The cardiovascular, renal, pulmonary, and dermatologic toxicities of interleukin-2 (IL-2) and gamma-interferon (IFN) are well described. However, autoimmune toxicities have only recently been noticed. The authors report the development of warm autoantibodies against erythrocytes in a patient receiving IL-2 (3.75 × 106 cetus units/m2 intravenous bolus three times per week) and gamma-IFN (0.1 mg/m2 subcutaneously three times per week) for metastatic renal cell carcinoma. Other potential causes of autoantibody formation, such as drugs, infection, and collagen vascular disease, were excluded. Both gamma-IFN and IL-2 have the potential to trigger or exacerbate autoimmunity due to either aberrant expression of restricted antigens or inhibition of normal cellular immune suppressor mechanisms.
A phase I study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor effect of mapatumumab, a fully-human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, DR4), in combination with paclitaxel and carboplatin.Patients with advanced solid malignancies received 3, 10, or 20 mg/kg of mapatumumab with standard doses of paclitaxel and carboplatin every 21 days for up to six cycles in the absence of disease progression. Additional cycles of paclitaxel and/or mapatumumab were permissible in selected cases.Twenty-seven patients (21 males), with a median age of 54 years, received mapatumumab in the following three cohorts: 3 mg/kg (n = 4), 10 mg/kg (n = 11), and 20 mg/kg (n = 12). The median number of cycles was four. Dose-limiting toxicities (DLTs) were grade 3 hypersensitivity reaction (n = 1) and neutropenic fever (n = 1), both at 10 mg/kg. Non-DLT treatment-related adverse events occurring in more than 10% of administered doses included alopecia, neutropenia, fatigue, nausea, anemia, thrombocytopenia, anorexia, and neuropathy. Paclitaxel and carboplatin exposures were similar in the presence or absence of mapatumumab. Plasma mapatumumab concentrations seemed similar to data from previous phase I monotherapy studies. Five patients (19%) achieved a confirmed radiologic partial response (including one pathologic complete response), and 12 patients (44%) had stable disease as their best response.Mapatumumab is well-tolerated up to 20 mg/kg in combination with paclitaxel and carboplatin. There are no apparent pharmacokinetic interactions among the drugs. Preliminary anticancer activity demonstrated clinical benefit for the majority of these patients.
Thirty-one patients with advanced metastatic carcinoma of the prostate were treated with the antiestrogen tamoxifen. Of these patients, 29 were refractory to prior hormonal manipulation with estrogens and/or orchiectomy and five achieved an objective response (partial regression of stable disease using National Prostatic Cancer Project criteria). Median survival of the responders was significantly longer than that of the nonresponders (P < 0.05). Two additional patients who had not previously received hormonal therapy both responded, for an overall response rate of 23% (seven of 31 patients). Toxicity was minimal and no tumor flares were reported. These preliminary results support the further clinical trial of tamoxifen in advanced cancer of the prostate.
Purpose To assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of mapatumumab (HGS-ETR1, TRM-1), a fully human agonist monoclonal antibody directed to the tumor necrosis factor–related apoptosis-inducing ligand receptor-1 (TRAIL-R1). Patients and Methods Patients with advanced solid malignancies were treated with escalating doses of mapatumumab intravenously (IV) administered over 30 to 120 minutes, initially as a single dose and then repetitively. Plasma mapatumumab concentrations were measured and serum was assayed to detect human antimapatumumab antibody formation. Archival tumor specimens were collected to detect the presence of TRAIL-R1 by immunohistochemistry. Results Forty-nine patients received 158 courses at doses ranging from 0.01 to 10 mg/kg IV. Initially, patients received mapatumumab as a single dose, then every 28 days repetitively, and then 10 mg/kg every 14 days. Mild (grade 1 or 2) fatigue, fever, and myalgia were the most frequently reported nonhematologic adverse events related to mapatumumab, whereas hematologic toxicity was not clinically significant. The mean (± standard deviation) clearance and terminal elimination half-life values for mapatumumab at 10 mg/kg every 14 days were 3.7 mL/d/kg (± 1.5 mL/d/kg) and 18.8 days (± 10.1 days), respectively. TRAIL-R1 was documented in 68% of patients' tumors assayed. Nineteen patients had stable disease, with two lasting 9 months. Conclusion Mapatumumab can be administered safely and feasibly at 10 mg/kg IV every 14 days. The absence of severe toxicities and the attainment of plasma mapatumumab concentrations that are active in preclinical models warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.
