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1.
Cytotherapy ; 26(7): 778-784, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38583170

ABSTRACT

BACKGROUND: Significant advancements have been made in the field of cellular therapy as anti-cancer treatments, with the approval of chimeric antigen receptor (CAR)-T cell therapies and the development of other genetically engineered cellular therapies. CAR-T cell therapies have demonstrated remarkable clinical outcomes in various hematological malignancies, establishing their potential to change the current cancer treatment paradigm. Due to the increasing importance of genetically engineered cellular therapies in the oncology treatment landscape, implementing strategies to expedite development and evidence generation for the next generation of cellular therapy products can have a positive impact on patients. METHODS: We outline a risk-based methodology and assessment aid for the data extrapolation approach across related genetically engineered cellular therapy products. This systematic data extrapolation approach has applicability beyond CAR-T cells and can influence clinical development strategies for a variety of immune therapies such as T cell receptor (TCR) or genetically engineered and other cell-based therapies (e.g., tumor infiltrating lymphocytes, natural killer cells and macrophages). RESULTS: By analyzing commonalities in manufacturing processes, clinical trial designs, and regulatory considerations, key learnings were identified. These insights support optimization of the development and regulatory approval of novel cellular therapies. CONCLUSIONS: The field of cellular therapy holds immense promise in safely and effectively treating cancer. The ability to extrapolate data across related products presents opportunities to streamline the development process and accelerate the delivery of novel therapies to patients.


Subject(s)
Genetic Engineering , Immunotherapy, Adoptive , Receptors, Chimeric Antigen , Humans , Cell- and Tissue-Based Therapy/methods , Genetic Engineering/methods , Immunotherapy, Adoptive/methods , Neoplasms/therapy , Neoplasms/immunology , Neoplasms/genetics , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/immunology
2.
Eur J Cancer ; 160: 112-133, 2022 01.
Article in English | MEDLINE | ID: mdl-34840026

ABSTRACT

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.


Subject(s)
Drug Development/organization & administration , Medical Oncology/organization & administration , Receptors, Antigen, T-Cell/genetics , Receptors, Chimeric Antigen/genetics , Adolescent , Child , Europe , Humans , Pediatrics , United States , United States Food and Drug Administration
4.
Nat Rev Drug Discov ; 17(12): 922, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30361553

ABSTRACT

This corrects the article DOI: 10.1038/nrd.2018.167.

6.
Front Hum Neurosci ; 9: 390, 2015.
Article in English | MEDLINE | ID: mdl-26236212

ABSTRACT

We report the case of an individual with acquired prosopagnosia who experiences extreme difficulties in recognizing familiar faces in everyday life despite excellent object recognition skills. Formal testing indicates that he is also severely impaired at remembering pre-experimentally unfamiliar faces and that he takes an extremely long time to identify famous faces and to match unfamiliar faces. Nevertheless, he performs as accurately and quickly as controls at identifying inverted familiar and unfamiliar faces and can recognize famous faces from their external features. He also performs as accurately as controls at recognizing famous faces when fracturing conceals the configural information in the face. He shows evidence of impaired global processing but normal local processing of Navon figures. This case appears to reflect the clearest example yet of an acquired prosopagnosic patient whose familiar face recognition deficit is caused by a severe configural processing deficit in the absence of any problems in featural processing. These preserved featural skills together with apparently intact visual imagery for faces allow him to identify a surprisingly large number of famous faces when unlimited time is available. The theoretical implications of this pattern of performance for understanding the nature of acquired prosopagnosia are discussed.

7.
Endocrinology ; 155(9): 3219-26, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24971614

ABSTRACT

We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1ß enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1ß, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1ß, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1ß may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Obesity/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adolescent , Adult , Alternative Splicing , Child , Female , Humans , Insulin/metabolism , Leptin/metabolism , Male , Mutation, Missense , Obesity/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Signal Transduction , Young Adult
8.
Hum Mutat ; 35(3): 289-93, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24375934

ABSTRACT

Inherited retinal dystrophies are a major cause of childhood blindness. Here, we describe the identification of a homozygous frameshift mutation (c.1194_1195delAG, p.Arg398Serfs*9) in TUB in a child from a consanguineous UK Caucasian family investigated using autozygosity mapping and whole-exome sequencing. The proband presented with obesity, night blindness, decreased visual acuity, and electrophysiological features of a rod cone dystrophy. The mutation was also found in two of the proband's siblings with retinal dystrophy and resulted in mislocalization of the truncated protein. In contrast to known forms of retinal dystrophy, including those caused by mutations in the tubby-like protein TULP-1, loss of function of TUB in the proband and two affected family members was associated with early-onset obesity, consistent with an additional role for TUB in energy homeostasis.


