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1.
Ann Oncol ; 19(1): 92-8, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17785764

ABSTRACT

BACKGROUND: A phase 3 study demonstrated that panitumumab, a human monoclonal anti-epidermal growth factor receptor antibody, significantly prolonged progression-free survival versus best supportive care (BSC) in patients with chemorefractory metastatic colorectal cancer. PATIENTS AND METHODS: This open-label extension study evaluated panitumumab monotherapy in BSC patients with radiographically documented disease progression in the phase 3 study. Patients received panitumumab 6 mg/kg every 2 weeks. The primary end point was safety; efficacy was also evaluated. RESULTS: One hundred and seventy-six patients were randomly assigned to the BSC arm of the phase 3 study received >/=1 panitumumab dose in this extension study. Panitumumab was well tolerated. The most frequent treatment-related adverse events were skin toxic effects. Three (2%) patients had a grade 4 treatment-related adverse event. There were no infusion reactions. One (0.6%) patient had a complete response; 19 (11%) patients had a partial response; and 58 (33%) patients had stable disease. Median progression-free survival time was 9.4 [95% confidence interval (CI): 8.0-13.4) weeks. Median overall survival time was 6.3 (95% CI: 5.1-6.8) months. Anti-panitumumab antibodies were detected in 3 (4.2%) of 71 patients with a post-baseline sample. CONCLUSIONS: These findings are comparable to those from the phase 3 study and support panitumumab monotherapy for chemorefractory colorectal cancer.


Subject(s)
Adenocarcinoma/therapy , Antibodies, Monoclonal/therapeutic use , Colorectal Neoplasms/therapy , ErbB Receptors/antagonists & inhibitors , Immunotherapy , Neoplasm Proteins/antagonists & inhibitors , Salvage Therapy , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/mortality , Disease Progression , Disease-Free Survival , Drug Eruptions/etiology , Drug Resistance, Neoplasm , ErbB Receptors/immunology , Female , Humans , Immunotherapy/adverse effects , Immunotherapy/statistics & numerical data , Male , Middle Aged , Neoplasm Proteins/immunology , Panitumumab , Salvage Therapy/statistics & numerical data , Survival Analysis
2.
Br J Cancer ; 97(11): 1469-74, 2007 Dec 03.
Article in English | MEDLINE | ID: mdl-18040272

ABSTRACT

In a randomised phase 3 trial, panitumumab significantly improved progression-free survival (PFS) in patients with refractory metastatic colorectal cancer (mCRC). This analysis characterises the association of PFS with CRC symptoms, health-related quality of life (HRQoL), and overall survival (OS). CRC symptoms (NCCN/FACT CRC symptom index, FCSI) and HRQoL (EQ-5D) were assessed for 207 panitumumab patients and 184 best supportive care (BSC) patients who had at least one post-baseline patient-reported outcome (PRO) assessment. Patients alive at week 8 were included in the PRO and OS analyses and categorised by their week 8 progression status as follows: no progressive disease (no PD; best response of at least stable disease) vs progressive disease (PD). Standard imputation methods were used to assign missing values. Significantly more patients were progression free at weeks 8-24 with panitumumab vs BSC. After excluding responders, a significant difference in PFS remained favouring panitumumab (HR=0.63, 95% CI=0.52-0.77; P<0.0001). At week 8, lack of disease progression was associated with significantly and clinically meaningful lower CRC symptomatology for both treatment groups and higher HRQoL for panitumumab patients only. Overall survival favoured no PD patients vs PD patients alive at week 8. Lack of disease progression was associated with better symptom control, HRQoL, and OS.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Colorectal Neoplasms/drug therapy , Quality of Life , Antibodies, Monoclonal/immunology , Colorectal Neoplasms/pathology , Disease Progression , Drug Administration Schedule , Drug Resistance, Neoplasm , ErbB Receptors , Humans , Neoplasm Metastasis , Panitumumab , Self-Examination , Severity of Illness Index , Survival Analysis , Treatment Outcome
3.
Ann Oncol ; 16(7): 1192-8, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15860486

