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1.
Biol Blood Marrow Transplant ; 23(4): 625-634, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28104514

ABSTRACT

Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells. In preclinical studies, a single intravenous infusion of RGI-2001 expanded Treg and could ameliorate GVHD in a mouse model of allogeneic HCT. To explore the role of RGI-2001 in clinical HCT, we initiated a phase 2A clinical trial (n = 29), testing 2 different doses of RGI-2001 administered as a single infusion on day 0 of allogeneic HCT. RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome. A subset of patients (8 of 29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios+ and Foxp3+, indicating that their accumulation was due to expansion of natural Treg. Notably, the incidence of grade 2 to 4 GVHD in the 8 patients who responded to RGI-2001 was 12.5%, compared with 52.4% in the 21 patients who did not respond. No grade 3 or 4 GVHD was observed in the responder group, compared with a 9.5% incidence among nonresponders. Immunosuppression with sirolimus was also associated with a low incidence of GVHD, suggesting that RGI-2001 may have synergized with sirolimus to promote Treg expansion.


Subject(s)
Bone Marrow Transplantation/adverse effects , Galactosylceramides/administration & dosage , Graft vs Host Disease/prevention & control , Sirolimus/administration & dosage , T-Lymphocytes, Regulatory/cytology , Acute Disease , Adult , Aged , Bone Marrow Transplantation/methods , Cell Proliferation/drug effects , Drug Synergism , Forkhead Transcription Factors , Galactosylceramides/pharmacology , Graft vs Host Disease/drug therapy , Humans , Ikaros Transcription Factor , Middle Aged , Natural Killer T-Cells/cytology , Sirolimus/pharmacology , T-Lymphocytes, Regulatory/drug effects , Transplantation, Homologous , Young Adult
2.
Haematologica ; 101(8): 968-75, 2016 08.
Article in English | MEDLINE | ID: mdl-27151994

ABSTRACT

Classical Hodgkin lymphoma treatment is evolving rapidly with high response rates from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response, therefore development of novel therapies is warranted to improve patient outcomes. In this phase II study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat, an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled: 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week); 16 patients on Schedule B (15 mg oral entinostat once weekly in 3 of 4 weeks). Patients received a median of 3 prior treatments (range 1-10), with 80% of the patients receiving a prior stem cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention-to-treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease beyond 6 months) was 24%. Seven patients did not complete the first cycle due to progression of disease. Tumor reduction was observed in 24 of 38 (58%) evaluable patients. Median progression-free survival and overall survival was 5.5 and 25.1 months, respectively. The most frequent grade 3 or 4 adverse events were thrombocytopenia (63%), anemia (47%), neutropenia (41%), leukopenia (10%), hypokalemia (8%), and hypophosphatemia (6%). Twenty-five (51%) patients required dose reductions or delays. Pericarditis/pericardial effusion occurred in one patient after 12 cycles of therapy. Future studies are warranted to identify predictive biomarkers for treatment response and to develop mechanism-based combination strategies. (clinicaltrials.gov identifier: 00866333).


Subject(s)
Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Hodgkin Disease/drug therapy , Pyridines/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Benzamides/administration & dosage , Benzamides/adverse effects , Benzamides/pharmacokinetics , Combined Modality Therapy , Cytokines/blood , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/pharmacokinetics , Hodgkin Disease/diagnosis , Hodgkin Disease/mortality , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multimodal Imaging , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridines/pharmacokinetics , Recurrence , Retreatment , Treatment Outcome , Young Adult
3.
Clin Cancer Res ; 22(23): 5829-5838, 2016 Dec 01.
Article in English | MEDLINE | ID: mdl-27189165