Subject(s)
Frameshift Mutation , Homozygote , Obesity/genetics , Proteins/genetics , Retinitis Pigmentosa/genetics , Adaptor Proteins, Signal Transducing , Child , Chromosome Mapping , Consanguinity , Eye Proteins/genetics , Female , Genes, Recessive , Homeostasis , Humans , Male , Pedigree , United Kingdom , White People/genetics
9.
Cell ; 155(4): 765-77, 2013 Nov 07.
Article in English | MEDLINE | ID: mdl-24209692

ABSTRACT

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.


Subject(s)
Insulin Resistance , Obesity/genetics , Protein Serine-Threonine Kinases/genetics , Age Factors , Age of Onset , Amino Acid Sequence , Animals , Child , Energy Metabolism , Fatty Acids/metabolism , Female , Glucose/metabolism , Humans , Hyperphagia/genetics , Hyperphagia/metabolism , MAP Kinase Signaling System , Male , Mice , Models, Molecular , Molecular Sequence Data , Obesity/epidemiology , Obesity/metabolism , Oxidation-Reduction , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/metabolism , Sequence Alignment
10.
J Clin Invest ; 122(12): 4732-6, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23160192

ABSTRACT

Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve growth factor (NGF). Targeted deletion of Sh2b1 in mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high-fat diet. We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early-onset obesity. Mutation carriers exhibited hyperphagia, childhood-onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Frameshift Mutation , Mutation, Missense , Obesity/genetics , Adolescent , Adult , Aggression , Base Sequence , Case-Control Studies , Cell Movement , Child , Child, Preschool , DNA Mutational Analysis , Energy Intake/genetics , Female , Genetic Association Studies , HEK293 Cells , Humans , Male , Middle Aged , Phenotype , Protein Transport , Social Isolation , Young Adult
11.
Biochem J ; 436(1): 169-79, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21413931

ABSTRACT

The mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth and is a key target for therapeutic intervention in cancer. Two complexes of mTOR have been identified: complex 1 (mTORC1), consisting of mTOR, Raptor (regulatory associated protein of mTOR) and mLST8 (mammalian lethal with SEC13 protein 8) and complex 2 (mTORC2) consisting of mTOR, Rictor (rapamycin-insensitive companion of mTOR), Sin1 (stress-activated protein kinase-interacting protein 1), mLST8 and Protor-1 or Protor-2. Both complexes phosphorylate the hydrophobic motifs of AGC kinase family members: mTORC1 phosphorylates S6K (S6 kinase), whereas mTORC2 regulates phosphorylation of Akt, PKCα (protein kinase Cα) and SGK1 (serum- and glucocorticoid-induced protein kinase 1). To investigate the roles of the Protor isoforms, we generated single as well as double Protor-1- and Protor-2-knockout mice and studied how activation of known mTORC2 substrates was affected. We observed that loss of Protor-1 and/or Protor-2 did not affect the expression of the other mTORC2 components, nor their ability to assemble into an active complex. Moreover, Protor knockout mice display no defects in the phosphorylation of Akt and PKCα at their hydrophobic or turn motifs. Strikingly, we observed that Protor-1 knockout mice displayed markedly reduced hydrophobic motif phosphorylation of SGK1 and its physiological substrate NDRG1 (N-Myc downregulated gene 1) in the kidney. Taken together, these results suggest that Protor-1 may play a role in enabling mTORC2 to efficiently activate SGK1, at least in the kidney.