ABSTRACT

BACKGROUND: This randomized, open-label study evaluated the efficacy, safety and pharmacokinetics of darbepoetin alfa administered intravenously (i.v.) or subcutaneously (s.c.) in chemotherapy-induced anemia. PATIENTS AND METHODS: Patients received darbepoetin alfa i.v. (n=59) or s.c. (n=59) at a dose of 4.5 mug/kg once weekly for 6 weeks (correction phase) followed by 4.5 mug/kg once every 3 weeks for the remainder of the 18-week treatment period (maintenance phase). RESULTS: During the correction phase, the mean [95% confidence interval (CI)] change in hemoglobin (intention-to-treat) was 1.1 (0.6-1.5) g/dl in the i.v. group and 1.3 (0.9-1.7) g/dl in the s.c. group; using available data, the mean change was 1.4 (1-1.9) g/dl and 1.6 (1.2-2) g/dl, respectively. The percentage (95% CI) of patients maintaining hemoglobin (i.e. average decrease < or =0.5 g/dl) during the maintenance phase was similar between the i.v. (82%; 95% CI 66% to 92%) and s.c. (80%; 95% CI 66% to 90%) groups. Thirty-five per cent (95% CI 20% to 50%) of patients in the i.v. group and 32% of patients in the s.c. group (95% CI 18% to 45%) received red blood cell transfusions during week 5 to the end of the treatment period. Darbepoetin alfa was well tolerated in both groups. No significant difference (P=0.36) in weekly darbepoetin alfa serum concentrations was observed between groups. CONCLUSIONS: Darbepoetin alfa can be administered i.v. or s.c. at equal doses for the treatment of anemia in this setting.


Subject(s)
Anemia/drug therapy , Antineoplastic Agents/adverse effects , Erythropoietin/analogs & derivatives , Aged , Darbepoetin alfa , Erythropoietin/administration & dosage , Erythropoietin/adverse effects , Erythropoietin/pharmacokinetics , Erythropoietin/therapeutic use , Female , Hemoglobins/analysis , Humans , Infusions, Intravenous , Injections, Subcutaneous , Male , Middle Aged
4.
Ann Oncol ; 13(4): 582-8, 2002 Apr.
Article in English | MEDLINE | ID: mdl-12056709

ABSTRACT

BACKGROUND: 5-Fluorouracil (5-FU)-based regimens have not been shown to prolong survival or provide clinical benefit in patients with advanced pancreatic cancer. The purpose of this study was to determine the tolerability of protracted venous infusion (PVI) of 5-FU, modulated by a low dose of the synthetic antifolate trimetrexate, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-three chemotherapy-naïve patients were evaluated. Patients were enrolled in four consecutive cohorts in which the weekly dose of trimetrexate was escalated in 10 mg/m2 increments, from 20 to 50 mg/m2. PVI 5-FU was administered at a fixed dose of 225 mg/m2/day. Treatment was administered for 6 successive weeks, every 8 weeks. RESULTS: Twenty-two patients were assessable. The maximum tolerated dose of trimetrexate was 40 mg/m2. The most common grade 3 and 4 toxicity was diarrhea. There were no treatment-related deaths. Preliminary analysis of activity revealed a response rate of 9%, with 41% of the patients having stable disease for a median duration of 3.8 months. The median survival for the entire group was 6.9 months (range 1-29 months). A clinical benefit response was experienced by 27.2% of patients. CONCLUSIONS: Low-dose trimetrexate can be safely administered in combination with PVI 5-FU. This treatment is well tolerated and is associated with palliative activity in advanced pancreatic cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Trimetrexate/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Combinations , Female , Fluorouracil/administration & dosage , Glucuronates/administration & dosage , Humans , Infusions, Intravenous , Male , Middle Aged , Palliative Care , Survival Analysis , Trimetrexate/administration & dosage
6.
Semin Oncol ; 27(2 Suppl 5): 82-9, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10877059

