A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab.
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ABSTRACT:
SUBMITTER: Mikhael J
PROVIDER: S-EPMC8116334 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab.
Mikhael Joseph J Belhadj-Merzoug Karim K Hulin Cyrille C Vincent Laure L Moreau Philippe P Gasparetto Cristina C Pour Ludek L Spicka Ivan I Vij Ravi R Zonder Jeffrey J Atanackovic Djordje D Gabrail Nashat N Martin Thomas G TG Perrot Aurore A Bensfia Samira S Weng Qilong Q Brillac Claire C Semiond Dorothée D Macé Sandrine S Corzo Kathryn P KP Leleu Xavier X
Blood cancer journal 20210512 5
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Project description:In this multi-center, Phase-1 study (NCT03733717), we characterized the pharmacokinetics (PK) of the anti-CD38 antibody isatuximab (Isa) after IV administration (primary objective), and evaluated safety, immunogenicity, and preliminary anti-myeloma activity in Chinese patients with relapsed/refractory multiple myeloma (RRMM). Isa 20-mg/kg was administered weekly (QW) in cycle 1, then biweekly (Q2W). Twenty-one extensively pretreated RRMM patients (median 4 prior lines; 95.2% refractory to last regimen), received ≥ 1 dose of Isa. After first IV-infusion, mean maximum observed concentration was 402 μg/mL and mean area-under-the-concentration-versus-time curve (first 1-week dosing interval) 37,000 μg·h/mL. After repeated administration, exposure (Ctrough) increased 3.11-folds (day 1/cycle 2) versus first administration (day 8/cycle 1). Safety findings were consistent with the known Isa safety profile, with no new safety signals. Any-causality, grade ≥ 3 treatment-emergent adverse events (TEAEs) were reported in 47.6% of patients. Serious, treatment-related AEs occurred in 2 patients. Isa treatment was generally well tolerated; only 1 patient discontinued due to TEAE. Preliminary efficacy results showed a 19.0% overall response rate (clinical benefit, 33.3%). Our results demonstrate a PK profile for Isa comparable to prior findings in Western and other East-Asian populations, as well as safety and tolerability of treatment with IV Isa 20-mg/kg QW-Q2W in Chinese RRMM patients.Trial registration: The trial was registered with ClinicalTrials.gov; NCT03733717. Date of first trial registration: 07/11/2018.
| S-EPMC11554793 | biostudies-literature
Project description:This phase I dose-escalation/expansion study evaluated isatuximab (anti-CD38 monoclonal antibody) monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). Patients progressing on or after standard therapy received intravenous isatuximab (weekly [QW] or every 2 weeks [Q2W]). The primary objective was to determine the maximum tolerated dose (MTD) of isatuximab. Overall, 84 patients received ≥ 1 dose of isatuximab. The MTD was not reached; no cumulative adverse reactions were noted. The most frequent adverse events were infusion reactions (IRs), occurring in 37/73 patients (51%) following introduction of mandatory prophylaxis. IRs were mostly grade 1/2, occurred predominantly during Cycle 1, and led to treatment discontinuation in two patients. CD38 receptor occupancy reached a plateau of 80% with isatuximab 20 mg/kg (highest dose tested) and was associated with clinical response. In patients receiving isatuximab ≥ 10 mg/kg, overall response rate (ORR) was 23.8% (15/63), including one complete response. In high-risk patients treated with isatuximab 10 mg/kg (QW or Q2W), ORR was 16.7% (3/18). Median (range) duration of response at doses ≥ 10 mg/kg was 25 (8-30) weeks among high-risk patients versus 36 (6-85) weeks for other patients. In conclusion, isatuximab demonstrated a manageable safety profile and clinical activity in patients with RRMM.
| S-EPMC6440961 | biostudies-literature
Project description:Isatuximab, an anti-CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open-label, single-arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose-limiting toxicities occurred; the recommended dose for the single-arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high-risk cytogenetic abnormalities had comparable results. In phase 2, the median progression-free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high-risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.
