scholarly journals DOP60 Vedolizumab treatment persistence and safety in an extended access program (XAP)

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S099-S100
Author(s):  
S Danese ◽  
K Subramanian ◽  
J Van Zyl ◽  
S Adsul ◽  
D Lindner ◽  
...  
Keyword(s):  
Data Analysis ◽  
Adverse Events ◽  
Dose Escalation ◽  
Open Label ◽  
Dose Escalation Study ◽  
Extended Access ◽  
Dosing Frequency ◽  
Access Program

Abstract Background Vedolizumab, a gut-selective, α 4β 7 integrin antagonist, has been established as an effective and safe treatment for patients with UC or CD in the GEMINI phase 3 program and long-term safety (LTS) study. An extended access program (XAP) was initiated to provide continued access to patients who were benefiting from vedolizumab in GEMINI LTS and to monitor safety. We now report persistence and safety results from a 2-year data analysis. Methods Vedolizumab XAP (NCT02743806) is a phase 3b/4 prospective, open-label, multinational interventional study. A rollover from GEMINI LTS (NCT00790933) to the XAP, patients reduced dosing frequency from vedolizumab 300 mg IV every 4 weeks (Q4W) to every 8 weeks (Q8W) or remained on vedolizumab 300 mg IV Q4W if medically indicated. This 2-year data analysis assessed persistence on Q8W dosing after dosing frequency reduction, need for escalation to Q4W dosing, incidence of relapse (defined as dose escalation, study withdrawal due to adverse event, loss of adequate benefit from vedolizumab, or increased corticosteroid [CS] or immunomodulator dose), and safety 2 years after rollover from GEMINI LTS. Results A total of 311 patients (142 UC, 169 CD) from GEMINI LTS enrolled in the XAP. Median (range) duration of exposure to vedolizumab prior to the XAP was 8.0 years (5.2–10.0) for patients with UC and 7.5 years (5.4–9.9) for patients with CD. Of patients with UC and CD, 93.0% and 84.6%, respectively, reduced dosing frequency to Q8W at XAP start, and 87.3% and 77.5%, respectively, remained on Q8W after 2 years. At baseline, 93.0% of all patients with UC and 88.2% of all patients with CD were in CS-free remission; patients who maintained Q4W dosing at baseline had lower CS-free remission rates (62.5% in UC and 69.2% in CD). Of patients who initiated Q8W dosing at enrolment in the XAP, 95% had no relapse for ≥6 months (97.0% UC, 93.7% CD; Table 1). Only 7.3% of patients required dose escalation to Q4W, and 11.6% experienced relapse during the 2-year follow-up. Times to dose escalation and relapse were similar in patients with UC and CD (Figures 1 and 2). At 2 years, 4 of 8 patients with UC and 4 of 12 patients with CD who required dose escalation to Q4W discontinued vedolizumab early due to loss of benefit or adverse events. Adverse events related to vedolizumab were infrequent; no new or serious events attributed to vedolizumab were reported. Conclusion High patient persistence on Q8W vedolizumab was observed in the first 2 years after reduction of dosing frequency in the XAP. Overall, there were low rates of Q4W dose escalation and CD or UC disease relapse. The safety profile was consistent with previous reports with no new signals observed.

THUR 173 Longterms: 10-year experience of fingolimod in RRMS patients

2018 ◽  
Vol 89 (10) ◽  
pp. A22.3-A22
Author(s):  
Cohen Jeffrey ◽  
Tenenbaum Nadia ◽  
Bhatt Alit ◽  
Pimentel Ron ◽  
Kappos Ludwig
Keyword(s):  
Adverse Events ◽  
Safety Profile ◽  
Brain Volume ◽  
Disability Progression ◽  
Open Label ◽  
T2 Lesions ◽  
Long Term Follow Up ◽  
Efficacy Measures