ABSTRACT

Significant advances in the field of sickle cell disease (SCD) in recent years have contributed to improving the life expectancy and symptoms of patients with this disease. These health care improvements include the implementation of infectious prophylaxis in children and the modulation of hemoglobin F production with chemotherapy. In spite of these advances, SCD continues to be associated with significant morbidity and mortality. Although standard allogeneic bone marrow transplantation can cure SCD and can halt the progression to end-organ damage, this treatment is associated with greater risk of toxicity and death in older patients and in those with evidence of severe end-organ damage. Nonmyeloablative conditioning regimens based on the use of purine analogs can induce sufficient immunosuppression to allow engraftment after allogeneic stem cell transplantation, resulting in less toxicity than standard conditioning regimens. We describe a clinical trial using a nonmyeloablative chemotherapy conditioning regimen followed by related allogeneic peripheral blood stem cell transplantation that represents a novel approach to the treatment of severe SCD in young adults. This study may afford chimeric engraftment resulting in the resolution or amelioration of disease-related symptoms and in the cessation of progression to organ failure.


Subject(s)
Anemia, Sickle Cell/therapy , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/therapeutic use , Pentostatin/therapeutic use , Transplantation Conditioning , Adult , Bone Marrow Transplantation , Child , Fetal Hemoglobin/drug effects , Humans , Purine Nucleosides/therapeutic use , Remission Induction , Transplantation, Homologous
7.
J Virol ; 74(3): 1286-95, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10627539

ABSTRACT

Recently, gene delivery vectors based on human immunodeficiency virus (HIV) have been developed as an alternative mode of gene delivery. These vectors have a number of advantages, particularly in regard to the ability to infect cells which are not actively dividing. However, the use of vectors based on human immunodeficiency virus raises a number of issues, not the least of which is safety; therefore, further characterization of marking and gene expression in different hematopoietic lineages in primate animal model systems is desirable. We use two animal model systems for gene therapy to test the efficiency of transduction and marking, as well as the safety of these vectors. The first utilizes the rhesus animal model for cytokine-mobilized autologous peripheral blood CD34(+) cell transplantation. The second uses the SCID-human (SCID-hu) thymus/liver chimeric graft animal model useful specifically for human T-lymphoid progenitor cell reconstitution. In the rhesus macaques, detectable levels of vector were observed in granulocytes, lymphocytes, monocytes, and, in one animal with the highest levels of marking, erythrocytes and platelets. In transplanted SCID-hu mice, we directly compared marking and gene expression of the lentivirus vector and a murine leukemia virus-derived vector in thymocytes. Marking was observed at comparable levels, but the lentivirus vector bearing an internal cytomegalovirus promoter expressed less efficiently than did the murine retroviral vector expressed from its own long terminal repeats. In assays for infectious HIV type 1 (HIV-1), no replication-competent HIV-1 was detected in either animal model system. Thus, these results indicate that while lentivirus vectors have no apparent deleterious effects and may have advantages over murine retroviral vectors, further study of the requirements for optimal use are warranted.


Subject(s)
Antigens, CD34/analysis , Gene Expression , Genetic Vectors , HIV-1/genetics , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/metabolism , T-Lymphocytes/metabolism , Animals , Cytomegalovirus/genetics , Green Fluorescent Proteins , Hematopoietic Stem Cells/virology , Humans , Leukemia Virus, Murine/genetics , Leukopoiesis , Liver Transplantation/immunology , Luminescent Proteins/biosynthesis , Luminescent Proteins/genetics , Lymphocyte Activation , Macaca mulatta , Mice , Mice, SCID , Promoter Regions, Genetic , T-Lymphocytes/immunology , T-Lymphocytes/virology , Thymus Gland/immunology , Thymus Gland/transplantation , Transduction, Genetic , Virus Replication
10.
J Virol ; 73(8): 6361-9, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10400728

