James A. Neidhart

Phase 1 Trial of Recombinant Human Interleukin-1β (rhIL-1β), Carboplatin, and Etoposide in Patients with Solid Cancers: Southwest Oncology Group Study 8940

Recombinant human interleukin-1β (rhIL-1β) was evaluated in a phase 1 Clinical Trial in which patients with metastatic or unresectable solid tumors received carboplatin and etoposide in cycle 1 and carboplatin, etoposide, and rhIL-1β in cycle 2. Recombinant hIL-1β was given intravenously for 5 days in one of three schedules: (1) immediately postchemotherapy, (2) delayed for 5 days after chemotherapy, or (3) concurrently with chemotherapy. Four dose levels of rhIL-1β were evaluated: 20, 50, 100, and 200 ng/kg. The doses of carboplatin and etoposide were not changed between cycle 1 and cycle 2 so that the effect ofrhlL-1β on chemotherapy-induced hematotoxicity was evaluated; 54 patients were entered on study and 42 patients received at least two cycles of therapy and were thus evaluablefor rhIL-1β toxicity and for the effect ofrhIL-1β on hematotoxicity of carboplatin andetoposide. The major toxicities of rhIL-1β were chills, rigors, headache, fatigue, and hypotension. The maximum tolerated dose of rhIL-1β w...

Phase II study of pibenzimol in pancreatic cancer - A Southwest Oncology Group study

SummaryTwenty-three patients with advanced pancreatic adenocarcinoma were treated with Pibenzimol utilizing a daily intravenous schedule for five days. There were no objective responses seen. The major toxicity was pancreatic with grade 3 hyperglycemia in eleven patients. Pibenzimol is inactive in patients with advanced pancreatic adenocarcinoma.

Dose-intensive treatment of breast cancer supported by granulocyte-macrophage colony-stimulating factor (GM-CSF)

SummarySubstantial intensification of chemotherapy doses is a promising approach to the treatment of refractory malignancy currently receiving increasing attention. For the past 4 years we have used 3 repeated cycles of a combination of cyclophosphamide (5 g/m2), etoposide (1500 mg/m2), and cisplatin (150 mg/m2) without replacement of progenitor cells and with and without colony-stimulating factor support. The duration of threatening levels of granulocytopenia with this regimen averages 10.2 days, although an occasional patient has prolonged recovery (range, 5–20 days) and most patients require antibiotic therapy for cytopenic fever. We have not yet identified the optimal dose of GM-CSF, but 500 µg/m2 significantly shortens the duration of cytopenia (ANC < 300/mm3) to 5.9 days with a resultant decrease in incidence and duration of cytopenic fever (from 10.8 to 1.7 days), use of antibiotics (from 10.8 to 7.6 days), and duration of hospitalization (from 22.2 to 16.3 days). Seventeen patients with metastatic breast cancer have received this regimen to date with a 35% complete response (CR) rate and a 53% partial response (PR) rate. Most of these patients were refractory to standard therapy. Four of six (67%) not refractory to standard therapy have achieved complete responses that are ongoing at 3.5 to 10.4 months. We conclude that dose-intensive therapy is an option that needs more careful exploration early in the treatment of advanced breast cancer and that GM-CSF decreases morbidity and risk of dose-intensive regimens.

Hematopoietic cytokines. Current use in cancer therapy.

The introduction of hematopoietic cytokines into the clinic has been rapid with three currently approved by the Food and Drug Administration and perhaps a dozen more in clinical trials. Combinations of cytokines have been relatively unexplored in the clinics. Knowledge about the use of cytokines with chemotherapy has grown considerably in the past few years.

Multiple Cycles of Dose-Intensive Cyclophosphamide, Etoposide, and Cisplatinum (DICEP) Produce Durable Responses in Refractory Non-Hodgkin's Lymphoma

Patients whose lymphoma is resistant to standard treatment regimens continue to do poorly, with only an occasional patient achieving long-term remission even with bone marrow transplantation. Twenty-three patients with primarily refractory (11), or refractory relapsed (12) non-Hodgkins lymphoma were treated with repeated cycles of dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP) without bone marrow transplantation. Each cycle of DICEP consisted of cyclophosphamide (2500 mg/m2/day, days 1-2), etoposide (500 mg/m2/day, days 1-3), and cisplatin (50 mg/m2/day, days 1-3). Twelve patients (52%) have achieved a complete response and 6 (26%)r a partial response. Three of the complete responders remain continuously free of disease for 19, 29, and 32 months, and 3 more are disease-free at 58, 59, and 65 months after receiving further therapy. Three-year survival for all patients is 45%. Patients with a good initial performance status (Zubrod 0 or 1) had a 58% complete response rate and a 2-year survival rate of 53%. One of 19 patients with an initial performance status of 0 or 1 had treatment-related mortality. Repeated cycles of DICEP can produce long-term responses in patients with refractory non-Hodgkins lymphoma.

