Background Median overall survival for patients with metastatic soft tissue sarcoma is 12 to 16 months. Olaratumab is a human anti–platelet-derived growth factor receptor α monoclonal antibody which has antitumour activity in human sarcoma xenografts. Methods We conducted an open-label phase 1b, randomised, phase 2 study of doxorubicin ± olaratumab in patients with unresectable/metastatic soft tissue sarcoma. The phase 1b primary endpoint was safety; the phase 2 primary endpoint was progression-free survival using a two-sided alpha level of 0·2 and statistical power of 0·8. This study was registered with ClinicalTrials.gov, number NCT01185964. Findings Fifteen patients were enrolled and treated with olaratumab+doxorubicin in the phase 1b portion; 133 patients were randomised (66 to olaratumab+doxorubicin; 67 to doxorubicin) in the phase 2 portion, 129 of whom (97%) received at least one dose of study treatment (64 olaratumab+doxorubicin; 65 doxorubicin). Median progression-free survival in phase 2 was 6·6 months (95% confidence interval [CI], 4·1–8·3) with olaratumab+doxorubicin and 4·1 months (95% CI, 2·8–5·4) with doxorubicin (stratified hazard ratio [HR], 0·672; 95% CI, 0·442–1·021; p=0·0615). Median overall survival was 26·5 months (95% CI, 20·9–31·7) with olaratumab+doxorubicin and 14·7 months (95% CI, 9·2–17·1) with doxorubicin (stratified HR, 0·463; 95% CI, 0·301–0·710; p=0·0003). Adverse events more frequent with olaratumab+doxorubicin vs doxorubicin alone included neutropenia (38 [59%] vs 25 [39%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [19%]), and diarrhea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade ≥3 was similar in both groups (olaratumab plus doxorubicin 8 (13%) vs doxorubicin 9 (14%). Interpretation This study of olaratumab with doxorubicin in patients with advanced soft tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11·8 months in median overall survival (P=0·0003; HR 0·46). Funding Eli Lilly and Company.
Purpose: The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma. Patients and Methods: TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m2 with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle. Results: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m2. DLTs at 340 mg/m2 were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Conclusions: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.
PurposeTherapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies.Experimental DesignWe conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2nd cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and <30% of liver involvement. The primary endpoint was RECIST response. Serial biopsies were performed at baseline and after 2 cycles of therapy.ResultsForty-seven patients were enrolled (24:Cohort 1, 23:Cohort 2). Patients were heavily pre-treated (median prior therapies 4: Cohort 1 and 2.5: cohort 2). No responses were observed. Median progression-free survival was 1.9 months; overall survival was 5.6 and 8.3 months in Cohorts 1 and 2, respectively. Toxicity was tolerable and as expected. Unsupervised cluster analysis of serial tumor biopsies suggested greater DNA demethylation in patients with PFS above the median.ConclusionIn this first trial of CRC patients with combination epigenetic therapy, we show tolerable therapy without significant clinical activity as determined by RECIST responses. Reversal of hypermethylation was seen in a subset of patients and correlated with improved PFS.
