ABSTRACT
Adrenocortical carcinoma (ACC) is an aggressive malignancy, which lacks an effective systemic treatment. Abnormal activation of insulin-like growth factor receptor 1 (IGF1R) has been frequently observed. Preclinical studies demonstrated that pharmacological inhibition of IGF1R signaling in ACC has antiproliferative effects. A previous phase I trial with an IGF1R inhibitor has demonstrated biological activity against ACC. The objective of this study is to assess the efficacy of the combination of the IGF1R inhibitor cixutumumab (IMC-A12) in association with mitotane as a first-line treatment for advanced/metastatic ACC. We conducted a multicenter, randomized double-arm phase II trial in patients with irresectable recurrent/metastatic ACC. The original protocol included two treatment groups: IMC-A12 + mitotane and mitotane as a single agent, after an initial single-arm phase for safety evaluation with IMC-A12 + mitotane. IMC-A12 was dosed at 10 mg/kg intravenously every 2 weeks. The starting dose for mitotane was 2 g daily, subsequently adjusted according to serum levels/symptoms. The primary endpoint was progression-free survival (PFS) according to RECIST (Response Evaluation Criteria in Solid Tumors). This study was terminated before the randomization phase due to slow accrual and limited efficacy. Twenty patients (13 males, 7 females) with a median age of 50.2 years (range 21.9-79.6) were enrolled for the single-arm phase. Therapeutic effects were observed in 8/20 patients, including one partial response and seven stable diseases. The median PFS was 6 weeks (range 2.66-48). Toxic events included two grade 4 (hyperglycemia and hyponatremia) and one grade 5 (multiorgan failure). Although the regimen demonstrated activity in some patients, the relatively low therapeutic efficacy precluded further studies with this combination of drugs.
Subject(s)
Adrenal Cortex Neoplasms/drug therapy , Adrenocortical Carcinoma/drug therapy , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mitotane/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Female , Humans , Male , Middle Aged , Mitotane/administration & dosage , Mitotane/adverse effects , National Cancer Institute (U.S.) , United States , Young AdultABSTRACT
INTRODUCTION: Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors-1, -2, and -3. METHODS: We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily. RESULTS: Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR+SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥grade 3 hypertension (8.5 vs. 4.1 months, p=0.024). CONCLUSION: This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated.
Subject(s)
Antineoplastic Agents/therapeutic use , Mesothelioma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Female , Humans , Male , Mesothelioma/mortality , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Quinazolines/administration & dosage , Quinazolines/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-ß, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. PATIENTS AND METHODS: We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of a 28 day cycle. RESULTS: Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. CONCLUSION: Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzenesulfonates/administration & dosage , Chicago , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Niacinamide/analogs & derivatives , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Phenylurea Compounds , Pyridines/administration & dosage , Sorafenib , Time Factors , Treatment Outcome , Universities , GemcitabineABSTRACT
OBJECTIVES: To determine the efficacy and safety of single agent sorafenib, an oral multi-targeted tyrosine kinase inhibitor, in patients with advanced uterine carcinoma and carcinosarcoma. METHODS: This multi-institutional non-randomized phase II trial enrolled two cohorts: patients with uterine carcinoma (cohort A) and uterine carcinosarcoma (cohort B). Eligibility criteria included measurable disease, 0-1 prior chemotherapy regimens, and ECOG performance status Subject(s)
Antineoplastic Agents/therapeutic use
, Benzenesulfonates/therapeutic use
, Carcinoma/drug therapy
, Carcinosarcoma/drug therapy
, Pyridines/therapeutic use
, Uterine Neoplasms/drug therapy
, Adult
, Aged
, Aged, 80 and over
, Antineoplastic Agents/adverse effects
, Benzenesulfonates/adverse effects
, Disease-Free Survival
, Female
, Humans
, Middle Aged
, Neoplasm Recurrence, Local/drug therapy
, Niacinamide/analogs & derivatives
, Phenylurea Compounds
, Pyridines/adverse effects
, Sorafenib
, Survival Rate
ABSTRACT
PURPOSE: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. EXPERIMENTAL DESIGN: Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. RESULTS: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. CONCLUSIONS: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Sarcoma/drug therapy , Adult , Aged , Anemia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carmustine/administration & dosage , Carmustine/adverse effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Female , Gastrointestinal Stromal Tumors/drug therapy , Guanine/administration & dosage , Guanine/adverse effects , Guanine/analogs & derivatives , Humans , Immunohistochemistry , Infant , Injections, Intravenous , Leiomyosarcoma/drug therapy , Male , Middle Aged , O(6)-Methylguanine-DNA Methyltransferase/antagonists & inhibitors , O(6)-Methylguanine-DNA Methyltransferase/metabolism , Survival Analysis , Tachycardia, Supraventricular/chemically induced , Thrombocytopenia/chemically induced , Treatment OutcomeABSTRACT
INTRODUCTION: Despite the extensive clinical experience with irinotecan, significant concerns remain regarding its toxicity. In a phase I trial, we modulated irinotecan pharmacokinetics by inhibiting biliary excretion of SN-38, the active metabolite of irinotecan, using cyclosporine. The modulation appeared to decrease the gastrointestinal toxicity of irinotecan and suggested that irinotecan activity might also be retained. Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine. PATIENTS AND METHODS: Sixteen patients with 5-fluorouracil refractory CRC were treated. Cyclosporine (5 mg/kg) was administered as a 6-h infusion and irinotecan (60 mg/m2/day, 90-min infusion) was started 3 h after initiation of the Cyclosporine. Both agents were given weekly for 4 weeks, every 6 weeks. Responses were assessed every 12 weeks, and toxicity was monitored weekly. RESULTS: Sixteen patients were evaluable for toxicity and 11 for response. There was 1 partial response (6%). Five patients had SD lasting a median of 12 weeks. Grade 3/4 diarrhea was observed in only 13% of the patients. CONCLUSION: Pharmacokinetic modulation of irinotecan using parenteral cyclosporine appears to decrease the incidence of diarrhea in CRC patients. Given the modest activity of irinotecan monotherapy, a larger study would be required to assess if the modulation improves the toxicity without compromising this activity. The available clinical data suggest that pharmacokinetic modulation of irinotecan should be evaluated further to define its optimal clinical utility.
Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Cyclosporine/therapeutic use , Immunosuppressive Agents/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Phytogenic/therapeutic use , Camptothecin/adverse effects , Camptothecin/therapeutic use , Drug Interactions , Female , Humans , Irinotecan , Male , Middle AgedABSTRACT
Enterococci are uncommon causes of CNS infection. We describe a case of ventriculitis and Ommaya reservoir infection due to vancomycin-resistant Enterococcus faecium successfully treated with the combination of i.v. quinupristin/dalfopristin and i.v. linezolid. The patient deteriorated after receiving three dosages of intraventricular quinupristin/dalfopristin. He recovered after discontinuation of intraventricular quinupristin/dalfopristin.