Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 23
Filter
1.
N Engl J Med ; 385(1): 46-58, 2021 07 01.
Article in English | MEDLINE | ID: mdl-34192431

ABSTRACT

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunoglobulin Light-chain Amyloidosis/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bortezomib/administration & dosage , Cyclophosphamide/administration & dosage , Dexamethasone/administration & dosage , Disease-Free Survival , Female , Humans , Immunoglobulin Light-chain Amyloidosis/mortality , Male , Middle Aged , Treatment Outcome
2.
Lancet ; 398(10297): 314-324, 2021 07 24.
Article in English | MEDLINE | ID: mdl-34175021

ABSTRACT

BACKGROUND: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis. METHODS: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events. INTERPRETATION: A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. FUNDING: Janssen Research & Development and Legend Biotech.


Subject(s)
B-Cell Maturation Antigen/administration & dosage , Immunotherapy, Adoptive/methods , Multiple Myeloma/drug therapy , Receptors, Chimeric Antigen/administration & dosage , Aged , Female , Humans , Male , Middle Aged , Progression-Free Survival , United States
3.
Lancet ; 394(10192): 29-38, 2019 07 06.
Article in English | MEDLINE | ID: mdl-31171419

ABSTRACT

BACKGROUND: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. METHODS: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). INTERPRETATION: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Hematopoietic Stem Cell Transplantation/methods , Multiple Myeloma/therapy , Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/administration & dosage , Bortezomib/therapeutic use , Chemotherapy, Adjuvant , Combined Modality Therapy , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Survival Analysis , Thalidomide/administration & dosage , Thalidomide/therapeutic use , Transplantation, Autologous , Treatment Outcome , Young Adult
4.
Future Oncol ; 11(1): 51-9, 2015.
Article in English | MEDLINE | ID: mdl-24901734

ABSTRACT

Ibrutinib is an orally administered, covalent inhibitor of Bruton's tyrosine kinase with activity in B-cell malignancies based on Phase I/II studies. We describe the design and rationale for the Phase III HELIOS trial (trial registration: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745) investigating whether ibrutinib added to bendamustine and rituximab (BR) provides benefits over BR alone in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible patients must have relapsed/refractory disease measurable on CT scan and meet ≥ 1 International Workshop on Chronic Lymphocytic Leukemia criterion for requiring treatment; patients with del(17p) are excluded. All patients receive BR (maximum six cycles) as background therapy and are randomized 1:1 to placebo or ibrutinib 420 mg/day. Treatment with ibrutinib or placebo will start concomitantly with BR and continue until disease progression or unacceptable toxicity. The primary end point is progression-free survival. Secondary end points include safety, objective response rate, overall survival, rate of minimal residual disease-negative remissions, and patient-reported outcomes. Tumor response will be assessed using the International Workshop on Chronic Lymphocytic Leukemia guidelines.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Adenine/analogs & derivatives , Administration, Oral , Adolescent , Adult , Aged , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Bendamustine Hydrochloride , Female , Humans , Kaplan-Meier Estimate , Leukemia, Lymphocytic, Chronic, B-Cell/epidemiology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Nitrogen Mustard Compounds/administration & dosage , Piperidines , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Rituximab
5.
J Clin Oncol ; 41(6): 1275-1284, 2023 02 20.
Article in English | MEDLINE | ID: mdl-36269898

