Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma.

BACKGROUND: We conducted this trial to determine the maximum tolerated dose (MTD) of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma. PATIENTS AND METHODS: A standard phase I cohort of three study design was utilized. The fixed doses of rituximab and cladribine were 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. There were five planned temsirolimus i.v. dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1, 8 and 15; and 25 mg days 1, 8, 15, and 22. RESULTS: Seventeen patients were treated: three each at levels 1-4 and five at dose level 5. The median age was 75 years (52-86 years). Mantle Cell International Prognostic Index (MIPI) scores were low in 6% (1), intermediate in 59% (10), and high in 35% (6) of patients. Five patients were treated at level 5 without dose limiting toxicity. Hematologic toxicity was frequent: grade 3 anemia in 12%, grade 3 thrombocytopenia in 41%, grade 4 thrombocytopenia in 24%, grade 3 neutropenia in 6%, and grade 4 neutropenia in 18% of patients. The overall response rate (ORR) was 94% with 53% complete response and 41% partial response. The median progression-free survival was 18.7 months. CONCLUSIONS: Temsirolimus 25 mg i.v. weekly may be safely added to rituximab and cladribine at 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. CLINICALTRIALSGOV IDENTIFIER: NCT00787969.

Phase II study of high-dose somatostatin analogue in patients either previously treated or untreated who have extensive-stage small cell lung cancer.

The authors conducted a phase II study of somatostatin analogue in 18 patients with extensive stage small cell lung cancer (four with previous treatment, 14 without previous treatment). Patients received 2,000 mg subcutaneously thrice daily. They were required to have an Eastern Cooperative Oncology Group performance score of 0-2 and acceptable pretreatment biochemical parameters. No patient responded to treatment. The median time to progression was 44 days. The median survival was 106 days. Toxicity related to treatment consisted of mild diarrhea and anorexia. Somatostatin analogue is not active as a single agent in the treatment of extensive-stage small cell lung cancer.

Phase II trial of irinotecan in patients with metastatic colorectal carcinoma.

PURPOSE: To evaluate the objective tumor response rate and toxicities of patients with metastatic colorectal carcinoma treated with irinotecan hydrochloride (CPT-11). PATIENTS AND METHODS: A total of 121 patients with advanced colorectal carcinoma--90 with prior fluorouracil (5-FU) exposure and 31 chemotherapeutically naive patients--were enrolled between May 1993 and June 1994. Patients were treated with CPT-11 at 125 mg/m2 intravenously weekly for 4 weeks followed by a 2-week rest. RESULTS: Among 90 patients with prior 5-FU chemotherapy, 12 partial responses were observed (response rate, 13.3%; 95% confidence interval [CI], 7.1% to 22.1%). Among 31 chemotherapy-naive patients, eight had partial responses (response rate, 25.8%; 95% CI, 11.9% to 44.6%). The median response duration as measured from time of initial treatment for the two groups was 7.7 months and 7.6 months, respectively. The major adverse reactions were gastrointestinal and hematologic. The incidence of grade 3 or 4 diarrhea was 36.4%, while the overall incidence of grade 3 or 4 leukopenia was 21.5% of patients. Only four of 121 patients (3.3%) developed neutropenic fever (grade 4 neutropenia with > or = grade 2 fever). The incidence of grade 4 leukopenia was higher in patients with prior pelvic radiotherapy (chi2 test P = .04), while the incidence of grade 3 or 4 diarrhea demonstrated no association with previous pelvic irradiation. CONCLUSION: According to the study design, CPT-11 showed promising activity in chemotherapy-naive patients with advanced colorectal carcinoma and modest activity in patients with prior 5-FU exposure. The toxicity with this schedule appears manageable with appropriate dose modification for individual patient tolerance and an intensive loperamide regimen for the management of diarrhea. Care should be taken when treating patients with prior pelvic radiotherapy because of the increased risk of neutropenia.

Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients.