ABSTRACT

PURPOSE: Randomized studies with gemtuzumab ozogamicin have validated CD33 as a target for antigen-specific immunotherapy of acute myelogenous leukemia (AML). Here, we investigated the potential of CD33/CD3-directed tandem diabodies (TandAbs) as novel treatment approach for AML. These tetravalent bispecific antibodies provide two binding sites for each antigen to maintain the avidity of a bivalent antibody and have a molecular weight exceeding the renal clearance threshold, thus offering a longer half-life compared to smaller antibody constructs. EXPERIMENTAL DESIGN: We constructed a series of TandAbs composed of anti-CD33 and anti-CD3 variable domains of diverse binding affinities and profiled their functional properties in CD33+ human leukemia cell lines, xenograft models, and AML patient samples. RESULTS: Our studies demonstrated that several CD33/CD3 TandAbs could induce potent, dose-dependent cytolysis of CD33+ AML cell lines. This effect was modulated by the effector-to-target cell ratio and strictly required the presence of T cells. Activation and proliferation of T cells and maximal AML cell cytolysis correlated with high avidity to both CD33 and CD3. High-avidity TandAbs were broadly active in primary specimens from patients with newly diagnosed or relapsed/refractory AML in vitro, with cytotoxic properties independent of CD33 receptor density and cytogenetic risk. Tumor growth delay and inhibition were observed in both prophylactic and established HL-60 xenograft models in immunodeficient mice. CONCLUSIONS: Our data show high efficacy of CD33/CD3 TandAbs in various preclinical models of human AML. Together, these findings support further study of CD33/CD3 TandAbs as novel immunotherapeutics for patients with AML. Clin Cancer Res; 22(23); 5829-38. ©2016 AACR.


Subject(s)
Antibodies, Bispecific/immunology , Antibodies, Monoclonal/immunology , CD3 Complex/immunology , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/therapy , Sialic Acid Binding Ig-like Lectin 3/immunology , Aminoglycosides/immunology , Animals , Antibodies, Monoclonal, Humanized/immunology , Binding Sites/immunology , Cell Line, Tumor , Gemtuzumab , Half-Life , Humans , Immunotherapy/methods , Mice , T-Lymphocytes/immunology
4.
Ann Hematol ; 94(2): 249-56, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25178517

ABSTRACT

The objective in this study was to characterize the pattern of the treatment-related lymphocytosis curve in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib, and assess the relationship between the baseline factors and absolute lymphocyte counts (ALC). The PCYC-1102-CA study was a five-arm phase Ib/II open-label, nonrandomized, multicenter study in CLL/SLL. The arms and accruals were 420 and 840 mg/day treatment-naive elderly CLL/SLL (N = 27 and N = 4, respectively), 420 and 840 mg/day relapsed/refractory CLL/SLL (N = 27 and N = 34, respectively), and 420 mg/day high-risk CLL/SLL (N = 24). The results were generated through statistical modeling using data from a clinical trial (PCYC-1102) in five cohorts of treatment-naïve or relapsed/refractory CLL patients treated at 420 and 840 mg daily of ibrutinib. In cases in which the initial increase in ALC doubles by day 28, it takes patients longer to reach their maximum ALC when compared with those with a lower rate of increase. Our models show that all of the cohorts exhibited the same pattern of treatment-related lymphocytosis from ibrutinib, and there are no significant differences between cohorts, including no detectable dose effect. The ALC of the majority of patients return to baseline ALC values by the end of cycle 5.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Linear Models , Adenine/analogs & derivatives , Aged , Cohort Studies , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance, Neoplasm , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Lymphocyte Count , Neoplasm Recurrence, Local , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Piperidines , Pyrazoles/administration & dosage , Pyrazoles/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use
5.
J Clin Oncol ; 32(17): 1797-803, 2014 Jun 10.
Article in English | MEDLINE | ID: mdl-24799467

ABSTRACT

PURPOSE: Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF. PATIENTS AND METHODS: Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n=287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. RESULTS: At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n=195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. CONCLUSION: This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.


