008). In 11 patients who had nadir differential counts performed, 7 (64%) demonstrated improved nadir granulocyte counts with WR-2721. The mean granulocyte count increased from 765/mm3 on cyclophosphamide to 1274/mm3 with WR-2721 + cyclophosphamide (p = 0.05). In the second trial, 25 patients received the reverse sequence: an initial dose of cyclophosphamide (1200-1800 mg/m2) alone, followed 4 weeks later by WR-2721 (450-1100 mg/m2) prior to the same dose of cyclophosphamide. With WR-2721 pretreatment, 12/25 (48%) patients had improved nadir WBC counts. The mean WBC increased from 1550/mm3 on cyclophosphamide alone to 1850/mm3 with WR-2721 + cyclophosphamide (p = 0.02), while the nadir granulocyte count increased from 449/mm3 to 844/mm3 (p = 0.001). No patient developed microscopic or gross hematuria or inappropriate antidiuretic hormone secretion. One patient developed mild thrombocytopenia. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced granulocytopenia, but the dose modification factors and degree of clinical benefit remain to be established. The current recommended WR-2721 dose for Phase II trials is 740 mg/m2 administered over 15 minutes.

Adult↗
PubMed1984

Phase I trials of WR-2721 and cis-platinum.

WR-2721 is a sulfhydryl compound which in the animal model improves renal tolerance to cis-platinum (DDP) by factors of 1.3 to 1.7. Phase I trials were initiated to establish the toxicity and dose modification factors when WR-2721 was given prior to escalating doses of DDP. Nineteen patients received 27 courses of WR-2721 (450-910 mg/m2) 20 minutes prior to DDP (50-120 mg/m2). Patients were prehydrated, but no mannitol or other diuretics were administered. Mild, transient nephrotoxicity was observed in only 2 of 15 courses of DDP 80-100 mg/m2 when WR-2721 was given prior to DDP. Although 5 of 9 patients treated with WR-2721 prior to 120 mg/m2 of DDP developed transient nephrotoxicity, their serum creatinines returned to normal baseline values within 1 to 2 weeks. Subsequently, the protocol was modified to include mannitol diuresis. Thirty-four courses of WR-2721 (740 mg/m2) prior to DDP 120-150 mg/m2 with mannitol diuresis were administered. Biweekly serum creatinine and monthly creatinine clearances have remained normal in all patients treated with 120 mg/m2 of platinum and WR-2721. Four of 10 patients treated with 150 mg/m2 of cis-platinum experienced transient nephrotoxicity 5-7 days after treatment. Mild ototoxicity was noted in 4 patients following 150 mg/m2 of DDP. WR-2721 does not appear to protect against the antitumor efficacy of DDP, as 57% of all patients achieved objective partial responses, lasting 1+ to 7+ months. Partial responses occurred in 3/4 (75%) of patients with melanoma and 7/10 (70%) patients with cancer of the head and neck. Compared to retrospective series, our data suggest that WR-2721 may provide some protection against platinum-induced nephrotoxicity, but the dose modification factors remain to be established.

Amifostine↗
PubMed1983

Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent).

We investigated the causes of the hypocalcemia associated with WR-2721, an investigational drug that protects normal tissues against the toxic effects of radiation and chemotherapy. Sixteen patients with advanced cancers had serial measurements of serum calcium and other studies of blood chemistry before and after taking the compound. In all 16 patients (18 courses) the mean serum calcium level fell from 2.33 to 1.90 mmol per liter (9.33 to 7.62 mg per deciliter, P less than 0.001) after WR-2721, and in all 8 patients from whom data were obtained, serum calcium levels remained depressed at 24 hours. In 12 patients, ionized calcium levels dropped from 0.98 to 0.80 mmol per liter (P less than 0.01). Serum magnesium values fell from 0.96 to 0.74 mmol per liter (1.91 to 1.48 mg per deciliter, P less than 0.001). There were no changes in arterial pH or serum phosphate concentrations. In nine patients urinary calcium excretion rose from 3.96 to 10.68 mumol per minute (P less than 0.01) after WR-2721. Despite hypocalcemia, parathyroid hormone levels fell in all subjects. WR-2721 also inhibited the release of parathyroid hormone from bovine parathyroid cells incubated in vitro in low (0.5 mM) concentrations of calcium. We conclude that WR-2721 inhibits the secretion of parathyroid hormone and enhances calciuria, thereby leading to hypocalcemia.