ABSTRACT

PURPOSE: CARTIFAN-1 aimed to evaluate the efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeting chimeric antigen receptor T-cell therapy, in Chinese patients with relapsed/refractory multiple myeloma (RRMM). METHODS: This pivotal phase II, open-label study (ClinicalTrials.gov identifier: NCT03758417), conducted across eight sites in China, enrolled adult patients with RRMM who had received ≥ 3 lines of prior therapy, including a proteasome inhibitor and immunomodulatory drug. Patients received a single infusion of cilta-cel (target dose 0.75 × 106 chimeric antigen receptor-positive viable T cells/kg). The primary end point was overall response rate. Secondary end points included progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs). RESULTS: As of the clinical cutoff of July 19, 2021, 48 patients received a cilta-cel infusion. At an 18-month median follow-up, the overall response rate was 89.6% (95% CI, 77.3 to 96.5), with a median time to first response of approximately 1 month; 77.1% of patients (95% CI, 62.7 to 88.0) achieved complete response or better. Medians for duration of response, PFS, and OS were not reached. The 18-month PFS and OS rates were 66.8% (95% CI, 49.4 to 79.4) and 78.7% (95% CI, 64.0 to 88.0), respectively. Hematologic AEs were common, including anemia (100%), neutropenia (97.9%), lymphopenia (95.8%), and thrombocytopenia (87.5%). Cytokine release syndrome occurred in 97.9% of patients (35.4% grade 3/4); the median time to onset was 7 days, and the median duration was 5 days. Infections occurred in 85.4% of patients (37.5% grade 3/4). Ten deaths occurred after cilta-cel infusion, eight of which were due to treatment-related AEs. CONCLUSION: These data demonstrate a favorable risk-benefit profile for a single infusion of cilta-cel, resulting in early, deep, and durable responses in heavily pretreated patients with RRMM in China.


Subject(s)
Anemia , Multiple Myeloma , Receptors, Chimeric Antigen , Adult , Humans , Anemia/etiology , B-Cell Maturation Antigen , Cell- and Tissue-Based Therapy , East Asian People , Immunotherapy, Adoptive , Multiple Myeloma/drug therapy , Receptors, Chimeric Antigen/therapeutic use
6.
Ann Hematol ; 89(11): 1133-40, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20532504

ABSTRACT

Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD + bortezomib. Its presence was associated with a longer time to progression (TTP; median 330 vs. 129 days; p = 0.0008), progression-free survival (PFS; median 338 vs. 129 days; p = 0.0006), and overall survival (p = 0.0045). MDR1/3435(C > T), which was in Hardy-Weinberg equilibrium, showed a trend of association with PFS (p = 0.0578), response rate (p = 0.0782) and TTP (p = 0.0923) in PLD + bortezomib patients, though no correlation was found in the bortezomib arm. In a recessive genetic model, MDR1/3435 T was significantly associated with a better TTP (p = 0.0405) and PFS (p = 0.0186) in PLD + bortezomib patients. These findings suggest a potential role for MRP1 and MDR1 SNPs in modulating the long-term outcome of relapsed and/or refractory myeloma patients treated with PLD + bortezomib. Moreover, they support prospective studies to determine if such data could be used to tailor therapy to the genetic makeup of individual patients.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Antineoplastic Agents/therapeutic use , Boronic Acids/therapeutic use , Doxorubicin/analogs & derivatives , Multiple Myeloma , Polyethylene Glycols/therapeutic use , Polymorphism, Single Nucleotide , Pyrazines/therapeutic use , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adult , Aged , Aged, 80 and over , Bortezomib , Clinical Trials as Topic , Disease Progression , Disease-Free Survival , Doxorubicin/therapeutic use , Humans , Kaplan-Meier Estimate , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Recurrence , Retrospective Studies , Time Factors , ATP-Binding Cassette Sub-Family B Member 4
7.
Biomed Environ Sci ; 22(3): 237-43, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19725467

ABSTRACT

OBJECTIVE: To prepare artificial antigens and anti-citrinin egg yolk-derived immunoglobulin (IgY) to build an enzyme-linked immunosorbent assay (ELISA) for citrinin (CTN). METHODS: CTN was conjugated with bovine serum albumin (BSA), ovalbumin (OVA) with formaldehyde condensation method to prepare artificial antigens and identified by ultraviolet (UV) spectrometry and Infrared (IR) spectrometry. Artificial antigens for CTN and anti-CTN IgY were purified with polyethylene glycol two-step precipitation method and identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). ELISA with IgY was established. Cross-reactivity of IgY with various structural similarities to CTN and possible co-occurrence with CTN in agricultural commodities were studied. RESULTS: UV and IR absorption spectra suggested that CTN was correlated with the carrier protein of BSA or OVA. SDS-PAGE patterns showed that the anti-CTN IgY was almost pure with a molecular weight of approximate 100 KD. The indirect competitive ELISA showed that the detection limit of CTN was 10 ng x mL(-1), with a good linearity ranging 20-640 ng x mL(-1). CONCLUSION: Artificial antigens of CTN can be successfully synthesized. The established ELISA can be used to determine CTN- contaminated samples.