| S-EPMC7734004 | biostudies-literature
Project description:This phase 2 study evaluated isatuximab as monotherapy or combined with dexamethasone in relapsed/refractory multiple myeloma (RRMM). Patients had RRMM refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or had received ≥3 prior lines of therapy incorporating an IMiD and PI. Patients received isatuximab either as monotherapy (20 mg/kg on days 1, 8, 15, and 22 [once weekly] of cycle 1 followed by 20 mg/kg on days 1 and 15 of subsequent cycles; Isa group) or in combination with dexamethasone (40 mg/d [20 mg/d in patients aged ≥75 years] once weekly; Isa-dex group). Treated patients (N = 164) had received a median of 4 (range, 2-10) prior treatment lines. Patients received a median of 5 (1-24) and 7 (1-22) treatment cycles; at data cutoff, 13 (11.9%) of 109 and 15 (27.3%) of 55 patients remained on treatment in the Isa and Isa-dex arms, respectively. Overall response rate (primary efficacy end point) was 23.9% in the Isa arm and 43.6% in the Isa-dex arm (odds ratio, 0.405; 95% confidence interval, 0.192-0.859; P = .008). Median progression-free survival and overall survival were 4.9 and 18.9 months for Isa, and 10.2 and 17.3 months for Isa-dex. Infusion reactions (mostly grade 1/2) and hematologic abnormalities were the most common adverse events. There was a similar incidence of grade 3 or higher infections in both groups (22.0% and 21.8%). In conclusion, addition of dexamethasone to isatuximab increased response rates and survival outcomes with no detrimental effect on safety. This trial was registered at www.clinicaltrials.gov as #NCT01084252.
| S-EPMC7933767 | biostudies-literature
Project description:This multicenter real-world analysis evaluated the efficacy of isatuximab, pomalidomide, and dexamethasone (IsaPd) in 51 patients with multiple myeloma (MM) who were refractory to daratumumab (Dara-R). The majority were under 70 years old (60.8%), predominantly female (56.9%), and heavily pretreated, with 74.5% being triple-class refractory (TCR); 32.1% of the 28 patients with cytogenetic data had high-risk abnormalities. The overall response rate (ORR) was 56.9%, including 3 patients with stringent complete response (sCR), 4 with CR, and 7 with very good partial response (VGPR). Neither age, number of prior therapies, TCR status, nor time from Dara refractoriness to IsaPd initiation significantly affected response rates. Median progression-free survival (PFS) was 5.8 months, with a 12-month PFS probability of 30.6%. Baseline hemoglobin (Hb) levels were a key predictor of PFS: patients with Hb < 11.8 g/L had a 3.5-fold increased risk of progression, with a median PFS of 4.6 months compared to 22 months in those with higher Hb. Median overall survival (OS) was 21.0 months, with a 12-month OS probability of 63.4%. Lower Hb levels (< 11 g/L) were associated with a tenfold increased risk of mortality. Among the 28 patients who underwent FISH analysis, while no significant difference in mortality risk was observed, those with high-risk cytogenetic abnormalities exhibited a nearly tenfold increased risk of disease progression. These results suggest that IsaPd offers a meaningful option for Dara-R patients, with Hb levels serving as a critical predictor of both PFS and OS. However, PFS remains modest, underscoring the need for novel combination therapies.
| S-EPMC11789454 | biostudies-literature
Project description:This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.
| S-EPMC6659612 | biostudies-literature
Project description:BackgroundGiven the incurable nature of multiple myeloma (MM), efforts are made to improve the efficacy of anti-CD38 monoclonal antibodies via combinations with other potentially synergistic therapies. This Phase 1/2 trial (NCT03194867) was designed to determine whether cemiplimab (anti-PD-1) enhances the anti-myeloma activity of isatuximab (anti-CD38) in patients with relapsed and refractory multiple myeloma (RRMM), to confirm the feasibility of the combination, determine its efficacy, and further evaluate its safety.MethodsPatients received isatuximab 10 mg/kg once weekly for 4 weeks followed by every 2 weeks (Isa), or isatuximab 10 mg/kg plus cemiplimab 250 mg every 2 (Isa + CemiQ2W) or every 4 weeks (Isa + CemiQ4W).ResultsOverall, 106 patients with RRMM treated with a median of 4 prior lines were included; 25.5% had high-risk cytogenetics, 63.2% were refractory to proteasome inhibitors and immunomodulatory agents, 26.4% were previously exposed to daratumumab, and 84.0% were refractory to their last treatment line. There were no major changes in the safety or pharmacokinetic profile of isatuximab with the addition of cemiplimab. As assessed by investigators, four patients (11.8%) in the Isa arm, nine patients (25.0%) in the Isa + CemiQ2W arm, and eight patients (22.2%) in the Isa + CemiQ4W arm were responders. Though response rates were numerically higher in cemiplimab-containing arms, differences were not statistically significant and did not translate to improved progression-free or overall survival after a median follow-up of 9.99 months.ConclusionOur results suggest a marginal benefit by adding cemiplimab to isatuximab, despite demonstration of target engagement, without additional observed safety issues.