Subject(s)
Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Hemocyanins/administration & dosage , Immunoglobulin Idiotypes/immunology , Lymphoma, Follicular/therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Vaccines/adverse effects , Cyclophosphamide/administration & dosage , Double-Blind Method , Female , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Hemocyanins/immunology , Humans , Immunotherapy/methods , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/immunology , Male , Middle Aged , Prednisone/administration & dosage , Vincristine/administration & dosage
6.
N Engl J Med ; 369(6): 507-16, 2013 Aug 08.
Article in English | MEDLINE | ID: mdl-23782157

ABSTRACT

BACKGROUND: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. METHODS: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS: The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)


Subject(s)
Lymphoma, Mantle-Cell/drug therapy , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Administration, Oral , Adult , Agammaglobulinaemia Tyrosine Kinase , Aged , Aged, 80 and over , Drug Resistance, Neoplasm , Female , Humans , Lymphocyte Count , Lymphoma, Mantle-Cell/mortality , Male , Middle Aged , Piperidines , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrimidines/adverse effects , Recurrence , Survival Analysis
7.
Clin Cancer Res ; 19(8): 2248-56, 2013 Apr 15.
Article in English | MEDLINE | ID: mdl-23447001

ABSTRACT

PURPOSE: Carfilzomib, a selective proteasome inhibitor, has shown safety and efficacy in relapsed and/or refractory multiple myeloma. This phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a phase II expansion study. EXPERIMENTAL DESIGN: Patients with multiple myeloma who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15 to 27 mg/m(2) on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly. RESULTS: Forty patients enrolled in six cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median duration of response and progression-free survival were 11.8 and 10.2 months, respectively. CONCLUSION: The maximum planned CRd dose, carfilzomib 27 mg/m(2), lenalidomide 25 mg, and dexamethasone 40 mg, was recommended for further study, with promising safety and efficacy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Diarrhea/chemically induced , Disease Progression , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Fatigue/chemically induced , Female , Humans , Lenalidomide , Male , Middle Aged , Multiple Myeloma/pathology , Neoplasm Recurrence, Local , Neutropenia/chemically induced , Oligopeptides/administration & dosage , Oligopeptides/adverse effects , Thalidomide/administration & dosage , Thalidomide/adverse effects , Thalidomide/analogs & derivatives , Treatment Outcome
8.
Clin Lymphoma Myeloma Leuk ; 12(5): 310-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23040437

ABSTRACT

UNLABELLED: An open-label single-arm multicenter pilot phase II study of the next-generation selective proteasome inhibitor carfilzomib was conducted in 46 patients with relapsed and refractory multiple myeloma (MM) after ≥ 2 previous therapies. The best overall response rate (ORR) was 16.7%, with a median duration of response of 7.2 months. This pilot study was the first phase II single-agent trial conducted with carfilzomib. BACKGROUND: Carfilzomib is a next-generation selective proteasome inhibitor that irreversibly binds its target and has demonstrated single-agent activity in patients with bortezomib-resistant multiple myeloma (MM). PX-171-003-A0, an open-label single-arm multicenter pilot phase II study, enrolled 46 patients with relapsed MM after ≥ 2 previous therapies including bortezomib and an immunomodulator (thalidomide or lenalidomide) and disease refractory to the last treatment regimen preceding study entry. METHODS: Patients received carfilzomib 20 mg/m(2) intravenously on days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles. Responses in 42 evaluable patients were assessed per International Myeloma Working Group Uniform Response Criteria, with minimal response assessed per European Group for Blood and Marrow Transplantation (EBMT) criteria. RESULTS: The primary endpoint of best ORR was 16.7%, including 7 partial responses. Median duration of response was 7.2 months. Clinical benefit response (CBR) rate was 23.8% with a median duration of response of 13.8 months. The most common treatment-emergent adverse events (AEs) of any grade were anemia (73.9%), fatigue (69.6%), and thrombocytopenia (50.0%). Notably, peripheral neuropathy and neuropathy-related AEs were generally mild and infrequent. CONCLUSION: This pilot study was the first phase II single-agent trial conducted with carfilzomib. Based on these findings, the study was amended to test a higher carfilzomib dose in an additional 250 patients (PX-171-003-A1).