Subject(s)
Antigens/chemistry , Citrinin/chemistry , Egg Yolk/immunology , Enzyme-Linked Immunosorbent Assay/methods , Immunoglobulins/immunology , Animals , Antibody Specificity , Chickens , Female
8.
J Clin Oncol ; 37(15): 1285-1295, 2019 05 20.
Article in English | MEDLINE | ID: mdl-30901302

ABSTRACT

PURPOSE: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL. PATIENTS AND METHODS: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Adenine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Double-Blind Method , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Piperidines , Placebos , Prednisone/administration & dosage , Prednisone/adverse effects , Progression-Free Survival , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Rituximab/administration & dosage , Rituximab/adverse effects , Survival Rate , Vincristine/administration & dosage , Vincristine/adverse effects , Young Adult
9.
Clin Lymphoma Myeloma ; 8(6): 352-5, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19064400

ABSTRACT

A retrospective analysis was undertaken of patients (n = 193) with renal insufficiency (creatinine clearance [CrCl] < 60 mL/min) from a phase III trial comparing bortezomib +/- pegylated liposomal doxorubicin (PLD) in relapsed/refractory myeloma (n = 646). The response rate (49% vs. 42%) and median time to disease progression (331 days vs. 199 days) were comparable or slightly better for patients with renal insufficiency treated with PLD/bortezomib compared with patients treated with bortezomib alone. There was a steady, clinically meaningful improvement in renal function for patients with renal insufficiency in both treatment arms. However, patients with impaired renal function were at a slightly increased risk of a drug-related serious adverse event (28% vs. 19% for CrCl < 60 and > or = 60 mL/min, respectively).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Boronic Acids/administration & dosage , Doxorubicin/analogs & derivatives , Multiple Myeloma/complications , Multiple Myeloma/drug therapy , Polyethylene Glycols/administration & dosage , Pyrazines/administration & dosage , Renal Insufficiency/complications , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bortezomib , Creatinine/urine , Doxorubicin/administration & dosage , Drug Resistance, Neoplasm , Humans , Recurrence , Renal Insufficiency/physiopathology , Retrospective Studies
10.
Clin Cancer Res ; 13(24): 7480-6, 2007 Dec 15.
Article in English | MEDLINE | ID: mdl-18094432

ABSTRACT

PURPOSE: Microtubule-stabilizing agents, such as taxanes, have been shown to be effective anticancer drugs. alpha-Tubulin, a basic unit of microtubules, can undergo several posttranslational modifications after assembly into stabilized microtubules, including acetylation and detyrosination. These modifications have been observed in cell cultures after exposure to microtubule stabilizers. Our objective was to develop a straightforward and dependable assay to show tubulin target engagement in tumor tissue after treatment of patients with ixabepilone(BMS-247550; Ixempra). EXPERIMENTAL DESIGN: Levels of posttranslationally modified alpha-tubulin were assessed in lysates of cultured malignant cell lines, as well as in both tumor tissue and peripheral blood mononuclear cells derived from patients before and after treatment with ixabepilone. Modification-specific antibodies permitted quantitative Western blot analysis. RESULTS: In cultured cell lines, the levels of detyrosinated (glu-terminated) and acetylated alpha-tubulin increased after microtubule stabilization induced by ixabepilone. ixabepilone treatment also induced a 2-fold to 25-fold increase in detyrosinated alpha-tubulin levels in 11 of 13 serial biopsies and a 2-fold to 100-fold increase in acetylated alpha-tubulin in 11 of 12 serial biopsies obtained from patients receiving ixabepilone. Overall, little or no difference in tubulin modifications were observed between the before and after ixabepilone treatment in lysates from their peripheral blood mononuclear cells at the time point examined. CONCLUSION: Assessing the levels of detyrosinated and/or acetylated alpha-tubulin seems to provide a simple and reliable assay to show target engagement by the microtubule-stabilizing agent ixabepilone. Such analyses may provide further understanding of therapeutic success or failure of microtubule-stabilizing agents in cancer therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Epothilones/therapeutic use , Kidney Neoplasms/drug therapy , Microtubules/drug effects , Tubulin/analysis , Blotting, Western , Cell Line, Tumor , Electrophoresis, Polyacrylamide Gel , Humans , Protein Processing, Post-Translational/drug effects , Tubulin/drug effects
11.
Ann N Y Acad Sci ; 1358: 82-94, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26348626

