Robert J. Belt

Multicenter Randomized Phase II Study of Weekly or Twice-Weekly Bortezomib Plus Rituximab in Patients With Relapsed or Refractory Follicular or Marginal-Zone B-Cell Lymphoma

PURPOSE To determine overall response rate (ORR), time to progression (TTP), and duration of response (DOR) with twice-weekly/weekly bortezomib plus rituximab, and evaluate safety/tolerability, in patients with relapsed or refractory CD20(+) follicular lymphoma (FL) or marginal-zone lymphoma. PATIENTS AND METHODS Patients were randomly assigned (minimization method) to bortezomib 1.3 mg/m(2) twice weekly (days 1, 4, 8, and 11; 21-day cycle, five cycles; arm A) or bortezomib 1.6 mg/m(2) weekly (days 1, 8, 15, and 22; 35-day cycle, three cycles; arm B) plus rituximab 375 mg/m(2) weekly for 4 weeks (both arms). Response/progression was determined by International Workshop Response Criteria using oncologist/radiologist-adjudicated data from independent radiology review and investigator assessment. RESULTS Eighty-one patients (arm A, n = 41; arm B, n = 40) were enrolled. Dose-intensity was higher in arm A; mean total bortezomib received was similar between arms (18.5 and 17.1 mg/m(2)). In arm A, ORR was 49% (14% complete response [CR]/CR unconfirmed [CRu]), median TTP was 7.0 months, and median DOR was not reached. In arm B, ORR was 43% (10% CR/CRu), and median TTP/DOR were 10.0/9.3 months. The weekly combination regimen seemed better tolerated. Grade 3 or worse adverse events seemed more common in arm A (54%) versus arm B (35%), including thrombocytopenia (10% v 0%) and peripheral neuropathy (10% v 5%), but diarrhea seemed less frequent (7% v 15%). No grade 4 toxicities were reported in arm B. CONCLUSION Both bortezomib plus rituximab regimens seem feasible in relapsed or refractory indolent lymphomas. The more convenient weekly combination regimen is being compared with single-agent rituximab in an ongoing phase III study in relapsed FL.

Studies of hydroxyurea administered by continuous infusion: toxicity, pharmacokinetics, and cell synchronization.

Hydroxyurea was administered by means of two schedules designed to provide continuous 72‐hour exposure of tumor cells to therapeutic drug levels. Toxicity and pharmacokinetics were determined for both an oral pulse dose schedule (every 4 hours × 18 doses) and continuous intravenous (IV) infusion for 72 hours. The maximal tolerated dose (MTD) was 800 mg/m2 every 4 hours for the oral route and 3.0 mg/m2/min × 72 hours for IV infusion. Granulocytopenia was dose‐limiting for both schedules and correlated well with plasma‐HU levels. Serial sampling of normal bone marrow (10 patients) and tumor tissue (3 patients) showed a modest degree of synchronization induced by continuous IV infusion of hydroxyurea. Interindividual pharmacokinetic variations severely limit the usefulness of the oral pulse schedule as a potential means of synchronizing cells. Hydroxyurea administered by continuous IV infusion may be useful as a synchronizing agent in humans. Cancer 46:455–462, 1980.

A Southwest Oncology Group study on the use of a human tumor cloning assay for predicting response in patients with ovarian cancer.

A total of 211 patients with epithelial ovarian cancer (168 with tumors refractory to prior chemotherapy and 43 with no prior chemotherapy) from 33 different Southwest Oncology Group institutions had their tumors sampled and specimens shipped to two central laboratories for drug‐sensitivity testing in a human tumor cloning assay. The 168 patients with a prior history of chemotherapy failure (median of four prior chemotherapeutic agents) were treated with the most effective agent(s) found in the cloning assay (23 patients), and those patients whose tumors did not form colonies in vitro or did not manifest any sensitivity to agent(s) were treated with a clinicians choice of agent(s) (101 patients). The remaining 44 of the 168 patients were not treated with chemotherapy because of deteriorating performance status or early death. The complete and partial response rate in patients treated according to assay results was 28% versus 11% for the patients treated according to clinicians choice (P = 0.03). There was no statistically significant difference in survival between the two options (6.25 versus 7 months, respectively). The 43 patients with no history of prior chemotherapy were all treated with standard combination chemotherapy, and their clinical response was compared with their in vitro sensitivity to the same agents. Overall there was a 100% true‐positive rate and 100% true‐negative rate for the seven evaluable patients. From these data the authors conclude that use of the human tumor cloning assay may increase the response rate but not the survival for selected patients with advanced chemotherapy‐refractory ovarian cancer. The study is weakened, however, by the many steps of patient selection necessitated by inadequate tumor colony formation in vitro and the inability to treat all patients (because of early death or a rapid decline in performance status). The assay does appear to be worthy of additional study for predicting response to combination chemotherapy in patients without a prior history of chemotherapy. Finally the use of central chemosensitivity testing laboratories is feasible for testing in vitro predictive assays in a cooperative group setting.

Phase I evaluation of ICRF‐187 (NSC‐169780) in patients with advanced malignancy

ICRF‐187 (NSC‐169780), the (+) enantiomer of the racemic antineoplastic agent ICRF‐159 (NSC‐129943), was administered intravenously for five days every three weeks to 18 patients in a phase I study. Leukopenia was the dose‐limiting toxicity. Mild reversible elevations in SGOT and bilirubin were common. Other toxicities were mild and infrequent. Recommended doses of ICRF‐187 for phase II studies are 800 mg/m2for heavily pretreated patients and 1250 mg/m2for patients with little or no prior therapy. A daily five day intravenous schedule should be used. Other potential clinical uses of ICRF‐187 are discussed.