Amifostine↗
PubMed1981

Phase I trials of WR2721 in combination with radiation therapy and with the alkylating agents cyclophosphamide and cis-platinum.

Three phase I trials of the radioprotector S-2-(3-aminopropylamino) ethylphosphorothioic acid (WR2721) have accessed 60 patients. Study 1 is devised to determine the maximum tolerated dose (MTD) of a single dose of the protector 15 to 30 minutes before a single radiation treatment of a size used routinely in palliative management. Study 2 plans to determine the MTD for up to 15 daily doses of the drug over 3 weeks during palliative radiotherapy. Also, the multipe-dose study will establish the MTD before palliative irradiation for fewer than five fractions a week. Study 3 uses the existing single-dose MTD determined in Study 1 as pretreatment 15 to 30 minutes before cyclophosphamide or cis-platinum. Toxic symptoms include emesis, hypotension, hypertension, somnolence, and sneezing. Only one serious episode of hypotension, considered idiosyncratic, and one instance of moderate to severe vomiting have occurred. Forty-one patients have been entered in Study 1 and a dose of 600 mg/m2 has been reached. The next step is to proceed to the planned highest level of 740 mg/m2. Of five patients in the multiple-dose study, one has been given, without toxicity, WR2721 at the level of 100 mg/m2 for 15 fractions over 3 weeks. Fourteen patients are accessed to the alkylating agent study. Using protector doses of 450 mg/m2, a cyclophosphamide level of 1500 mg/m2 has been accomplished. However, two of three patients who received 450 mg/m2 of WR2721 before 120 mg/m2 of cis-platinum have shown moderate elevation of the serum creatinine, both of which returned to normal.

Amifostine↗
PubMed1980

Quantitation of the late effects of X-radiation on the large intestine.

A model for quantitating late effects of x-radiation on the large intestine utilizing the rectum of the Sprague-Dawley rat is reported. This model was constructed prefatory to establishing relative biological effectiveness for negative pions as a component of preclinical trials at the Clinton P. Anderson Meson Physics Facility, Los Alamos Scientific Laboratory, Los Alamos, New Mexico. The endpoint involves microscopic evaluation of the severity of the experimental lesion, compared with surgically resected bowel lesions we have studied following clinical radiation exposure of the bowel. Individual components of the overall lesion include mucosal ulceration, atypical epithelial regeneration, colitis cystica profunda, fibrosis, and vascular sclerosis. Dose response curves were established for animals receiving 1, 2, 5 and 10 fractions with groups sacrificed at both four and 12 months after completion of radiation exposures.

Adenocarcinoma↗
PubMed1980

Phase I clinical studies with WR-2721.

Toxicity studies of S-2-(3 aminopropylamino)-ethylphosphorothioic acid (WR-2721) access patients in remission following radiation therapy. The dose has been escalated from 25 to 250 mg/m2 without significant symptoms. Inconsistent variation in the systolic blood pressure in some patients has been observed over an 8-10-point range without producing any symptoms. The variation could be within the patient's normal range. However, tests are planned to rule out cardiac toxicity or peripheral vascular reaction. Combining WR-2721 with conventional radiotherapy is contemplated by intravenous injection of the drug 20-30 minutes before irradiation. This will start as weekly injections, and the number of weekly injections will be increased progressively. Animal studies suggest that the level already safely reached could give significant protection to the normal tissues without protecting tumor.

Amifostine↗