ObjectivesPresent results for up to 10 years of fingolimod treatment in RRMS patients.MethodsLONGTERMS is an open-label, single-arm, extension study evaluating the long-term safety, tolerability and efficacy of fingolimod in patients who previously participated in earlier fingolimod studies. Key efficacy measures: annualised relapse rate (ARR), proportion of patients free of 6 month confirmed disability progression (6 m-CDP), annualised rate of new or newly enlarging T2 lesions (ARneT2), and annualised rate of brain atrophy (ARBA). Safety analyses: adverse events (AEs) and serious AEs (SAEs) frequencies.Results3168 patients were included in the analysis. ARR decreased with longer exposure from 0.26 (Month [M] 0–12) to 0.20 (M0–60) and 0.19 (M0–120). Most patients remained free from 6 m-CDP at M60 (79.3%) and M120 (68.1%). ARneT2 decreased from 1.31 (M0–12) to 0.90 (M0–60), and 0.71 (M0–120). Change in brain volume was stable throughout the study (−0.37 [M12], −0.33 [M60] and −0.32 [M120]). Long-term exposure did not raise new safety concerns. No increase in frequencies of AEs or SAEs per year was observed over long-term fingolimod treatment.ConclusionsLong-term follow-up confirmed the established safety profile of fingolimod. Treatment was associated with a sustained low level of disease activity as expressed by clinical and MRI outcomes.DisclaimerPreviously presented at ECTRIMS 2017

Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9533-9533 ◽  
Author(s):  
Michael B. Atkins ◽  
John M. Kirkwood ◽  
Jedd D. Wolchok ◽  
Margaret K. Callahan ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Performance Status ◽  
Study Drug ◽  
Advanced Melanoma ◽  
Post Treatment ◽  
Dose Escalation Study ◽  
Term Survival

9533 Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months (range 0.9-76.7) in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57% (95% CI: 47, 67). The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% (48, 74) versus 49% (32, 65); for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% (41, 65) and 61% (38, 77), respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively, and in pts who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231.

An armored GPC3-directed CAR-T for refractory or relapsed hepatocellular carcinoma in China: A phase I trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4095-4095
Author(s):  
Zhongwei Zhao ◽  
Wenyuan Guo ◽  
Shiji Fang ◽  
Shaohua Song ◽  
Jingjing Song ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Setting ◽  
Intravenous Route ◽  
High Dose ◽  
Specific Marker ◽  
Single Infusion ◽  
Open Label ◽  
Dose Escalation Study ◽  
Car T

4095 Background: HCC is a leading cause of cancer-related morbidity and mortality worldwide, of which glypican 3 is a highly specific marker. GPC3-directed CAR-T had shown promising safety but limited efficacy in the treatment of HCC. We developed an armored GPC3-directed CAR-T G3-CAR-ori2 by inserting of a novel and proprietary Ori2 element following the 4-1BB and CD3ζ domains in a second-generation CAR-T. Pre-clinical studies showed a significantly higher memory stem cell ratio and dramatically improved proliferation and persistence, compared with traditional CAR-T, thus offering prolonged efficacy in vitro and in vivo and potentiality leading to improved activity in the clinical setting (ChiCTR1900028121). Methods: This is an open-label, dose-escalation study of G3-CAR-ori2 cell HCC patients in two centers. Eligible patients were aged 18-70 years with histologically confirmed GPC3+ HCC, Child-Pugh score A or B, ECOG≤1, relapsed or refractory to standard therapies. Patients were pre-conditioned with fludarabine (25̃30 mg/m2) and cyclophosphamide (200̃300 mg/m2) daily for 3 days. G3-CAR-Ori2 was administered as a single infusion via intrahepatic or intravenous route with a total dose of 0.9 to 3x10e8 CAR-T. The objective was to assess the safety, preliminary efficacy, persistence and cytokine profiling of G3-CAR-ori2. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 5.0). Tumor responses were evaluated per RECIST (version 1.1). CAR-T cell expansion and persistence were measured by qPCR and flow cytometry. Results: As of Jan 21, 2021, 10 patients had received single infusion, in which 6 received G3-CAR-ori2 via intravenous route and 4 via intrahepatic route. 7 patients received the highest dose level of 3x10e8. 9 patients reached at least 1 month of follow-up and tolerated the treatment well with no dose-limiting toxicity. All patients experienced transient grade 4 decrease in lymphocyte count resulted from the lymphodepletion regimen. Cytokine release syndrome (CRS) was observed in 8 patients, in which 6 at grade 1 or 2 and 2 at grade 4 notably infused with 3 x10e8 both via intravenous route and reversed within 7 days by administering high-dose steroids and tocilizumab. Other grade 4 hematologic toxicities include thrombocytopenia (2/9) and neutropenia (1/9). No neurotoxicity was observed. Two subjects were not evaluable due to early withdrawal from the trial. Among the 7 evaluable subjects, the best responses achieved are 3 PR, 2 SD, 2 PD. The duration of remission of one patient with PR is more than 4 months, follow up is ongoing. CAR-T gene detected by q-PCR provide preliminary indication that G3-CAR-ori2 is able to expand and persist well in the clinical setting. Conclusions: These initial data provide evidence that G3-CAR-ori2 is safe and holds promising antitumor potential, and supports its continuing development in the treatment of r/r GPC3+HCC. Clinical trial information: ChiCTR1900028121.