Subject(s)
Multiple Myeloma/drug therapy , Oligopeptides/administration & dosage , Proteasome Inhibitors/administration & dosage , Secondary Prevention , Adult , Aged , Aged, 80 and over , Boronic Acids/pharmacology , Bortezomib , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Drug Tolerance , Female , Humans , Male , Middle Aged , Oligopeptides/adverse effects , Pilot Projects , Proteasome Inhibitors/adverse effects , Pyrazines/pharmacology
9.
Br J Haematol ; 158(6): 739-48, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22845873

ABSTRACT

Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, carfilzomib has shown efficacy in patients with relapsed and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open-label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1-3 prior therapies, including at least one bortezomib-based regimen, received carfilzomib 20 mg/m(2) in a twice-weekly, consecutive-day dosing schedule for ≤12 monthly cycles. The best overall response rate (ORR) was 17·1% and the clinical benefit response rate (ORR + minimal response) was 31·4%. The median duration of response was >10·6 months and the median time to progression was 4·6 months. The most common adverse events were fatigue (62·9%), nausea (60·0%), and vomiting (42·9%). No exacerbation of baseline peripheral neuropathy was observed. Single-agent carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of carfilzomib as single agent or in combination with other agents.


Subject(s)
Antineoplastic Agents/therapeutic use , Boronic Acids/therapeutic use , Multiple Myeloma/drug therapy , Oligopeptides/therapeutic use , Protease Inhibitors/therapeutic use , Pyrazines/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Bortezomib , Disease Progression , Drug Resistance, Neoplasm , Fatigue/chemically induced , Female , Gastrointestinal Neoplasms/chemically induced , Hematologic Diseases/chemically induced , Humans , Male , Middle Aged , Oligopeptides/adverse effects , Protease Inhibitors/adverse effects , Recurrence , Treatment Outcome
10.
Blood ; 120(14): 2817-25, 2012 Oct 04.
Article in English | MEDLINE | ID: mdl-22833546

ABSTRACT

Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m(2) intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m(2) for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.


Subject(s)
Drug Resistance, Neoplasm , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Oligopeptides/therapeutic use , Salvage Therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Multiple Myeloma/mortality , Neoplasm Recurrence, Local/mortality , Neoplasm Staging , Pilot Projects , Prognosis , Survival Rate
11.
Clin Cancer Res ; 18(17): 4830-40, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22761464

ABSTRACT

PURPOSE: Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies. EXPERIMENTAL DESIGN: Carfilzomib (doses ranging from 1.2-27 mg/m(2)) was administered i.v. on 2 consecutive days for 3 weeks of a 4-week cycle. Single-agent dose escalation (n = 37) was followed by a dose-expansion phase (n = 11) that comprised 2 cohorts (carfilzomib or carfilzomib + dexamethasone). During dose expansion, carfilzomib was administered starting with 20 mg/m(2) during the first week (days 1, 2) and then escalated to 27 mg/m(2) thereafter. RESULTS: A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events were manageable and primarily of grade I or II. The main hematologic adverse events of ≥ grade III were anemia and thrombocytopenia. Notably, there were no observations of grade III or more peripheral neuropathy. Carfilzomib was cleared rapidly with an elimination half-life of less than 30 minutes but still induced dose-dependent inhibition of the 20S chymotrypsin-like proteasome activity. At doses of 15 to 27 mg/m(2), there was evidence of activity among patients with multiple myeloma and with non-Hodgkin lymphoma. CONCLUSIONS: Escalated dosing of carfilzomib on a schedule of 2 consecutive days for 3 weeks of a 4-week cycle was tolerable and showed promising activity. This dose regimen has been selected for ongoing and future clinical studies, including PX-171-003A1 and the pivotal trial ASPIRE.


Subject(s)
Lymphoma/drug therapy , Multiple Myeloma/drug therapy , Oligopeptides , Proteasome Inhibitors , Adult , Aged , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug-Related Side Effects and Adverse Reactions/chemically induced , Female , Humans , Lymphoma/pathology , Male , Maximum Tolerated Dose , Middle Aged , Multiple Myeloma/pathology , Oligopeptides/administration & dosage , Oligopeptides/adverse effects , Oligopeptides/pharmacokinetics , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/adverse effects , Proteasome Inhibitors/pharmacokinetics , Recurrence
12.
Blood ; 119(24): 5661-70, 2012 Jun 14.
Article in English | MEDLINE | ID: mdl-22555973

ABSTRACT

Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m(2) for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m(2) for cycle 1 and then 27 mg/m(2) for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy-17.1% overall (1 grade 3; no grade 4)-in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.


