P953: PHASE I STUDY OF TQB3602 CAPSULE, AN ORAL PROTEASOME INHIBITOR, IN RELAPSED/REFRACTORY MULTIPLE MYELOMA
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SUBMITTER: Tang W
PROVIDER: S-EPMC9431121 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTQB3602 is a novel orally bioavailable proteasome inhibitor. This study is the first-in-human phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TQB3602 in relapsed/refractory multiple myeloma (RRMM).MethodsThis is a multicenter phase I clinical trial consisting of the 3+3 dose-escalation phase and dose expansion phase. Patients with MM who have received ≥2 prior antimyeloma therapies were enrolled. TQB3602 is administered at a dose of 0.5~7mg on days 1, 8, 15 in 28-day cycle.ResultsTwenty-five RRMM patients who relapsed or failed ≥2 lines of therapies were enrolled in the dose escalation phase. Two patients in the 7.0 mg dose group developed dose-limiting toxicity events (one with grade 2 peripheral neuropathy [PN] complicated by pain and one with diarrhea and abdominal pain), leading to a maximum tolerated dose of 6.0 mg. Any-grade adverse events (AEs) occurred in 24 (96.0%) patients, while grade ≥3 AEs occurred in 13 (52.0%). The most common grade ≥3 AEs was anemia (6, 24.0%). The incidence rate of PN was 16% with no grade ≥3 PN occurred. TQB3602 was rapidly absorbed, resulting in a time-to-plasma peak concentration of 0.8-1.5 h. The mean half-life was approximately 82 h. The AUClast and Cmax were approximately 1.9 times higher on day 15 than on day 1. Among 22 response-evaluable patients, 63.7% achieved stable disease or better.ConclusionsTQB3602 is well tolerated, with a favorable neurotoxicity profile, and has shown preliminary efficacy in patients with RRMM. The anticipated therapeutic dose was 6 mg and was adopted for an ongoing dose-expansion phase.
| S-EPMC11259557 | biostudies-literature
Project description:Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received ≥12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade ≥3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade ≥3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.
| S-EPMC4574453 | biostudies-literature
Project description:Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.
| S-EPMC4468583 | biostudies-literature
Project description:Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic [grade ≥ 3 vs ≤ 2] or non-hematologic [grade ≥ 2 vs ≤ 1] adverse events [AEs], and clinical benefit [≥stable disease vs progressive disease]) using phase 1 data in relapsed/refractory MM (NCT00963820; N = 44). Results Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p < 0.05). Dose-response relationships indicated a favorable benefit/risk ratio at 3 mg and 4 mg weekly, which are below the maximum tolerated dose of 5.5 mg. At 3 mg, the model predicted that: 37 % of patients will achieve clinical benefit; incidence of grade ≥ 3 neutropenia and thrombocytopenia will be 10 % and 23 %, respectively; and incidence of grade ≥ 2 rash, fatigue, and diarrhea will be 8 %, 19 %, and 19 %, respectively. Conclusions Based on the findings, patients in the phase 3 maintenance trial will initiate ixazomib at a once-weekly dose of 3 mg, increasing to 4 mg if acceptable tolerability after 4 cycles, to provide maximum clinical benefit balanced with adequate tolerability.
| S-EPMC4859859 | biostudies-literature
Project description:BackgroundThe oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study.ObjectiveThe objective of this study was to quantitatively characterize the benefit-risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule.MethodsWe report early-phase study data and exposure-response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule.ResultsSingle-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure-response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity.ConclusionsThese analyses support a favorable benefit-risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program.Trial registration numbersClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537.
| S-EPMC5610674 | biostudies-literature
Project description:The ubiquitin-proteasome pathway was first validated as a target for cancer therapy with the demonstration of the activity of the boronic acid proteasome inhibitor (PI) bortezomib (Velcade) against relapsed and relapsed/refractory multiple myeloma. Another generation of PIs is now entering the clinical arena; this includes intravenous agents such as carfilzomib, CEP-18770, and marizomib, and oral drugs such as MLN9708 and ONX 0912. These novel agents will likely first be used for patients with disease that has either relapsed or been refractory to prior therapy (including bortezomib-based regimens) because of their ability to overcome drug resistance, or will be used in patients who are intolerant of, or are not candidates for bortezomib. Preclinical studies also suggest that PIs may act synergistically with other conventional and novel agents, or even with one another in rationally designed combination regimens. In addition, other inhibitors that selectively target only the immunoproteasome and not the constitutive proteasome, as well as agents that bind to noncatalytic proteasome subunits, are emerging as potential drug candidates. Taken together, it seems likely that we have only begun to appreciate the full potential of inhibition of the proteasome. This article extrapolates our current knowledge into an algorithm for the future use of these inhibitors against multiple myeloma.
| S-EPMC4163602 | biostudies-literature
Project description:High-througput transcriptome analysis by RNA-seq of multiple myeloma tumor samples (CD138+ cells) in subjects treated with pomalidomide, daily low dose oral cyclophosphamide and dexamethasone in the context of a phase II clinical trial. Samples were collected at baseline as a correlative study to determine whether gene expression profiles could distinguish patients with (un)favorable response to treatment.
2019-10-11 | GSE138717 | GEO
Project description:This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902 A phase 3 study is ongoing (#NCT01659658).
| S-EPMC6911836 | biostudies-literature
Project description:PurposeAZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma.Experimental designAZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles.ResultsThirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, three additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138(+) cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation.ConclusionsSingle-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population.
| S-EPMC4775365 | biostudies-literature
Project description:The inexpensive, well-tolerated, immunomodulatory agent leflunomide, used extensively for the treatment of rheumatoid arthritis, has been shown to produce significant activity against multiple myeloma (MM) in pre-clinical studies. We conducted a phase 1 study (clinicaltrials.gov: NCT02509052) of single agent leflunomide in patients with relapsed/refractory MM (≥3 prior therapies). At dose levels 1 and 2 (20 and 40 mg), no dose-limiting toxicities (DLTs) were observed. At dose level 3 (60 mg), one patient experienced elevated alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. Overall, toxicities were infrequent and manageable. Nine out of 11 patients achieved stable disease (SD), two subjects experiencing SD for nearly one year or longer. The tolerable safety profile of leflunomide, combined with a potential disease stabilization, is motivating future studies of leflunomide, in combination with other MM drugs, or as an approach to delay progression of smoldering MM.
| S-EPMC7384948 | biostudies-literature