Multicenter phase II study of brequinar sodium in patients with advanced gastrointestinal cancer

SummaryEighty-six patients with advanced colorectal, gastric or pancreatic carcinoma and no prior exposure to chemotherapy were treated with brequinar sodium. Brequinar was administered at a median weekly dose of 1200 mg/m2 intravenously. The toxicity was moderate, with thirty patients (35%) experiencing grade 3 or 4 toxicity. Objective responses were observed in 1/32 evaluable colorectal and 2/29 evaluable gastric carcinoma patients. There were no objective responses in 17 evaluable pancreatic cancer patients. We conclude that, at this dose and schedule, brequinar does not have sufficient activity in these gastrointestinal malignancies to warrant further evaluation.

SWOG 8825: Melphalan GM-CSF: A phase I study

The use of intravenous melphalan at higher doses is limited by severe myelosuppression. It was postulated that GM-CSF would permit the use of higher dose melphalan with only moderate myelosuppression easily manageable in an outpatient setting. Therefore, a phase I study of intravenous melphalan utilizing GM-CSF (recombinant granulocyte-macrophage colony-stimulating factor) support was initiated. Intravenous melphalan at doses of 15-45 mg/m2 was administered every 28 days. GM-CSF was utilized at doses of 10-20 micrograms/kg/day subcutaneously Days 2-21 on a 28-day cycle. Twenty-five patients received 53 courses of therapy. The dose-limiting toxicities were severe or life-threatening granulocytopenia and thrombocytopenia. Utilizing 20 micrograms/kg/day GM-CSF, the maximum tolerated dose (MTD) of melphalan is 30 mg/m2 and, with 10 mg/kg/day GM-CSF, the maximum tolerated melphalan dose is only 20 mg/m2. One patient with ovarian cancer achieved a partial response. Because the reported MTD of intravenous melphalan without GM-CSF is 30 mg/m2, GM-CSF has not allowed sufficient escalation of the intravenous melphalan dose for routine outpatient use.

Phase II study of L-alanosine (NSC 153353) in patients with advanced breast cancer. A Southwest Oncology Group study.

Daniel D. Von Hof f 1, Stephanie J. Green 2, James A. Neidhart 3, Carol Fabian 4, Thomas Budd 5, James F. Boyd 6 and C. Kent Osborne 1 1University of Texas Health Science Center, San Antonio, Texas, 2Southwest Oncology Group Biostatistical Center, Seattle, Washington, 3University o f New Mexico, Albuquerque, New Mexico, 4University of Kansas Medical Center, Kansas City, Kansas, 5Cleveland Clinic Foundation, Cleveland, Ohio, 6Brooke Army Medical Center, Fort Sam Houston, USA

Dose-Intensification Chemotherapy for Patients With Advanced Breast Cancer.

It is now possible to adminster doses of chemotherapy several-fold those used in standard treatment regimens. This can be done with relative safety, and in patients with metastatic breast cancer or refractory nonHodgkins lymphoma such treatment produces a high complete-remission rate. Some patients enjoy a long-term disease-free survival following dose-intensive therapy. Chemotherapy intensified to this degree produces prolonged periods of myelosuppression. This can be managed rather well with progenitor-cell infusion and cytokine support. There is little experience with such regimens in the treatment of locally advanced or locally aggressive breast cancer. However, early experience in several institutions, including our own is encouraging. In this article the rationale for dose intensity, the experience in metastatic breast cancer, and the available information on outcomes in locally advanced cancer are reviewed. The appropriate role for dose-intensive chemotherapy in locally advanced breast cancer treatment remains to be defined.

GM-CSF, carboplatin, doxorubicin: a phase I study

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m2, administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1–21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m2, 325 mg/m2 and 400 mg/m2. At carboplatin 400 mg/m2 and doxorubicin 60 mg/m2, thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m2, doxorubicin 60 mg/m2, and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.