Subject(s)
GTPase-Activating Proteins/physiology , Immediate-Early Proteins/metabolism , Kidney/enzymology , Protein Serine-Threonine Kinases/metabolism , Proteins/physiology , Trans-Activators/metabolism , Amino Acid Motifs , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Mice , Mice, Knockout , Phosphorylation , Protein Isoforms/genetics , Protein Isoforms/metabolism , Proteins/genetics , Proteins/metabolism , Trans-Activators/genetics , Transcription Factors , Transfection
12.
Biochem J ; 431(2): 245-55, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20704563

ABSTRACT

S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) signalling pathways. S6K1 regulates numerous processes, such as protein synthesis, growth, proliferation and longevity, and its inhibition has been proposed as a strategy for the treatment of cancer and insulin resistance. In the present paper we describe a novel cell-permeable inhibitor of S6K1, PF-4708671, which specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases. PF-4708671 was also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1). PF-4708671 is the first S6K1-specific inhibitor to be reported and will be a useful tool for delineating S6K1-specific roles downstream of mTOR.


Subject(s)
Imidazoles/pharmacology , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Cell Line , Humans , Imidazoles/chemistry , Mechanistic Target of Rapamycin Complex 1 , Multiprotein Complexes , Phosphorylation/drug effects , Phosphothreonine/metabolism , Piperazines/chemistry , Protein Kinase Inhibitors/chemistry , Proteins , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Substrate Specificity/drug effects , TOR Serine-Threonine Kinases , Transcription Factors/metabolism
13.
Nat Rev Mol Cell Biol ; 11(1): 9-22, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20027184

ABSTRACT

The AGC kinase subfamily of protein kinases contains 60 members, including PKA, PKG and PKC. The family comprises some intensely examined protein kinases (such as Akt, S6K, RSK, MSK, PDK1 and GRK) as well as many less well-studied enzymes (such as SGK, NDR, LATS, CRIK, SGK494, PRKX, PRKY and MAST). Research has shed new light onto the architecture and regulatory mechanisms of these kinases. In addition, AGC kinases mediate diverse and important cellular functions, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes.


Subject(s)
Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/physiology , Animals , Diabetes Mellitus/enzymology , Enzyme Activation , Humans , Neoplasms/enzymology
14.
Sci Signal ; 2(67): pe27, 2009 Apr 21.
Article in English | MEDLINE | ID: mdl-19383978

ABSTRACT

The mammalian target of rapamycin complex 2 (mTORC2) plays critical roles in regulating cell growth and proliferation. mTORC2 promotes the activation of the serum glucocorticoid-induced protein kinase (SGK). This mTOR complex also promotes the constitutive phosphorylation of proline-directed serine or threonine sites in the turn motif of Akt and protein kinase C isoforms. mTORC2 may control phosphorylation of the turn motif by promoting the activity of a kinase that targets the Ser/Thr-Pro sequence or by inhibiting the activity of a phosphatase.


Subject(s)
Protein Kinases/metabolism , Signal Transduction , Transcription Factors/metabolism , Amino Acid Sequence , Animals , Cell Proliferation , Humans , Immediate-Early Proteins/metabolism , Models, Biological , Phosphorylation , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Serine/metabolism , TOR Serine-Threonine Kinases , Threonine/metabolism
15.
Biochem J ; 405(3): 513-22, 2007 Aug 01.
Article in English | MEDLINE | ID: mdl-17461779

ABSTRACT

The mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth. Two complexes of mTOR have been identified: complex 1, consisting of mTOR-Raptor (regulatory associated protein of mTOR)-mLST8 (termed mTORC1), and complex 2, comprising mTOR-Rictor (rapamycininsensitive companion of mTOR)-mLST8-Sin1 (termed mTORC2). mTORC1 phosphorylates the p70 ribosomal S6K (S6 kinase) at its hydrophobic motif (Thr389), whereas mTORC2 phosphorylates PKB (protein kinase B) at its hydrophobic motif (Ser473). In the present study, we report that widely expressed isoforms of unstudied proteins termed Protor-1 (protein observed with Rictor-1) and Protor-2 interact with Rictor and are components of mTORC2. We demonstrate that immunoprecipitation of Protor-1 or Protor-2 results in the co-immunoprecipitation of other mTORC2 subunits, but not Raptor, a specific component of mTORC1. We show that detergents such as Triton X-100 or n-octylglucoside dissociate mTOR and mLST8 from a complex of Protor-1, Sin1 and Rictor. We also provide evidence that Rictor regulates the expression of Protor-1, and that Protor-1 is not required for the assembly of other mTORC2 subunits into a complex. Protor-1 is a novel Rictor-binding subunit of mTORC2, but further work is required to establish its role.


