Recombinant Circularly Permuted TRAIL (CPT) for the Treatment of Relapsed or Refractory Multiple Myeloma: An Open-Label, Multicenter Phase II Clinical Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 78-78 ◽  
Author(s):  
Wenming Chen ◽  
Lugui Qiu ◽  
Jian Hou ◽  
Yaozhong Zhao ◽  
Ling Pan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Independent Review ◽  
Clinical Responses

Abstract Abstract 78 Background: Circularly permuted TRAIL (CPT) is a recombinant mutant of human Apo2L/TRAIL developed by Beijing Sunbio Biotech Co., Ltd. as a targeted therapy for multiple myeloma and other hematologic malignancies. CPT is a dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). CPT selectively induces apoptosis in a variety of cancer cells, while sparing most normal cells in preclinical models. Objective: CPT has shown preliminary activities for patients with relapsed or refractory multiple myeloma (Rel/Ref MM) in phase I study. The aim of this phase II study is to investigate the effect and safety of CPT for Rel/Ref MM patients. Methods: In this multi-center, open-label, single arm phase II study, twenty-seven Rel/Ref MM patients were enrolled to receive CPT treatment alone at the dose of 2.5 mg/kg/day intravenously, once daily for 14 consecutive days of each 21-day cycle. Clinical responses to CPT after 2 cycle's treatment were assessed by an independent review committee according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT). Results: Among the 27 patients, one patient (3.7%) achieved near complete response (nCR) and eight patients (29.63%) exhibited partial response (PR). The overall response rate (ORR) was 33.3%. The median PFS was not reached within 2 cycle's treatment. The drug related adverse events (≥10%) included fever, AST/ALT elevation, leucopenia, neutropenia, rash, thrombocytopenia, and LDH elevation. The severe adverse events were occurred in 3 patients (11%), one of them was CPT-related liver injury. Anti-drug antibodies were detected in 6 patients without reduced efficacy or increased toxicities. Conclusions: The CPT is a very effective and well-tolerated new agent for Rel/Ref MM, and it is worthy to be further studied. Disclosures: Yang: Beijing Sunbio Biotech Co. Ltd.: Employment. Cui:Beijing Sunbio Biotech Co. Ltd.: Employment.

Circularly Permuted TRAIL (CPT) combined with Thalidomide for the Treatment of Relapsed or Refractory Multiple Myeloma: An Open-Label, Multicenter Phase II Clinical Trial.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2958-2958 ◽  
Author(s):  
Wenming Chen ◽  
Jian Hou ◽  
Yaozhong Zhao ◽  
Lugui Qiu ◽  
Xiaoyan Ke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase Ii ◽  
Response Rate ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Phase Ii Studies ◽  
Better Than

Abstract Abstract 2958 Background: Circularly permuted TRAIL (CPT) is a recombinant mutant of human Apo2L/TRAIL developed by Beijing Sunbio Biotech Co. Ltd. as a targeted therapy for multiple myeloma and other hematologic malignancies. CPT is a dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). CPT selectively induces apoptosis in a variety of cancer cells, while sparing most normal cells in preclinical models. Objective: CPT as a mono-therapy has shown definitive activities for patients with relapsed or refractory multiple myeloma (Rel/Ref MM) in phase I and phase II studies. The aim of this study is to observe the effect and safety of CPT in combination with thalidomide for Rel/Ref MM patients. Methods: In this multiple-center, open-label, single arm phase II study, 43 Rel/Ref MM patients who had received prior therapies and were resistant to thalidomide were recruited. These patients were divided into three groups, and received CPT 5.0mg/kg, 8.0mg/kg, and 10.0mg/kg on days1–5 of each 21-day cycle, respectively, until having finished six cycle‘s treatment or progression disease or intolerant adverse events. All the patients received thalidomide 100mg daily until to the disease progression or intolerant adverse events. Clinical responses of CPT were assessed by an independent review committee according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT). Results: Among the 43 patients, 41 patients can be evaluated. There were 11, 15 and 15 patients in the three groups respectively. Among the 41 patients, two patients achieved complete response (CR), three showed near complete responses (nCR), four exhibited partial responses (PR), and five obtained minor responses (MR). The total response rates were 34% (including MR or better than MR), or 22% (including PR or better than PR). Among the three groups, the dose of 10mg/kg seemed to be optimal with 26.7% response rate (including PR or better than PR), superior to the other two groups. Duration of response of CPT was not evaluated accurately, because most patients who achieved PR, nCR, or CR were progression free at the end of the trial. The common treatment related adverse events (≥10%) were neutropenia, leucopoenia, fever, AST/ALT/LDH elevation, and thrombocytopenia. The grade 3 non-haematological toxicities were AST elevation (4.65%) and LDH elevation (2.33%). The elevation of AST and LDH seems to be related to tumor lysis, but not to liver injury. The grade 4 haematological toxicities were neutropenia and thrombocytopenia (2.33%, respectively) which might be related to thalidomide. Conclusions: The CPT combined with thalidomide was well-tolerated and an effective regimen for the treatment of Rel/Ref MM. The combination of CPT and thalidomide seems to be superior to CPT alone in CR/nCR response rate. Disclosures: Zheng: Beijing Sunbio Biotech Co., Ltd.: Employment. Zhu:Beijing Sunbio Biotech Co., Ltd.: Employment. Yang:Beijing Sunbio Biotech Co., Ltd.: Employment.

Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM).

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 8000-8000 ◽  
Author(s):  
R. Vij ◽  
D. S. Siegel ◽  
J. L. Kaufman ◽  
A. J. Jakubowiak ◽  
A. K. Stewart ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase

An Open-Label Single-Arm Pilot Phase II Study (PX-171-003-A0) of Low-Dose, Single-Agent Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma

2012 ◽  
Vol 12 (5) ◽  
pp. 310-318 ◽  
Author(s):  
Sundar Jagannath ◽  
Ravi Vij ◽  
A. Keith Stewart ◽  
Suzanne Trudel ◽  
Andrzej J. Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Study ◽  
Single Agent ◽  
Pilot Phase ◽  
Open Label ◽  
Refractory Multiple Myeloma

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Phase II study of sintilimab combined with FLOT regimen for neoadjuvant treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 216-216
Author(s):  
Ning Li ◽  
Zhi Li ◽  
Qiang Fu ◽  
Bin Zhang ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Gastroesophageal Junction ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
R0 Resection ◽  
Resection Rate ◽  
First Choice

216 Background: Perioperative treatments have significantly improved survival in patients with resectable gastric cancer, increasing 5-year overall survival from 23% with surgery alone to 45% with FLOT, Although FLOT has been recognized as the first choice for neoadjuvant chemotherapy in gastric or GEJ adenocarcinoma, its efficacy needs to be improved. Sintilimab, a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1 (PD-1), has shown remarkable clinical efficacy in various cancers. We aimed to assess the activity and safety profile of the combination of FLOT and sintilimab for neoadjuvant treatment of gastric or GEJ adenocarcinoma. Methods: In this ongoing, single-arm, phase II study, we recruited patients from Henan Cancer Hospital in China with histopathologically diagnosed resectable gastric or GEJ adenocarcinoma who had clinical T3/N+ or higher stage. Patients were given 4 cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 80 mg/m2, leucovorin 200 mg/m2, fluorouracil 2600 mg/m2, 24-h infusion on day 1, q2w) in combination with 3 cycles of sintilimab (200mg, iv, d1, q3w), followed by D2 surgery and 4 postoperative cycles of FLOT. The primary endpoint was pathological complete response (pCR). The secondary endpoints included major pathological remission (MPR) and R0 resection rate and adverse events . Results: A total of 20 patients were enrolled in the study between Aug 10 2019 and Sep 15 2020. One patient refused surgery, one person's disease progressed. Two patients have not yet completed neoadjuvant treatment . 16 pts who experienced D2 resection, 10 (62.5%) achieved major pathologic response (MPR), including 3 (18.8%) with a pathologic complete response (pCR) in primary tumor. The R0 resection rate was up to 93.8%, The grade 3 or 4 treatment-related adverse events (TRAE) included lymphopenia(25%), anaemia (20%),fatigue (20%),leucopenia (15%), neutropenia (5%), diarrhea(5%), Alanine aminotransferase increased(5%),There was no surgical delays or unexpected surgical complications related to drug toxicity. Conclusions: Neoadjuvant combination of sintilimab and FOLT is a safe and efficacious treatment option for patients with gastric or GEJ adenocarcinoma, 18.8% pCR rate and 62.5%MPR rate is encouraging. Our clinical study is still enrolling, and the survival effects are under follow up. Clinical trial information: NCT04341857.

scholarly journals Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1875-1884 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Meletios A. Dimopoulos ◽  
Darrell J. White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Intent To Treat ◽  
Line Of Therapy

Abstract In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1–21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10–5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31–0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42–0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.