Rituximab-Relapsing Patients with Non-Hodgkins Lymphoma Respond Even at Lower Doses of Humanized Anti-CD20 Antibody, IMMU-106 (hA20): Phase I/II Results.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2719-2719 ◽  
Author(s):  
Franck Morschhauser ◽  
John P. Leonard ◽  
Luis Fayad ◽  
Bertrand Coiffier ◽  
STephen J. Schuster ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Post Treatment ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Open Label ◽  
Dose Escalation Study ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Background: An open-label, multicenter, dose-escalation study in patients with recurrent NHL was initially undertaken to establish the safety, tolerance, PK, and immunogenicity (HAHA) of humanized anti-CD20 antibody, IMMU-106 (hA20), administered once-weekly for 4 weeks at different doses. Additional patients have now been entered to confirm the efficacy of 120 and 375 mg/m2 dosing, and to determine the feasibility of using even lower hA20 doses. Methods: A total of 55 patients (23 male, 32 female; 51 Caucasian; 40–84 years old) received hA20 at 120 (N=21), 200 (N=6), 375 (N=25) or 750 mg/m2 (N=3). They had follicular (FL, N=37) or other (N=18) B-cell lymphomas, were predominantly stage III/IV (N=44) at study entry, and had received 1–7 prior treatments (median, 2), including 1 (N=34) or more (N=14) rituximab regimens (without progression within 6 months). Results: Fifty-two patients completed all 4 infusions, 2 are currently being treated, and one patient with hives and chills after prior rituximab discontinued treatment after similar NCI CTC v.3 grade 1–2 reactions at 1st hA20 infusion. hA20 was generally well tolerated with a median infusion time at the lowest dose of 120 mg/m2 of 2.2 h for 1st infusion and 1.2 h for subsequent infusions. Twenty-one patients had drug-related adverse events; these were all transient, mild-to-moderate (Grade 1–2) events, most occurring only at first infusion. No consistent pattern of abnormal laboratory changes occurred, and there was no evidence of immunogenicity in 29 patients now evaluated for HAHA. Mean antibody serum levels increased with dose and with repeated infusions, and limited post-treatment data indicate the serum clearance at 375 mg/m2 dosing is similar to rituximab. Even at 120 mg/m2, peripheral blood B-cell depletion occurred after the first infusion and persists after 4th infusion, with analysis continuing > 6 mo. Thirty-nine patients with at least 12 wks follow-up had one or more responses evaluated by Cheson criteria (Table), with all CR/CRu occurring in follicular lymphoma except for one patient with marginal zone lymphoma; 6 pts progressed by week 4. Of 18 pts with OR’s, 9 have continuing responses (median follow-up, 9 mos post-treatment), including 4 with long-lived responses (12–18 mos). Conclusions: hA20 is well tolerated, with no evidence of significant toxicity or pattern of adverse events other than minor infusion reactions, even at short infusion times. All dose levels studied so far, including the lowest dose of 120 mg/m2, resulted in B-cell depletion and objective responses (including CR/CRu), with no clear-cut evidence of dose response in efficacy. As such, further dose de-escalation is ongoing. Treatment Response hA20 Dose OR CR/CRu All patients (n = 39) 46% (18/39) 21% (8/39) 120 mg/m2 (n = 11) 36% (4/11) 27% (3/11) 200 mg/m2 (n = 6) 67% (4/6) 33% (2/6) 375 mg/m2 (n =19) 42% (8/19) 11% (2/19) 750 mg/m2 (n = 3) 67% (2/3) 33% (1/3)

scholarly journals Long-term outcomes of antibiotic combination therapy for ulcerative colitis