Subject(s)
Carrier Proteins/metabolism , Protein Kinases/metabolism , Cell Line , Gene Silencing , Humans , Protein Binding , Protein Isoforms , Rapamycin-Insensitive Companion of mTOR Protein , TOR Serine-Threonine Kinases
16.
Invest New Drugs ; 24(2): 159-67, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16502349

ABSTRACT

DNA methyltransferases (DNMTs) methylate DNA, promoting local chromatin condensation and consequent repression of gene expression. The purpose of this two-stage phase II trial was to assess the antitumor activity of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1, in patients with metastatic renal carcinoma (MRC). Untreated adult patients with measurable MRC were treated with MG98 at a dose of 360 mg/m2 via 2-h iv infusion twice weekly for three consecutive weeks out of four. The primary endpoint was objective response or absence of progression for at least eight weeks. Pharmacokinetics and DNMT1 mRNA levels in peripheral blood mononuclear cells (PBMCs) were also analyzed at pre-specified intervals. Seventeen eligible patients received a median of two cycles of treatment (range, 1-7), and no objective responses were seen. Nine patients had progressive disease, six had stable disease, and the study was stopped after the first stage. The most common symptomatic toxicities were rigors, fatigue, fever, and nausea. Hematological toxicity was mild. Seven patients treated with prior nephrectomy had grade 3 or 4 elevations in hepatic transaminases. Significantly higher Cmax and AUC(0-->inf) values were observed in these patients. No conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment. The lack of objective responses observed may be explained by a lack of target effect or the choice of tumor type. Transaminitis was observed in patients with prior nephrectomy and appeared to be associated with altered drug exposure in these patients.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Oligodeoxyribonucleotides/therapeutic use , Repressor Proteins/antagonists & inhibitors , Thionucleotides/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/metabolism , Canada , Carcinoma, Renal Cell/enzymology , Carcinoma, Renal Cell/secondary , Female , Humans , Kidney Neoplasms/enzymology , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Oligodeoxyribonucleotides/adverse effects , Oligodeoxyribonucleotides/metabolism , RNA, Messenger/blood , Thionucleotides/adverse effects , Thionucleotides/metabolism
17.
J Clin Oncol ; 22(2): 269-76, 2004 Jan 15.
Article in English | MEDLINE | ID: mdl-14722035

ABSTRACT

PURPOSE: N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is a novel agent that augments chemotherapy cytotoxicity in vitro and in vivo. A phase II trial combining DPPE and doxorubicin (DOX) in metastatic breast carcinoma showed increased response over that expected with DOX. We report a phase III trial comparing DOX with DPPE plus DOX in metastatic or recurrent breast cancer. PATIENTS AND METHODS: Anthracycline-naive women with measurable metastatic disease were randomly assigned to receive, every 21 days, either DOX 60 mg/m(2) intravenously or DOX during the last 20 minutes of an 80-minute infusion of DPPE (5.3 mg/kg), in both cases to cumulative DOX doses of 450 mg/m(2). Patients receiving DPPE were aggressively premedicated to ameliorate toxicity. End points included progression-free survival (PFS), response rate (RR), and response duration (RD), quality of life (QOL), toxicity, and overall survival (OS). RESULTS: A planned interim analysis failed to detect an RR difference more than 5%. The study was closed to additional accrual and all DPPE was discontinued. The final analysis was conducted as planned after 256 progression events (median follow-up, 20.5 months). There was no significant difference in RR, RD, or PFS between arms. DPPE plus DOX was statistically superior to DOX in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; P =.021). DPPE plus DOX was associated with more gastrointestinal and CNS toxicity. No consistent influence on QOL was detected. CONCLUSION: This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Doxorubicin/administration & dosage , Phenyl Ethers/administration & dosage , Phenyl Ethers/pharmacology , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacology , Breast Neoplasms/pathology , Disease-Free Survival , Female , Humans , Infusions, Intravenous , Middle Aged , Neoplasm Metastasis , Quality of Life , Treatment Outcome
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