ABSTRACT

Human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu thymic implants depleted of CD4(+) cells can support renewed thymopoiesis derived from both endogenous and exogenous T-cell progenitors after combination antiretroviral therapy. However, successful production of new thymocytes occurs transiently. Possible explanations for the temporary nature of this thymic reconstitution include cessation of the thymic stromal support function, exhaustion of T-cell progenitors, and viral resurgence. Distinguishing between these processes is important for the development of therapeutic strategies aimed at reconstituting the CD4(+) T-cell compartment in HIV-1 infection. Using an HIV-1 strain engineered to express the murine HSA heat-stable antigen surface marker, we explored the relationship between HIV-1 expression and CD4(+) cell resurgence kinetics in HIV-1-depleted SCID-hu implants following drug therapy. Antiviral therapy significantly suppressed HIV-1 expression in double-positive (DP) CD4/CD8 thymocytes, and the eventual secondary decline of DP thymocytes following therapy was associated with renewed viral expression in this cell subset. Thymocytes derived from exogenous T-cell progenitors induced to differentiate in HIV-1-depleted, drug-treated thymic implants also became infected. These results indicate that in this model, suppression of viral replication occurs transiently and that, in spite of drug therapy, virus resurgence contributes to the transient nature of the renewed thymic function.


Subject(s)
Anti-HIV Agents/therapeutic use , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV Infections/therapy , HIV-1/immunology , Hematopoietic Stem Cell Transplantation , Thymus Gland/immunology , Animals , Didanosine/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , HIV-1/physiology , Humans , Indinavir/therapeutic use , Kinetics , Lymphocyte Depletion , Mice , Mice, SCID , Reverse Transcriptase Inhibitors/therapeutic use , Thymus Gland/cytology , Zidovudine/therapeutic use
11.
Front Biosci ; 4: D468-75, 1999 May 15.
Article in English | MEDLINE | ID: mdl-10331991

ABSTRACT

Although antiretroviral drug therapy has had a significant impact on the natural history of HIV infection, complete virus eradication still remains an unattainable goal. Drug-mediated virological control only occurs transiently, in part as a result of the development of drug resistance. Gene therapy for the treatment of AIDS is a promising area of research that has as its goal the replacement of the HIV-infected cellular pool with cells engineered to resist virus replication. A variety of anti-HIV genes have been designed and tested in laboratory systems, and available results from pilot clinical trials demonstrate the safety and feasibility of this approach. Obstacles to effective application of this technology include partial protection of HIV resistance genes, lack of effective vectoring systems, and unregulated gene expression. Herein, we review recent advances in transduction methods, data from in vivo preclinical studies in relevant animal models, and emerging results derived from pilot clinical gene therapy studies.


Subject(s)
Acquired Immunodeficiency Syndrome/therapy , Genetic Therapy , Animals , Disease Models, Animal , Gene Products, rev/genetics , Gene Products, rev/therapeutic use , Gene Transfer Techniques , HIV/genetics , HIV/pathogenicity , Hematopoiesis , Humans , Macaca mulatta , Mice , Mice, SCID , RNA, Catalytic/therapeutic use , Simian Immunodeficiency Virus/pathogenicity , Stem Cells/cytology , Stem Cells/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Thymus Gland/virology , Transduction, Genetic , rev Gene Products, Human Immunodeficiency Virus
12.
Hum Gene Ther ; 9(2): 173-83, 1998 Jan 20.
Article in English | MEDLINE | ID: mdl-9472777