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Project description:Biomarkers of bone turnover in serum are suggestive of bone dynamics during treatment in multiple myeloma (MM). We evaluated the role of daratumumab on bone remodeling among patients with relapsed/refractory MM in the prospective, open-label, phase 2 study REBUILD. Daratumumab was administered according to the approved indication. A total of 33 out of 57 enrolled patients completed 4 months of treatment. The median percent change from baseline to 4 months in C-terminal cross-linking telopeptide of type 1 collagen (CTX) (primary endpoint) was 3.9%, with 13 (39.4%) and 11 (33.3%) patients showing at least 20% and 30% reduction in CTX levels, respectively. The median percent decrease from baseline to 4 months in tartrate resistant acid phosphatase 5b (TRACP-5b) levels (co-primary endpoint) was 2.6%, with 10 (30.3%) and 6 (18.2%) patients showing at least 20% and 30% reduction in TRACP-5b levels, respectively. However, the changes in these markers of bone catabolism were not statistically significant. Furthermore, the levels of osteocalcin, bone-specific alkaline phosphatase and procollagen type-I N-pro-peptide (bone formation markers) increased from baseline to 4 months (secondary endpoints) by 18.4%, 92.6% and 10.2%, respectively. Furthermore, the median levels of dickkopf-1 and C-C motif ligand-3 showed a significant decrease at 4 months by 17.5% and 16.0%, respectively. In conclusion, daratumumab improved bone turnover by inducing bone formation and reducing osteoblast inhibition.
| S-EPMC9179322 | biostudies-literature
Project description:This phase 1b, open-label, dose-escalation study assessed the safety, efficacy, and pharmacokinetics of anti-CD38 monoclonal antibody isatuximab given in 2 schedules (3, 5, or 10 mg/kg every other week [Q2W] or 10 or 20 mg/kg weekly [QW] for 4 weeks and then Q2W thereafter [QW/Q2W]), in combination with lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (QW), in patients with relapsed/refractory multiple myeloma (RRMM). Patients received 28-day treatment cycles; the primary objective was to determine the maximum tolerated dose (MTD) of isatuximab with lenalidomide and dexamethasone. Fifty-seven patients (median 5 [range 1-12] prior regimens; 83% refractory to previous lenalidomide therapy) were treated. Median duration of dosing was 36.4 weeks; 15 patients remained on treatment at data cutoff. Isatuximab-lenalidomide-dexamethasone was generally well tolerated with only 1 dose-limiting toxicity reported (grade 3 pneumonia at 20 mg/kg QW/Q2W); the MTD was not reached. The most common isatuximab-related adverse events were infusion-associated reactions (IARs) (56%), which were grade 1/2 in 84% of patients who had an IAR and predominantly occurred during the first infusion. In the efficacy-evaluable population, the overall response rate (ORR) was 56% (29/52) and was similar between the 10 mg/kg Q2W and 10 and 20 mg/kg QW/Q2W cohorts. The ORR was 52% in 42 evaluable lenalidomide-refractory patients. Overall median progression-free survival was 8.5 months. Isatuximab exposure increased in a greater than dose-proportional manner; isatuximab and lenalidomide pharmacokinetic parameters appeared independent. These data suggest that isatuximab combined with lenalidomide and dexamethasone is active and tolerated in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT01749969.
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Project description:Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8+ T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance.
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