ABSTRACT

Ibrutinib is a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase that has demonstrated clinical benefit for many patients with B cell malignancies. Positive results in initial trials led the U.S. Food and Drug Administration to grant ibrutinib three breakthrough therapy designations for mantle cell lymphoma (MCL), del17p chronic lymphocytic leukemia (CLL), and Waldenström's macroglobulinemia (WM). Ibrutinib was approved for these three cancers within 14 months of the original U.S. approval. Additionally, ibrutinib is approved for patient subsets with MCL and/or CLL in >45 other countries. Via a unique mechanism of action, ibrutinib inhibits B cell signaling pathways that regulate the survival, proliferation, adhesion, and homing of cancerous cells. This marks a paradigm shift from the conventional cytotoxic chemotherapy approach to treating B cell malignancies. Ibrutinib continues to be evaluated across a range of B cell malignancies, either as single-agent therapy or in combination with other therapies, and continues to transform the lives of these patients.


Subject(s)
B-Lymphocytes/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , B-Lymphocytes/pathology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/metabolism , Piperidines , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage
13.
Clin Lymphoma Myeloma Leuk ; 11(1): 44-9, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21454189

ABSTRACT

INTRODUCTION: Bortezomib with pegylated liposomal doxorubicin (PLD) is superior to bortezomib alone in the relapsed and/or refractory setting, based on the results of a randomized, parallel-group, open-label, multicenter phase III study. To identify patients who might most benefit from this new standard of care, we performed retrospective analyses evaluating the effects of clinically defined, high-risk features on the outcomes with this regimen. PATIENTS AND METHODS: Patients received either bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every-21-day cycle with PLD 30 mg/m2 on day 4 (n=324) or bortezomib alone (n=322). Four high- and low-risk subgroup categories were identified, including age≥65, ≥2 previous therapies, International Staging System stage II/III, and disease refractory to last previous therapy. RESULTS: Compared with bortezomib alone, PLD plus bortezomib significantly prolonged the time to progression and duration of response in all of these subgroups. PLD plus bortezomib was well tolerated in all subgroups, and had a safety profile that was not affected by response to previous therapy. CONCLUSION: Treatment of relapsed/refractory myeloma with the combination of PLD plus bortezomib provides better outcomes over bortezomib alone, even in the presence of high-risk prognostic factors. These results suggest that PLD plus bortezomib may represent an additional standard of care for this population of patients with multiple myeloma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Aged , Boronic Acids/administration & dosage , Boronic Acids/adverse effects , Bortezomib , Disease Progression , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/analogs & derivatives , Female , Humans , Male , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Prognosis , Pyrazines/administration & dosage , Pyrazines/adverse effects , Retrospective Studies
14.
Clin Cancer Res ; 17(19): 6313-21, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21831953

ABSTRACT

PURPOSE: Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose. PATIENTS AND METHODS: Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3+3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Plasma was collected for pharmacokinetic analyses. Paired baseline and on-treatment skin and tumor biopsies were done; blood samples were collected for pharmacodynamic analyses, including p53 and macrophage inhibitory cytokine-1 induction. RESULTS: The MTD of serdemetan was determined to be 350 mg once daily. During this study, grade 3 QTc prolongation was the most common DLT and nausea (66.2%) was the most frequent treatment-emergent adverse event. Serdemetan was rapidly absorbed after oral administration and exhibited dose-proportional pharmacokinetics. At steady state, mean maximum plasma concentration (C(max)) was 2,330 ng/mL and mean area under plasma concentration curve (AUC(0-24h)) was 43.0 µg.h/mL, with serdemetan 300 mg/d. There was a dose- and exposure-dependent p53 induction. One patient with breast cancer showed a partial response; 22 (38.6%) patients had stable disease. CONCLUSIONS: Serdemetan treatment was associated with p53 induction in both tumor and surrogate tissue pharmacodynamic studies and modest clinical activity. Although serdemetan was well tolerated with dose-proportional pharmacokinetics, exposure-related QTc liability was observed.


Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Tryptamines/therapeutic use , Administration, Oral , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Tryptamines/adverse effects , Tryptamines/pharmacokinetics
16.
Clin Cancer Res ; 16(5): 1634-41, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20179242

ABSTRACT

PURPOSE: Ixabepilone (Ixempra; BMS-247550) is an epothilone B analog and nontaxane microtubule-stabilizing compound with clinical activity in a range of solid tumors. This phase II study was conducted to assess the efficacy and safety of ixabepilone in patients with metastatic renal cell carcinoma. EXPERIMENTAL DESIGN: Patients with metastatic renal cell carcinoma who had measurable disease and had not received previous cytotoxic or targeted therapy were treated with 6 mg/m(2) ixabepilone i.v. daily for 5 days every 3 weeks. Levels of Glu-terminated and acetylated tubulin, markers of microtubule stabilization, were assessed by Western blot. VHL gene mutation status was determined by sequencing. RESULTS: Eighty-seven patients received a total of 590 cycles, with a median of 5 cycles (range, 1-29). The overall response rate was 13% (Response Evaluation Criteria in Solid Tumor). One patient had a complete response, 10 patients had partial responses, and 59 patients had stable disease. The median duration of response was 5.5 months. The median overall survival of renal cell carcinoma Motzer grade 0 and 1 patients with clear cell histology was 19.25 months. Treatment-related adverse events were primarily alopecia, gastrointestinal toxicity, neuropathy, and fatigue. Biopsies were done at baseline and after five doses of ixabepilone. Microtubule target engagement was achieved in 84.6% to 92.3% of patients evaluated. No correlation was identified between the target engagement, VHL gene mutation status, and clinical response. CONCLUSION: Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Epothilones/therapeutic use , Kidney Neoplasms/drug therapy , Blotting, Western , Female , Humans , Male , Middle Aged , Tubulin/drug effects
17.
Cancer J ; 15(5): 395-400, 2009.
Article in English | MEDLINE | ID: mdl-19826359

ABSTRACT

Overall survival (OS) has been the gold standard for demonstrating clinical benefit for cancer drugs. It is 100% accurate for the event and time, it is assessed daily, its importance is unquestioned, and it addresses both safety and efficacy. However, OS as the primary efficacy end point requires large studies, long periods of follow-up, and it is potentially confounded by effective crossover, subsequent therapies, and noncancer death. Progression-free survival (PFS) or time to progression (TTP) directly measures the treatment effects of drugs on cancer growth, and they are not confounded by subsequent or crossover therapy. Although PFS and TTP benefits do not translate into OS benefits in all clinical settings examined so far, PFS or TTP improvement with a sufficient magnitude and in the context of favorable benefit-risk ratio should also be considered an important clinical benefit. Acceptance of PFS and TTP improvement demonstrated by well designed and conducted studies as direct evidence of clinical benefit will accelerate cancer drug development and make effective therapy available to patients with cancer sooner. The availability of sequential therapies, each delivers incremental progress in tumor control and PFS, may collectively lead to transformation of cancer to a curable or controllable chronic disease.


Subject(s)
Antineoplastic Agents/therapeutic use , Disease Progression , Neoplasms/drug therapy , Neoplasms/pathology , Antineoplastic Agents/standards , Disease-Free Survival , Drug Approval , Humans , Neoplasm Metastasis/drug therapy , Randomized Controlled Trials as Topic , Treatment Outcome
18.
J Clin Oncol ; 27(27): 4522-9, 2009 Sep 20.
Article in English | MEDLINE | ID: mdl-19687336