Macrophage colony-stimulating factor (M-CSF) is a known inducer of proliferation and differentiation of cells of the mononuclear phagocyte lineage, and gamma-interferon (gamma-IFN) is a known activator of mononuclear phagocytes. In this Phase I clinical trial of combined therapy with M-CSF and gamma-IFN, 36 patients were treated with 14-day continuous infusions of M-CSF at doses ranging from 10 to 140 micrograms/kg/day. In all but five patients, gamma-IFN was administered by daily s.c. injection on days 8-14 of the M-CSF infusion at doses of 0.05 or 0.1 mg/m2/day. A total of 73 courses of M-CSF and 66 courses of gamma-IFN were administered. The maximally tolerated dose combination was 120 micrograms/kg/day M-CSF, 0.1 mg/m2/day gamma-IFN. The addition of gamma-IFN did not alter the maximally tolerated dose of M-CSF therapy, although some additional toxicities were noted with combined therapy. At the 140-micrograms/kg/day M-CSF dose level, grade 4 thrombocytopenia occurred in 2 of 3 patients, with a median platelet count nadir of 26,000/mm3 after 7-10 days of M-CSF infusion. At this dose level, there was one reversible grade 3 hepatic toxicity, and one grade 3 exacerbation of underlying chronic obstructive lung disease. Peripheral blood monocytosis was observed at all M-CSF dose levels exceeding 40 micrograms/kg/day, approaching 3-fold elevations at the 100-micrograms/kg/day M-CSF dose level. The induction of monocytosis was correlated with the development of thrombocytopenia. At the conclusion of therapy with 100 micrograms/kg/day M-CSF, 0.1 mg/m2/day gamma-IFN, 78% of peripheral blood monocytes expressed the low affinity Fc gamma receptor for aggregated immunoglobulin, Fc gamma RIII (CD16), and CD14 was expressed by only 36% of the cells. This phenotype has been shown previously to be associated with cellular activation. In contrast, 35% of monocytes from patients treated with M-CSF therapy alone at the same dose expressed CD16 and 88% expressed CD14. A partial clinical response was noted in a patient with metastatic renal cell carcinoma, and minor clinical responses were observed in patients with a diffuse/follicular lymphoma, metastatic renal cell carcinoma, and metastatic thymoma. At M-CSF doses exceeding 20 micrograms/kg/day within the maximally tolerated dose range, gamma-IFN did not modulate the ability of M-CSF to reliably induce peripheral blood monocytosis. This study shows that M-CSF and gamma-IFN therapy induces the proliferation and differentiation of circulating mononuclear phagocytes.
A phase I trial was performed to evaluate the feasibility of escalating the dose of etoposide in dose-intensive ifosfamide, carboplatin, and etoposide (ICE) with granulocyte-macrophage colony-stimulating factor (GM-CSF).Twenty-four patients were entered between November 1990 and November 1991. Patients received ifosfamide 5 g/m2 by continuous infusion over 48 hours, carboplatin 400 mg/m2 by intravenous bolus, and GM-CSF 5 micrograms/kg/d subcutaneously from day 4 until neutrophil recovery. The etoposide dose was escalated, with six patients receiving 300 mg/m2 total dose (level 1), six receiving 600 mg/m2 (level 2), three receiving 900 mg/m2 (level 3), and five receiving 1,200 mg/m2 (level 4). Level 4B consisted of three patients who received etoposide 1,200 mg/m2 and GM-CSF 10 micrograms/kg/d. Cycles were repeated every 21 days. The maximum-tolerated dose (MTD) was prospectively defined as the dose level at which the next higher level produced greater than 7 days of grade 4 myelosuppression in two or more of six patients.Twenty-three patients were assessable. The median duration of neutropenia was < or = 7 days on cycle 1 at all dose levels. The initial criteria for determination of the MTD was never achieved. However, seven of eight patients treated at levels 4 and 4B required hospitalization for neutropenic fever on cycle 1 of therapy, with three of four septic events occurring at these levels. Cumulative thrombocytopenia occurred at all dose levels, with > or = 50% of patients requiring platelet transfusions on cycle 3. This became the dose-limiting toxicity above level 3. The overall response rate was 48%, with 11 of 23 objective responses, including two complete responses (CRs). Seven of 11 (64%) patients with non-small-cell lung cancer (NSCLC) responded, including one CR. Two of four (50%) heavily pretreated non-Hodgkin's lymphoma (NHL) patients responded, with one CR.The addition of GM-CSF to a dose-intensive ICE regimen permitted dose escalation of etoposide to 900 mg/m2, with cumulative thrombocytopenia as the dose-limiting toxicity. Carboplatin dosing by the area under the curve (AUC) may minimize thrombocytopenia. This appears to be an active regimen for patients with NSCLC and refractory NHL.