2021 ◽  
Vol 12 ◽  
pp. 204062232110287
Author(s):  
Yuriko Nishikawa ◽  
Nobuhiro Sato ◽  
Shintaro Tsukinaga ◽  
Kan Uchiyama ◽  
Shigeo Koido ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Side Effects ◽  
Adverse Events ◽  
Medical Information ◽  
Compliance Rate ◽  
University Hospital ◽  
Open Label ◽  
Antibiotic Combination

Aims: An antibiotic combination of amoxicillin, tetracycline and metronidazole (ATM) is effective for ulcerative colitis (UC), but this regimen is discontinued in some cases due to adverse events. This study aimed to assess a revised combination, namely, amoxicillin, fosfomycin and metronidazole (AFM), in UC patients with the goal of reducing side effects while maintaining therapeutic efficacy. Methods: A prospective open-label trial was undertaken in 104 adult UC patients. A combination of oral amoxicillin (1500 mg), fosfomycin (3000 mg) and metronidazole (750 mg) was administered to patients daily for 2–4 weeks in addition to their conventional medication. Clinical assessment was performed using the Lichtiger index before treatment and at 0, 3, 6, 9 and 12 months and 2 and 3 years. Endoscopic evaluation was performed using the Mayo score before treatment and at 3 and 12 months. Results: The compliance rate was 99.2%. Response and remission rates were 80.8% and 63.5% at completion, 73.1% and 64.4% at 3 months, and 39.4% for both at 12 months, respectively. Of the 41 patients who were in remission at 12 months, 63.4% maintained that status until the 2-year follow-up. Similarly, 69.2% of those in remission at 2 years remained relapse free at the 3-year follow-up. Side effects were observed in 44.2% of the participants. Fever occurred in one patient (1.0%), which was lower than the rate observed with ATM therapy. Conclusion: These results indicate that AFM therapy induces remission and is appropriate for long-term maintenance of UC while producing fewer and milder adverse events than ATM therapy. Clinical trials: This study was registered in the University Hospital Medical Information Network (No. R000046546).

scholarly journals Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study

2018 ◽  
Vol 36 (4) ◽  
pp. 391-398 ◽  
Author(s):  
Margaret K. Callahan ◽  
Harriet Kluger ◽  
Michael A. Postow ◽  
Neil H. Segal ◽  
Alexander Lesokhin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Dose Escalation ◽  
Objective Response ◽  
Safety Data ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Grade 3

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

Long-Term Safety and Effectiveness of Mixed Amphetamine Salts Extended Release in Adults With ADHD

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S20) ◽  
pp. 16-25 ◽  
Author(s):  
Joseph Biederman ◽  
Thomas J. Spencer ◽  
Timothy E. Wilens ◽  
Richard H. Weisler ◽  
Stephanie C. Read ◽  
...  
Keyword(s):  
Adverse Events ◽  
Adult Adhd ◽  
Extended Release ◽  
Rating Scale ◽  
Vital Signs ◽  
Therapeutic Effects ◽  
Open Label ◽  
Dose Escalation Study ◽  
Double Blind

AbstractObjective: Assess the long-term safety and effectiveness of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) combined subtype.Methods: A 24-month, open-label extension of a 4-week, multicenter, double-blind, placebo-controlled, parallel-group, forced–dose-escalation study of MAS XR in adults (≥ 18 years of age) with ADHD. The 223 enrolled subjects started treatment at 20 mgl day for 1 week, with subsequent titration up to 60 mgl day for optimal therapeutic effects. At monthly visits, efficacy was assessed based on the ADHD Rating Scale IV (ADHD-RS-N). Safety assessments included spontaneously reported adverse events, laboratory assessments, and monitoring of vital signs.Findings: ADHD symptoms significantly improved for all subjects as measured by change from baseline in mean ADHD-RS-IV total scores (-7.2±13.04 unit points; P<.001); this was sustained for up to 24 months. The most common treatment-related adverse events were dry mouth (43% of subjects reporting at least one occurrence), infection (33%), insomnia (32%), anorexia/decreased appetite (32%), headache (30%), and nervousness (26%). Most adverse events were mild to moderate in intensity.Conclusion: Treatment with MAS XR 20–60 mgl day for adult ADHD was generally well tolerated and was associated with sustained symptomatic improvement for up to 24 months.