PURPOSE: A minority of cancer survivors develops long-term postsurgical neuropathic pain. Based on evidence that capsaicin, the pungent ingredient in hot chili peppers, might be useful for treating neuropathic pain, we developed the present clinical trial. PATIENTS AND METHODS: Ninety-nine assessable patients with postsurgical neuropathic pain were entered onto this study. After stratification, patients were to receive 8 weeks of a 0.075% capsaicin cream followed by 8 weeks of an identical-appearing placebo cream, or vice versa. A capsaicin/placebo cream was to be applied to the painful site four times daily. Treatment evaluation was performed by patient-completed weekly questionnaires. RESULTS: During the first 8-week study period, the capsaicin-cream arm was associated with substantially more skin burning, skin redness, and coughing (P < .0001 for each). Nonetheless, treatment was stopped for patient refusal or toxicity just as often while patients were receiving the placebo as compared with the capsaicin. The capsaicin cream arm had substantially more pain relief (P = .01) after the first 8 weeks, with an average pain reduction of 53% versus 17%. On completion of the 16-week study period, patients were asked which treatment period was most beneficial. Of the responding patients, 60% chose the capsaicin arm, 18% chose the placebo arm, and 22% chose neither (P = .001). CONCLUSION: A topical capsaicin cream decreases postsurgical neuropathic pain and, despite some toxicities, is preferred by patients over a placebo by a three-to-one margin among those expressing a preference.

Inhibition of 5-fluorouracil-induced ocular irritation by ocular ice packs.

BACKGROUND: This clinical trial was developed to determine whether ocular ice pack therapy would decrease 5-fluorouracil (5-FU)-induced ocular toxicity. METHODS: Sixty-two patients who suffered from 5-FU-induced ocular toxicity, and were scheduled to receive another cycle of the chemotherapy that caused the ocular toxicity, were entered in this clinical trial. A randomized, crossover design was used, with patients documenting their ocular toxicity by the use of daily diaries. RESULTS: The results from the first cycle of treatment suggested that ocular ice pack therapy decreased 5-FU-induced ocular toxicity (P = 0.056). The 38 evaluable patients in the crossover analyses demonstrated decreased ocular toxicity with ocular ice pack therapy (p = .001). The ocular ice pack therapy was well tolerated by most of the study participants. CONCLUSION: Ocular ice pack therapy appears to lessen 5-FU-induced ocular toxicity to a clinically moderate degree. Better methods for decreasing 5-FU-induced ocular toxicity are necessary.

Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics.

The effects of low-dose estrogen oral contraceptives (OC) on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprazolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR) were studied in two parallel crossover studies of 20 women each. Women taking OC steroids containing low doses of estrogen and women matched for age, weight, and cigarette smoking received single oral doses of TRZ (0.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Kinetics were determined as plasma concentrations during 48 hr after dosing. OCs inhibited the metabolism of ALP: The AUC increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. In contrast, OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. Low-dose estrogen OCs may therefore inhibit the metabolism of some oxidized benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines.

PIP: Because benzodiazepines and oral contraceptives (OCs) are among the most widely prescribed drugs and have a potential for interaction, 2 parallel crossover studies were conducted to determine the effects of OCs on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprozolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR). 20 healthy women taking OCs containing does of under 35 mcg of ethinyl estradiol for 3 months or more and 20 women matched for age, weight, and cigarette smoking received single oral doses of TRZ (.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Treatments were seperated by 28 days to control for effects of menstural cycle on drug metabolism. Kinetics were determined as plasma concentrations during 48 hours after dosing. The data indicated that OCs differentially affect the elimination of the benzodiazepines studied. OCs inhibited the metabolism of ALP: the area under the curve (AUC) increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. It was concluded that low-dose estrogen OCs may inhibit the metabolism of some conjugated benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines, but the clinical implications are unclear. The relationship between plasma concentration and effect has not been determined for most benzodiazepines, but the results suggest that the time required to achieve steady-state concentrations would be longer and that there would be higher steady state concentrations of ALP in OC users. Because both TMZ and LOR are eliminated more rapidly by OC users, women taking OCs should achieve steady-state concentrations more rapidly than nonusers. Because TMZ clearance is increased by OCs, mean plasma concentration may be decreased. The usual 30 mg dose of TMZ may therefore be less effective as a hypnotic in OC users.