HE long-term survival of donor lymphoid cells in recipients of solid-organ transplants or of fetal lymphocytes that cross the placenta and enter the maternal circulation has been established, 1-3 but the fate of other hematopoietic progenitors in organ allografts, especially those of the myeloid lineage, is not known. We describe a case in which acute promyelocytic leukemia developed in a recipient of a liver transplant two years after transplantation. The leukemic clone had genetic and phenotypic markers of the donor, a previously healthy 16-year-old boy who died of a head injury. Our findings indicate that leukemic transformation of donor myeloid cells that were resident in the transplanted liver occurred in this patient. CASE REPORTA 57-year-old woman presented with fatigue, palpitations, malaise, and diarrhea. She had a history of primary biliary cirrhosis and had received a liver transplant two years earlier from an unrelated 16-year-old boy who suffered a head injury while playing football and subsequently died of a subdural hematoma. The patient had two episodes of acute graft rejection 2.5 and 17 months after transplantation but never had symptoms or signs of graftversus-host disease. At the time of the most recent presentation, she was taking prednisone (7.5 mg per day) and cyclosporine (100 mg twice daily) for post-transplantation immunosuppression. The patient had no history of exposure to radiation or alkylating agents and no family history of cancer.The patient appeared pale and ill and had cushingoid features. There were multiple ecchymoses on her arms and legs. There was no mucosal bleeding or gingival hyperplasia. The hemoglobin level was 10.7 g per deciliter, the white-cell count was 5200 per cubic millimeter, and the platelet count was 41,000 per cubic millimeter. A blood smear showed 18 percent leukemic cells (blasts T and dysplastic promyelocytes). The results of coagulation tests were consistent with findings of disseminated intravascular coagulation and were as follows: prothrombin time, 17.2 seconds (normal range, 11.0 to 13.0); partial-thromboplastin time, 29.7 seconds (normal range, 21.1 to 32.1); fibrin-and fibrinogen-degradation products, 128 mg per liter (normal value, <8 mg per liter); and fibrinogen, 35 mg per deciliter (normal range, 150 to 360 mg per deciliter).Bone marrow aspiration and biopsy confirmed the diagnosis of the microgranular variant of acute promyelocytic leukemia, with 80 percent blast cells. As determined by flow cytometry, the leukemic cells expressed CD33, CD13, and CD34, but not HLA-DR, results that are consistent with the diagnosis of acute promyelocytic leukemia.Antibiotics, cryoprecipitate, and heparin (600 U per hour) were administered. Alltrans -retinoic acid (tretinoin), at a dose of 45 mg per square meter of body-surface area per day, was begun the day after diagnosis. Mild respiratory distress developed several hours before the first dose of alltrans -retinoic acid. The patient's clinical status deteriorated rapidly, and within 12 hours severe hypotension...
to effect their critical functions. Certain myeloid growth factors, including G-CSF, inhibit random migration of neutrophils in vitro and theoretically may alter neutrophil G-CSF administration to normal donors results in granulocyte apheresis yields generally greater than those migration to these sites in vivo. 11 To assess the distribution of G-CSF-mobilized neutrophils in vivo, LA products col-observed with other neutrophil mobilizing agents. In vitro, neutrophils cultured with G-CSF exhibit pro-lected from normal donors receiving G-CSF were labeled with indium-111 and infused into neutropenic allogeneic longed survival; however, the random migration of neutrophils exposed to this agent is inhibited. Although BMT recipients. Serial scintigraphic images were obtained post-infusion. Results of this pilot study of five patients transfused neutrophils mobilized with agents other than G-CSF migrate to sites of inflammation or infection in support the hypothesis that G-CSF-mobilized neutrophil products retain their ability to localize to sites of inflam-vivo, this has yet to be demonstrated with infusion of G-CSF-mobilized neutrophils into neutropenic human mation in vivo. subjects. Five neutropenic allogeneic bone marrow transplant (BMT) patients each received a fresh infusion of G-CSF-mobilized indium-labeled irradiated Methods white blood cells (WBC) apheresed from HLA-matched normal donors on day +5 post-transplant. Localization In all cases, the donor of the granulocyte apheresis products was also the donor of the bone marrow product for each of activity on delayed scintigraphic images of indiumlabeled WBC scans to sites of tissue damage recipient. The protocol was approved by the Institutional Review Board and accrued five donor/recipient pairs. Eligi-(oral/nasopharynx in two patients with mucositis and terminal ileum/cecum in one with diarrhea) occurred, bility criteria for donors included age у15 and р70 years, WBC у4000/l, ANC у1500/l, platelet count and supports the hypothesis that G-CSF-mobilized HLA-matched donor neutrophils which have been у100 000/l, hematocrit (Hct) у30%. All donors were HLA-A, B, DR six antigen serologic matched and ABO irradiated are functional after infusion into neutropenic recipients. compatible with the recipients. Otherwise, donors satisfied standard blood donation criteria as determined by the Food Keywords: granulocyte transfusions; G-CSF; indium labeled and Drug Administration (FDA) and as interpreted by the Blood Bank Director. Recipients between the ages of 15 and 55 years undergoing related donor allogeneic BMT for malignant disease were eligible. Alloimmunization, as G-CSF is a safe and effective agent for mobilization of defined by unresponsiveness to platelet transfusions, 12 was neutrophils in normal donors, consistently resulting in cell not evident in the study recipients. Antileukocyte antibodies yields of 4-10 × 10 10 per leukapheresis (LA) procedure 1,2 were not measured. Informed consent for entry of recipients as opposed to Ͻ3 × 10 10 cells/LA procedure with ot...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.