scholarly journals Phase 1, Open-Label, Dose Escalation Study of I-131-CLR1404 in Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4485-4485
Author(s):  
Sikander Ailawadhi ◽  
Patrick J. Stiff ◽  
Michele Maharaj ◽  
Katherine Oliver ◽  
Natalie Scott Callander
Keyword(s):  
Radiation Therapy ◽  
Adverse Events ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase 1 ◽  
Study Drug ◽  
External Beam Radiation ◽  
Open Label ◽  
Label Dose

Abstract Background: I-131-CLR1404 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on initial preclinical and clinical experience and the exquisite radiosensitivity of MM, I-131-CLR1404 is being examined in RRMM in an open-label, dose escalation Phase 1 trial (NCT02278315) evaluating up to 5 cohorts and a maximum of 37.5 mCi/m2. Methods: The primary objective is to determine safety and tolerability of I-131-CLR1404 with and without dexamethasone (dex) in RRMM. Secondary objectives are to determine the recommended Phase 2 dose (RP2D) and therapeutic activity in RRMM. Eligibility criteria include progressive, relapsed/refractory MM, and at least one previous exposure to proteasome inhibitor (PI) and immunomodulatory (IMiD) drugs. Prior autologous stem cell transplant (ASCT) and external beam radiation therapy are allowed (≤ 20% of total marrow irradiated). There is no limit to the number of prior therapies. I-131-CLR1404 is administered intravenously as a single 30 minute infusion on day 1 with 40 mg dex orally weekly for 12 weeks. Dose-escalation uses a minimally modified, standard 3+3 schema with dose-limiting toxicities (DLTs) assessed through day 85 post-infusion. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the International Myeloma Working Group Uniform Response Criteria. Results: Ten patients have been enrolled in the study with data presented as of 30 Jun 2016 for 8 patients. Accrual is ongoing in the additional cohorts. Five patients were enrolled to cohort 1 (12.5 mCi/m2 + dex); 4 were evaluable and 1 patient was taken off study for rapid disease progression. Five patients have been enrolled to cohort 2 (18.75 mCi/m2 + dex), with data presented on 3 enrolled prior to data cutoff. The median age was 68.5 (range 55-85) and included 5 males and 3 females. All patients were standard risk (karyotyping) and median bone marrow plasma cell involvement was 25% (range 4-50%). Median number of prior therapies was 4 (range 2-12) (Table 1). Four of 8 patients previously underwent ASCT and 25% were previously treated with radiation therapy. Hematologic AEs (grade 3+) and non-hematologic AEs (grade 2+) potentially related to study drug are shown in Table 1. No difference in the toxicity profile was noted for patients with previous radiation therapy. Two serious adverse events (SAEs) have been reported, both in patients treated with 18.75 mCi/m2 I-131-CLR1404. One patient was hospitalized for a seizure (Day 62), assessed as unrelated to study drug and another patient was hospitalized for a grade 1 upper GI bleed in the setting of grade 4 thrombocytopenia (Day 23). This is believed to be the result of rapidly progressive disease, however relationship to I-131-CLR1404 could not be ruled out. Stable disease was achieved in 100% of evaluable patients (n=7). One subject in cohort 1 demonstrated a > 30% reduction in serum m-protein. Figure 1 provides a summary of percent change in serum free light chain assay (FLC) from baseline. Three patients had a reduction in FLC > 50%, 2 in cohort 1 and 1, to date, in cohort 2. Three patients had a stable FLC response through at least 22 days following treatment and 1 subject was unresponsive with regard to FLC. Median follow-up is 6.8 months (range 1.2-14.2). Patients did not receive subsequent systemic therapy for a median of 3.5 months (range 0.6-4.7). Furthermore, 1 subject in cohort 2 maintains stable disease and has not initiated subsequent treatment. Median progression free survival (PFS) is 3 months and included 4 patients with stable disease at the end of the 85 day study follow-up. In patients with progression after I-131-CLR1404, treatment included daratumumab (n=4), ASCT (n=1), and bortezomib, lenalidomide, and dex (VRD) (n=1). Conclusions: I-131-CLR1404 represents a unique, first in class targeted radiotherapeutic for MM. Preliminary data from this trial show an acceptable and expected safety profile with an efficacy signal in the initial 2 of a potential 5 cohorts. All evaluable patients, despite extensive previous therapy and refractoriness to new therapies, achieved disease stabilization. The study is ongoing to determine the RP2D and long term efficacy. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Oliver:Cellectar Biosciences: Employment.