ABSTRACT

PURPOSE: To determine whether the combination of pegylated liposomal doxorubicin (PLD) and docetaxel significantly prolongs time to disease progression compared with docetaxel alone without an increase in cardiac toxicity in women with advanced breast cancer who had experienced relapse at least 1 year after prior adjuvant or neoadjuvant anthracycline therapy. PATIENTS AND METHODS: This international, phase III study randomly assigned 751 patients to receive either docetaxel 75 mg/m(2) (n = 373) or PLD 30 mg/m(2) followed by docetaxel 60 mg/m(2) every 21 days (n = 378) and continued until disease progression or prohibitive toxicity. The primary end point was time to progression (TTP). Secondary end points were overall survival (OS), objective response rate (ORR), cardiac toxicity, and safety. RESULTS: Treatment with PLD-docetaxel significantly improved median TTP from 7.0 to 9.8 months (hazard ratio [HR] = 0.65; 95% CI, 0.55 to 0.77; P = .000001) and the ORR from 26% to 35% (P = .0085). OS was similar between the two groups (HR = 1.02; 95% CI, 0.86 to 1.22). The incidence of grade 3 or 4 adverse events were similar (78% v 72%), although a higher incidence of hand-foot syndrome (24% v 0%) and mucositis/stomatitis (12% v 1%) were observed in the PLD-docetaxel combination. Protocol-defined left ventricular ejection fraction decreases and congestive heart failure were reported in 5% and 1% in both treatment arms, respectively. CONCLUSION: The PLD-docetaxel combination was more effective than docetaxel alone in women with metastatic breast cancer who had experienced relapse at least 1 year after prior adjuvant anthracycline therapy without an increase in cardiac toxicity, although mucocutaneous toxicity was more common.


Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Doxorubicin/analogs & derivatives , Polyethylene Glycols/administration & dosage , Taxoids/administration & dosage , Adult , Aged , Aged, 80 and over , Anthracyclines/therapeutic use , Breast Neoplasms/secondary , Chemotherapy, Adjuvant , Disease Progression , Docetaxel , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Heart Diseases/chemically induced , Humans , Middle Aged , Neoadjuvant Therapy , Polyethylene Glycols/adverse effects , Taxoids/adverse effects , Time Factors
19.
Cancer ; 112(7): 1529-37, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18300257

ABSTRACT

BACKGROUND: Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current analysis, they determined 1) the efficacy of PLD plus bortezomib versus bortezomib alone in patients with MM who had failed on prior thalidomide/lenalidomide (immunomodulatory drug [IMiD]) treatment and 2) the efficacy and safety profile of PLD plus bortezomib in IMiD-exposed and IMiD-naive patients. METHODS: This prespecified analysis included 646 patients who were randomized to receive either PLD with bortezomib (n=324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n=322; 184 IMiD-naive patients and 138 IMiD-exposed patients). The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety. RESULTS: The median TTP was significantly longer with PLD plus bortezomib compared with bortezomib alone in IMiD-exposed patients (270 days vs 205 days). No statistical difference was noted with respect to TTP between IMiD-naive (295 days) versus IMiD-exposed (270 days) subgroups who received PLD plus bortezomib. A sustained trend favoring combination therapy was observed in analyses of overall survival. In patients who achieved a response, the response duration was comparable for IMiD-naive patients and IMiD-exposed patients in the combination treatment group and lasted a median of 310 days and 319 days, respectively. The incidence of grade 3/4 adverse events was similar with PLD plus bortezomib regardless of prior IMiD exposure. CONCLUSIONS: A significantly prolonged TTP was observed with combined PLD plus bortezomib combination therapy compared with bortezomib alone despite prior IMiD exposure. For the combination treatment arm in the IMiD-naive and IMiD-exposed subgroups, TTP was comparable. Similarly, the safety profile of the PLD plus bortezomib combination was unaltered by prior IMiD exposure.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Boronic Acids/administration & dosage , Bortezomib , Disease Progression , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Female , Humans , Lenalidomide , Male , Middle Aged , Multiple Myeloma/complications , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/etiology , Polyethylene Glycols/administration & dosage , Pyrazines/administration & dosage , Salvage Therapy , Survival Rate , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives
20.
J Clin Oncol ; 25(25): 3892-901, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17679727

ABSTRACT

PURPOSE: This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. PATIENTS AND METHODS: Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m(2) on day 4. RESULTS: Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome. CONCLUSION: PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Boronic Acids/administration & dosage , Doxorubicin/analogs & derivatives , Multiple Myeloma/drug therapy , Polyethylene Glycols/administration & dosage , Pyrazines/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bortezomib , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/epidemiology , Disease Progression , Disease-Free Survival , Doxorubicin/administration & dosage , Drug Resistance, Neoplasm , Female , Hematologic Diseases/chemically induced , Humans , Incidence , Male , Middle Aged , Neoplasm Recurrence, Local
SELECTION OF CITATIONS
SEARCH DETAIL