ABSTRACT

Murine retroviral vectors have the potential to mediate stable gene transfer into hematopoietic progenitor cells. A known drawback to the use of these vectors is that transduction can only take place in cells actively progressing through the cell cycle. Thrombopoietin, the c-mpl ligand, is known to support division of hematopoietic precursors of primitive origin. Polyethylene glycol (PEG)-conjugated recombinant human megakaryocyte growth and development factor (MGDF) is a polypeptide related to thrombopoietin that stimulates megakaryocyte production. To investigate whether MGDF would also induce stem cell division and support retroviral transduction of CD34+ cells, we compared the effects of MGDF, stem cell factor (SCF), interleukin-3 (IL-3), and IL-6, alone or in combination, using amphotropic and vesicular stomatitis virus (VSV-G) pseudotyped murine retroviral vectors. Similar transduction efficiency was observed when CD34+ cells were transduced in the presence of SCF and MGDF as compared to SCF, IL-3, and IL-6. Using the SCID-hu mouse model of thymopoiesis, we investigated whether CD34+ cells transduced in the presence of these cytokines could reconstitute irradiated thymic implants, and whether vector sequences were present in mature thymocytes. At early timepoints, no significant differences were observed on engraftment of donor progenitors incubated with each cytokine combination. However, a significant difference in the percentage of donor derived CD4+/CD8+ immature thymocytes was observed 9 weeks after implantation of CD34+ cells exposed to the combination of SCF and MGDF as compared to SCF, IL-3, and IL-6 (p = 0.04), indicating that MGDF/SCF better supported the survival of thymocyte precursor cells. Approximately 4% of thymocytes in both cytokine groups harbored vector sequences. These studies provide evidence that MGDF and SCF in combination can mediate transduction of hematopoietic progenitors capable of contributing to long-term thymopoiesis. These results may have important applications for the implementation of gene therapy strategies in disorders affecting the T lymphoid system.


Subject(s)
Polyethylene Glycols/pharmacology , Retroviridae/genetics , Stem Cells/drug effects , T-Lymphocyte Subsets/drug effects , Thrombopoietin/pharmacology , Transduction, Genetic/drug effects , Animals , Antigens, CD/analysis , Bone Marrow Cells/metabolism , Bone Marrow Cells/virology , Cell Survival/drug effects , Cells, Cultured , Cytokines/pharmacology , Humans , Immunophenotyping , Leukosialin , Mice , Mice, SCID , Recombinant Proteins/pharmacology , Sialoglycoproteins/analysis , Stem Cells/metabolism , Stem Cells/virology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/virology
13.
Nat Med ; 3(10): 1102-9, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9334721

ABSTRACT

Stem cell gene therapy strategies for AIDS require that differentiation-inducing stromal elements of HIV-infected individuals remain functionally intact to support the maturation of exogenous progenitor cells into mature CD4+ cells. To investigate the feasibility of stem cell reconstitution strategies in AIDS, we used the SCID-hu mouse to examine the ability of HIV-infected CD4+ cell-depleted human thymic implants to support renewed thymopoiesis. Here we report that following treatment of these implants with antiretroviral drugs, new thymopoiesis is initiated. This suggests that antiviral therapies might allow de novo production of T lymphocytes and provides support for the concept of therapeutic strategies aimed at reconstitution of the peripheral CD4+ T-cell compartment.


Subject(s)
Antiviral Agents/therapeutic use , CD4-Positive T-Lymphocytes , HIV Infections/immunology , HIV Infections/therapy , HIV-1/pathogenicity , Hematopoietic Stem Cells/immunology , Thymus Gland/transplantation , Animals , Antigens, CD/analysis , Antigens, CD34/analysis , Didanosine/therapeutic use , Drug Therapy, Combination , Flow Cytometry , HIV Protease Inhibitors/therapeutic use , HIV-1/isolation & purification , Humans , Lymphocyte Depletion , Methylurea Compounds/therapeutic use , Mice , Mice, SCID , Polymerase Chain Reaction , Proviruses/isolation & purification , Pyridines/therapeutic use , T-Lymphocytes/immunology , T-Lymphocytes/virology , Thymus Gland/immunology , Transplantation, Heterologous , Valine/analogs & derivatives , Zidovudine/therapeutic use
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