scholarly journals Long-Term Safety and Efficacy of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter, Open-Label, Phase II Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Yuqin Song ◽  
Yongping Song ◽  
Lihong Liu ◽  
Mingzhi Zhang ◽  
Zhiming Li ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chinese Patients ◽  
Severe Bleeding ◽  
Open Label ◽  
Mantle Cell ◽  
Btk Inhibitor ◽  
Grade 3 ◽  
Depth Response

Background: In spite of years of effort, Mantle Cell Lymphoma (MCL) remains a clinical challenge. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitor has been validated with the approvals by FDA for the treatment of multiple subtypes of NHL including refractory and relapse (r/r) MCL. However, some serious adverse events (AEs) due to poor target selectivity (inhibition of EGFR, TEC, BMX and others), such as diarrhea, sever bleeding and atrial fibrillation, remain as challenges in clinic. Orelabrutinib is a novel, potent irreversible BTK inhibitor with high selectivity for BTK. Results of early clinical study showed that it has excellent safety/tolerability profiles and favorable pharmacokinetic/pharmacodynamic properties. Sustained ~100% BTK occupancy at 24 hours was achieved with once daily dosing regimen of 50 mg and above. In this presentation, we will report an updated analysis of orelabrutinib in Chinese patients with r/r MCL with minimum of 12 cycles of treatment. Aims: To evaluate the sustained efficacy and long-term safety of orelabrutinib in Chinese patients with r/r MCL. Methods: This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) assessed per Lugano criteria (2014). Safety and other efficacy (DOR, PFS, OS) evaluations were chosen as secondary endpoints. Results: A Total 106 patients, were enrolled in this study with median follow up time of 15.0 months. 79.2% of the patients were male and median age of 62.0 years old. Most patients were at advanced stage (73.6% were at stage IV and 20.8% were at stage III). According to per protocol analysis, 87 (87.9%) patients achieved ORR and 93.9% patients achieved disease control. The median duration of response (DOR) was not reached, the DOR rate at 12 months was 73.7%, as expected the median PFS and OS were not reached, the PFS and OS rates at 12-month were 70.8% and 88.7% respectively. Comparing to the results of previous analysis, the CR rate, by conventional CT method, increased to 27.4% and it was expected a higher rate of in depth response may occur with prolonged treatment. Further analysis showed orelabrutinib was efficacious in all subgroups (age, gender, status, stage, prior therapy, etc.). Orelabrutinib demonstrated excellent safety profile in r/r MCL patients. The frequently reported treatment related adverse events (TRAE) were primarily hematological toxicities including thrombocytopenia, neutropenia, leukopenia, and hypertension. The frequently reported grade 3 or higher AEs of any cause was thrombocytopenia . No treatment related ≥grade 3 GI and cardio toxicity, nor severe bleeding, were observed. Of the 106 patients, 32 experienced serious AEs; and 17 of them, mainly hematological toxicities and / or infections were treatment-related. Comparing to the safety data of median follow up of 10.5 months, there was only a mild increase of adverse events rate after extended treatments; the safety profiles were essentially the same. These results suggested that safety events primarily occurred during early treatment and it appeared less eventful with orelabrutinib continue treatment. Conclusion: Orelabrutinib showed continuous efficacious in treating patients with r/r MCL. In addition, orelabrutinib is safe and well tolerated with no treatment related grade 3 or higher diarrhea, atrial fibrillation/flutter or severe bleeding in this study. Results of prolong treatment expected to produce a higher rate of in depth response without altering its safety profiles support orelabrutinib being a better selection for BTKi therapy. The improved safety as a resulting of high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as preferred therapeutic choice for B cell malignancy. Disclosures Zhang: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

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