Subject(s)
Antineoplastic Agents/therapeutic use , Boronic Acids/therapeutic use , Multiple Myeloma/drug therapy , Oligopeptides/therapeutic use , Pyrazines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Bortezomib , Cohort Studies , Demography , Disease-Free Survival , Female , Humans , Male , Middle Aged , Oligopeptides/administration & dosage , Oligopeptides/adverse effects , Recurrence , Time Factors , Treatment Outcome
13.
Clin Cancer Res ; 16(5): 1673-81, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20179219

ABSTRACT

PURPOSE: RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell surface proteins. RAAG12 is highly expressed on many adenocarcinomas, particularly those of gastrointestinal origin. A phase 1 dose-escalation safety and pharmacokinetics trial was conducted in patients with metastatic or recurrent adenocarcinomas. EXPERIMENTAL DESIGN: RAV12 was initially given i.v. weekly x4, then by fractionated dosing twice or thrice weekly. Thirty-three patients were treated in the dose escalation segment of the trial in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7); and 0.5 mg/kg biw (3), 0.75 mg/kg biw (3), and 0.5 mg/kg tiw (6). Twenty patients were enrolled in a maximum tolerated dose cohort expansion at 0.75 mg/kg biw. RESULTS: Two clinical syndromes were associated with drug administration: abdominal cramping pain with diarrhea, and asymptomatic, self-limited increases of liver function tests. These effects were partially ameliorated with fractionated dosing. Pharmacokinetics was dose dependent. Maximum concentration was reduced, whereas area under the concentration versus time curve was maintained with fractionated dosing. One patient with colorectal cancer experienced a durable partial remission, with a time to progression (TTP) of >8 months. Three additional patients experienced a TTP of >4 months. CONCLUSIONS: RAV12 has activity in recurrent adenocarcinomas. However, the safety profile of the antibody seems to preclude the delivery of highly efficacious doses. Re-engineering the molecule to remove FcRn binding (while maintaining FcgammaR binding) and to humanize it may improve the toxicity profile and efficacy.


Subject(s)
Adenocarcinoma/drug therapy , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/pharmacokinetics , Antigens, Tumor-Associated, Carbohydrate/drug effects , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Dose-Response Relationship, Drug , Female , Half-Life , Humans , Immunohistochemistry , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Recurrence, Local/drug therapy
14.
Clin Cancer Res ; 15(22): 7085-91, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19903785

ABSTRACT

PURPOSE: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. EXPERIMENTAL DESIGN: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. RESULTS: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patients-mostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses > or =11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenström's macroglobulinemia). CONCLUSION: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing.


Subject(s)
Antineoplastic Agents/therapeutic use , Hematologic Neoplasms/drug therapy , Oligopeptides/therapeutic use , Protease Inhibitors/therapeutic use , Proteasome Inhibitors , Adult , Aged , Aged, 80 and over , Dose-Response Relationship, Drug , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Treatment Outcome
15.
Leuk Lymphoma ; 48(12): 2338-44, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18067008

ABSTRACT

Clonotypic B lymphocytes may underlie relapse of patients with multiple myeloma. Rituximab, a CD20 monoclonal antibody, may result in eradication of the monoclonal B cells. We conducted a phase II study of rituximab in combination with melphalan and prednisone therapy (MP) followed by rituximab maintenance in newly diagnosed multiple myeloma patients. Sixteen patients (35%) had CD20 positive bone marrow plasma cells, while 9 patients (20%) had unknown CD20 status. No patient had a complete remission, 26 patients (58%) had a partial response, 6 patients (13%) had a minimal response, and 8 patients (18%) had stable disease. The median event-free survival was 14 months, and the 7-year overall survival was 30%. The toxicity of the combination was overall manageable and consistent with what is generally noted with MP chemotherapy. The combination of rituximab to MP therapy did not result in improved response rate or event-free survival.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melphalan/administration & dosage , Multiple Myeloma/drug therapy , Prednisone/administration & dosage , Administration, Oral , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Antigens, CD20/analysis , Female , Humans , Male , Melphalan/adverse effects , Middle Aged , Multiple Myeloma/mortality , Prednisone/adverse effects , Prospective Studies , Rituximab
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