Fifty-one patients with advanced metastatic carcinoma of the prostate were treated with the antiestrogen tamoxifen. Thirty-eight of these patients were refractory to prior hormonal manipulation with estrogens and/or orchiectomy, and five (13%) achieved an objective response (partial regression or stable disease using the National Prostate Cancer Project criteria). Median survival of the responders was significantly longer than that of the nonresponders (P < 0.05). An additional 13 patients who had not previously received hormonal manipulation were treated with tamoxifen; one partial response and three disease stabilizations were noted. Response was separately evaluated for 15 patients with objectively measurable lesions using standard Phase II response criteria. Only 1/15 (7%) partial response and 3/15 (20%) disease stabilizations were documented. Subjective benefit in terms of significant pain relief was noted in 17/50 (34%) of patients. Toxicity was mild, but two possible "tumor flares" were noted. These results do not support the continued investigation of tamoxifen in advanced carcinoma of the prostate.
Journal Article Depletion of Glutathione in Normal and Malignant Human Cells In Vivo by Buthionine Sulfoximine: Clinical and Biochemical Results Get access P. J. O'Dwyer, P. J. O'Dwyer * Fox Chase Cancer CenterPhiladelphia, Pa. *Correspondence to : P. J. O'Dwyer, M.D., Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme AVE., Philadelphia, PA 19111. Search for other works by this author on: Oxford Academic PubMed Google Scholar T. C. Hamilton, T. C. Hamilton Fox Chase Cancer CenterPhiladelphia, Pa. Search for other works by this author on: Oxford Academic PubMed Google Scholar R. C. Young, R. C. Young Fox Chase Cancer CenterPhiladelphia, Pa. Search for other works by this author on: Oxford Academic PubMed Google Scholar F. P. LaCreta, F. P. LaCreta Fox Chase Cancer CenterPhiladelphia, Pa. Search for other works by this author on: Oxford Academic PubMed Google Scholar N. Carp, N. Carp Fox Chase Cancer CenterPhiladelphia, Pa. Search for other works by this author on: Oxford Academic PubMed Google Scholar K. D. Tew, K. D. Tew Fox Chase Cancer CenterPhiladelphia, Pa. Search for other works by this author on: Oxford Academic PubMed Google Scholar K. Padavic, K. Padavic Fox Chase Cancer CenterPhiladelphia, Pa. Search for other works by this author on: Oxford Academic PubMed Google Scholar R. L. Comis, R. L. Comis Fox Chase Cancer CenterPhiladelphia, Pa. Search for other works by this author on: Oxford Academic PubMed Google Scholar R. F. Ozols R. F. Ozols Fox Chase Cancer CenterPhiladelphia, Pa. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 4, 19 February 1992, Pages 264–267, https://doi.org/10.1093/jnci/84.4.264 Published: 19 February 1992 Article history Received: 22 April 1991 Revision received: 12 November 1991 Accepted: 04 December 1991 Published: 19 February 1992
2515 Background: HGS-ETR1 (mapatumumab) is a fully-human monoclonal antibody agonistic to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1, DR4). Activation of TRAIL-R1 by HGS-ETR1 initiates a caspase cascade leading to apoptosis. HGS-ETR1 in combination with platinum or taxanes results in at least additive activity in preclinical models. Phase 1 and 2 trials have demonstrated that single agent HGS-ETR1 is well tolerated. Methods: This Phase 1 study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of HGS-ETR1 in combination with standard doses of paclitaxel and carboplatin. Patients received 3, 10 or 20 mg/kg HGS-ETR1 with paclitaxel (200 mg/m 2 ) and carboplatin (AUC 6) every 21 days for up to 6 cycles in the absence of disease progression. Results: Enrollment is complete; 28 patients have received 106 cycles of HGS-ETR1, including 12 patients in each of the 10 mg/kg and 20 mg/kg cohorts. Fourteen of 28 pts received at least 3 cycles (median = 2.5, range 1–12). Dose-limiting toxicity has been neutropenic fever (attributed to chemotherapy) and hypersensitivity (attributed to HGS-ETR1). Other non-dose limiting adverse events at least possibly related to HGS-ETR1 include fatigue, myalgia, transaminitis, anorexia and arthralgia. Preliminary analyses reveal that carboplatin and paclitaxel PK are not affected by HGS-ETR1. Similarly, the PK profile of HGS-ETR1 is not affected by paclitaxel and carboplatin, with plasma HGS-ETR1 concentrations consistent with those observed in the Phase 1 single agent trials. Three patients with NSCLC and 1 with adenocarcinoma of an unknown primary have experienced a confirmed partial response. Conclusions: HGS-ETR1 can be safely administered with carboplatin and paclitaxel. Evaluation of HGS-ETR1 in combination with other chemotherapeutic regimens is warranted. [Table: see text]