Effect of mannitol and plasma on the cytotoxicity of cisplatin

A soft agar cell culture for human granulocyte precursor cells (CFU-c) was used to assess the cytotoxic effect of cisplatin before and after preincubating the drug with either mannitol and/or fresh human plasma. Consistent growth inhibition of CFU-c was found with survival of 87, 64 and 34% at cisplatin concentrations of 10(-7) M, 10(-6) M and 10(-5) M respectively. Dose-related survival was not changed by preincubating cisplatin with mannitol in molar ratios of 1:100 and 1:1000 for 4 and 24 hr. Preincubating 10(-5) M cisplatin with human plasma increased CFU-c survival corresponding to a loss of activity of 92 and 98% after 4- and 24-hr preincubations respectively. No significant difference in survival of CFU-c was noted whether bone marrow cells were exposed to cisplatin in human plasma or in the ultrafiltrate of human plasma. Mannitol did not change the decrease in cisplatin activity due to plasma protein binding. These data indicate that the cytotoxic effect of cisplatin can be reduced by exposure to human plasma but not to mannitol.

A phase II trial of 5-fluorouracil and recombinant alpha-2a-interferon in previously untreated metastatic gastric carcinoma

A Phase II clinical trial of the combination of 5‐fluorouracil (5‐FU) and recombinant alpha‐2a‐interferon (α‐2a‐IFN) was conducted in 44 patients. Patients had not received chemotherapy previously and had measurable metastatic gastric carcinoma. 5‐FU was administered as a continuous infusion at a dose of 750 mg/m2/d for 5 consecutive days and as an intravenous bolus at a dose of 750 mg/m2 weekly for 7 weeks beginning on day 12. Recombinant α‐2a‐IFN was administered subcutaneously at a dose of 9 × 106 U three times a week during weeks 1 to 8. Patients were examined for response during week 9. Of 44 patients entered, 40 could be examined for response. Nine patients experienced a partial clinical response and one achieved a complete response, for an overall response rate of 25% (95% confidence interval, 13% to 41%). The median duration of response was 13 weeks (range, 9 to 67 weeks) and the median survival time was 29 weeks. Grade 3 to 4 toxicities included granulocytopenia (nine patients), diarrhea (three patients), oral mucositis (seven patients), skin rash (one patient), and fatigue (four patients). One patient died of neutropenic sepsis. This regimen had modest activity with significant toxicity and produced responses of short duration. It did not appear to be superior to existence of metastatic gastric carcinoma. Cancer 1992; 69:878–882.

Phase I evaluation of AT-125 single dose every three weeks

SummaryA Phase I trial of AT-125 was completed for the bolus dose every three week schedule. Dose limiting toxicity was primarily central nervous system (CNS) in the form of ataxia, confusion, hallucinations and dysarthria. Although this was most severe at doses of 150 mg/m2, lesser symptoms were reported at all dose levels. Nausea and vomiting were moderate to severe at higher doses. Myelosuppression did not occur. This schedule is not recommended for Phase II studies until methods are developed to reduce drug-related CNS toxicity.

Phase II trial of piroxantrone for advanced or metastatic soft tissue sarcomas : a southwest oncology group study

SummaryPiroxantrone is an anthrapyrazole compound undergoing phase II testing in a variety of diseases. The anthrapyrazoles are a series of compounds synthesized with the intent of maintaining the broad antitumor activity of anthracyclines, but with lessened cardiac toxicity. The Southwest Oncology Group (SWOG) conducted a phase II trial of piroxantrone in advanced soft tissue sarcoma. Treatment consisted of piroxantrone 150 mg/M2 administered intravenously over 1 hour every 21 days. Twenty-five eligible patients were registered to the trial. Twenty-three patients received treatment and are fully evaluable for response and toxicity. Two partial responses were seen for an overall response rate of 9% (95% confidence limit 1%–28%). Abnormal cardiac ejection fraction occurred in five patients, and fatal congestive heart failure developed in one patient on study. Toxicities other than cardiac were tolerable. Based on the observed response rate and cardiac toxicity, further trials of piroxantrone in the treatment of soft tissue sarcoma do not appear warranted.

Phase I evaluation of chlorozotocin: single dose every six weeks.

A phase I trial of chlorozotocin was completed for the single dose every six week schedule. At 250 mg/m2 i.v. push, excessive thrombocytopenia, nausea, and anorexia occurred. Two cases of cholestatic jaundice were seen, and one patient had worsening of his diabetes mellitus after one course. Partial response or prolonged disease stabilization with increased survival was documented in four of seven patients with non‐small cell carcinoma of the lung. A starting dose of 225 mg/m2 is recommended for good risk patients with little or no prior bone marrow toxicity from chemotherapy or irradiation. A dose of 200 mg/m2 is recommended for patients with limited previous treatment and good bone marrow reserve.

Phase I-II study of ftorafur and methyl-CCNU in advanced colorectal cancer.

The combination of Ftorafur (NSC‐148958) and methyl‐CCNU (NSC‐95441) was evaluated in 36 patients with advanced colorectal cancer. The principle toxicities encountered were myelosuppression, gastrointestinal, and neurological. There were no complete responses and only 5/34 (14.7%) patients achieved a partial response. Methyl‐CCNU and Ftorafur does not appear to be an effective combination in advanced adenocarcinoma of the colon and rectum.