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.
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.
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).
This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing.
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.
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.
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.
Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)
The primary muscle disorders are a diverse group of diseases caused by various defective structural proteins, abnormal signaling molecules, enzymes and proteins involved in posttranslational ...modifications, and other mechanisms. Although there is increasing clarification of the primary aberrant cellular processes responsible for these conditions, the decisive factors involved in the secondary pathogenic cascades are still mainly obscure. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs regulated during the degenerative process of muscle to gain insight into the specific regulation of genes that are disrupted in pathological muscle conditions. We describe 185 miRNAs that are up- or down-regulated in 10 major muscular disorders in humans Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis, dermatomyositis, and inclusion body myositis. Although five miRNAs were found to be consistently regulated in almost all samples analyzed, pointing to possible involvement of a common regulatory mechanism, others were dysregulated only in one disease and not at all in the other disorders. Functional correlation between the predicted targets of these miRNAs and mRNA expression demonstrated tight posttranscriptional regulation at the mRNA level in DMD and Miyoshi myopathy. Together with direct mRNA-miRNA predicted interactions demonstrated in DMD, some of which are involved in known secondary response functions and others that are involved in muscle regeneration, these findings suggest an important role of miRNAs in specific physiological pathways underlying the disease pathology.
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.
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.
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.
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.
Summary
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/m2 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.
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/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 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.
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.
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.
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.
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.
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 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.
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.
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.
Micro-Abstract 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.
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