A phase II study of AT9283, an aurora kinase inhibitor, in patients with relapsed or refractory multiple myeloma: NCIC clinical trials group IND.191

2015 ◽  
Vol 57 (6) ◽  
pp. 1463-1466 ◽  
Author(s):  
Annette E. Hay ◽  
Alli Murugesan ◽  
Ashley M. DiPasquale ◽  
Tom Kouroukis ◽  
Irwindeep Sandhu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Refractory Multiple Myeloma

A Phase II Study of Intravenous Azacitidine Alone in Patients with Myelodysplastic Syndromes NCT00384956.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1451-1451
Author(s):  
Richard Walgren ◽  
Crystal Dao ◽  
Frederieke Kreisel ◽  
Peter Westervelt ◽  
Camille Abboud ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
De Novo ◽  
Phase Ii Study ◽  
Study Drug ◽  
Complete Response ◽  
Subsequent Treatment ◽  
Open Label ◽  
Erythroid Response

Abstract Rationale: 5-Azacytidine (Aza), a DNA hypomethylating agent, has now been shown in 2 clinical trials involving high-risk MDS patients to provide a survival benefit over supportive/conventional care regimens. While one phase II study used a continuous 7-day IV infusion, Aza was administered subcutaneously (SQ) in most pre-approval studies. However, injection site reactions are not uncommon with SQ dosing, especially in thrombocytopenic patients. Aza given as a short intravenous (IV) infusion is anticipated to be efficacious from pharmacokinetic profiling and is FDA approved, but prospective efficacy data for short IV infusion are lacking. Study aim and design: To determine the efficacy of IV Aza when given as a short infusion, we have undertaken an open-label, single-arm, single-center phase II study of Aza in patients with MDS, either de novo or secondary, defined by FAB classification. Previously treated subjects were ineligible if they had already received Aza or decitabine. Treatment consisted of Aza 75 mg/m2 given as a 20 minute IV infusion once daily on Days 1–5 of a 28-day cycle. Response was evaluated by IWG 2000 criteria. After two cycles at the 75 mg/m2 dose, patients failing to achieve a CR were eligible for an increased dose of 100 mg/m2. After 6 cycles of therapy, patients must have demonstrated at least a hematologic improvement to continue on study. Study endpoints include determination of the complete response (CR) and partial response (PR) rates, and secondary endpoints examined the rates of hematological improvement, time to progression, and cytogenetic response. Results: Accrual began 8/17/06 with a target of 21 subjects. As of 7/31/07, 15 subjects have accrued with a median follow-up of 77 days (range 4 to 246). Subjects consisted of 9 males and 6 females with a median age of 69.6 yr (range 53 to 82). The median time from diagnosis is 213 days (range 0 days to 4 yr). By FAB criteria, subjects consist of 4 RA, 9 RAEB, 1 RAEB-t, and 1 CMML, and subjects are categorized by IPSS risk as 1 Low, 4 Int-1, and 10 Int-2. Two patients had therapy related MDS. The data remain preliminary with subjects having completed a mean of 3 cycles (range 1 to 6). None of the 5 subjects who have completed at least 4 cycles of therapy have achieved a CR. However, 2 (40%) of these subjects achieved a PR. Additionally, 1 (20%) patient had a major erythroid response, while another had a minor erythroid response. Median time to response was 2 months. Ten subjects remain on study, 1 patient withdrew due to progressive disease (in first week of therapy), and 4 deaths have occurred on study (2 due to sepsis, 1 each due to pneumonia and acute MI). No deaths were attributed to study drug. Common adverse events include nausea, emesis, and hematologic toxicities. Grade 2–3 nausea and grade 2–3 emesis each occurred in 5 subjects. Observed grade 3 or 4 hematologic toxicities included: anemia (n=7), thrombocytopenia (n=4), leukopenia (n=3), neutropenia (n=7), and febrile neutropenia (n=1). Hematologic toxicities have resulted in transient treatment delays (&lt; 4 weeks) and dose reduction, but hematologic toxicities have not prevented subsequent treatment on study. Conclusions: Although follow-up is short for assessment of efficacy, this is the first prospective study to report on efficacy and toxicity of short infusional Aza in the treatment of MDS.

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