Updated analysis of phase 2 study of bendamustine and dexamethasone in patients with relapsed/refractory systemic light chain (AL) amyloidosis

Amyloid ◽  
2019 ◽  
Vol 26 (sup1) ◽  
pp. 113-114
Author(s):  
Suzanne Lentzsch ◽  
Galina G. Lagos ◽  
Raymond L. Comenzo ◽  
Jeffrey A. Zonder ◽  
Silva Pregja ◽  
...  
Keyword(s):  
Light Chain ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
Phase 2 Study

A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis

Blood ◽  
2012 ◽  
Vol 119 (23) ◽  
pp. 5384-5390 ◽  
Author(s):  
Efstathios Kastritis ◽  
Evangelos Terpos ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
Constantinos Pamboukas ◽  
...  
Keyword(s):  
Light Chain ◽  
Low Dose ◽  
Phase 1 ◽  
Al Amyloidosis ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Light Chain Amyloidosis ◽  
Intention To Treat ◽  
Oral Regimen ◽  
Dose Oral

Abstract In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.

scholarly journals Efficacy and Safety of Daratumumab Monotherapy in Newly Diagnosed Patients with Stage 3B Light Chain Amyloidosis: A Phase 2 Study By the European Myeloma Network

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2730-2730
Author(s):  
Efstathios Kastritis ◽  
Monique C. Minnema ◽  
Meletios A. Dimopoulos ◽  
Giampaolo Merlini ◽  
Foteini Theodorakakou ◽  
...  
Keyword(s):  
Adverse Event ◽  
Median Time ◽  
Research Funding ◽  
Nyha Class ◽  
Median Number ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
First Response ◽  
Phase 2 Study ◽  
Grade 3

Abstract Introduction: In systemic light chain (AL) amyloidosis free light chains produced by clonal plasma cells form amyloid fibrils that are deposited in tissues and organs resulting in organ dysfunction. Cardiac involvement by AL amyloidosis is frequent and the most critical prognostic factor. Prognostic evaluation in AL is based on cardiac biomarkers and patients with very high levels of both NTproBNP (≥8500 pg/ml) and cardiac Troponins (Mayo stage 3B) are at high-risk of early death and have a median survival of just 3-6 months in most series. The outcome of stage 3B patients has not improved despite the introduction of bortezomib-based therapies and there is an urgent need for new non-toxic treatments which can also lead to rapid and deep hematologic responses. Daratumumab, an IgGκ monoclonal antibody targeting CD38, has proved highly effective either alone or in combination with bortezomib, cyclophosphamide and dexamethasone and with good tolerability in AL amyloidosis patients. Methods: EMN22 is a phase 2, open-label, multicenter study planning to enroll 40 newly diagnosed patients with stage 3B AL amyloidosis from 5 sites in Greece, the Netherlands, Italy and France. Eligible patients should have high-sensitivity troponin T (hsTnT) >54 pg/mL and NT-proBNP ≥8500 pg/mL. Primary treatment consists of daratumumab monotherapy, initially administered intravenously at 16 mg/mL, and since February 2020 administered subcutaneously at a fixed dose of 1800 mg; weekly during Cycles 1-2, every 2 weeks for Cycles 3-6 and every 4 weeks thereafter. Patients who do not achieve a hematologic VGPR or better by Cycle 4 may also receive at investigator's discretion weekly bortezomib and low dose dexamethasone. Treatment continues until disease progression according to major organ deterioration progression-free survival criteria, start of new therapy, or for a maximum of 2 years. The current analysis includes patients who started treatment at least 3 months prior to the cut-off date (16 June 2021). Results: Among 17 patients included in this analysis, 9 (53%) are still on treatment and 8 (47%) have discontinued, either due to an adverse event (n=5, 29%), or due to disease progression (n=3, 18%). Most patients were males (n=12, 71%) and median age was 65 years (range 45-84). Eastern Cooperative Oncology Group performance status was 1 for 5 (29%), 2 for 11 patients (65%), and 3 for one patient (6%). Eight (47%) patients had New York Heart Association (NYHA) class II symptoms, and 9 (53%) NYHA class IIIA. At screening, median NT-proBNP was 13,994 pg/mL (range 8,816-40,428), median hsTnT 119.1 pg/mL (range 59.8-692) and median difference of involved to uninvolved free light chains (dFLC) was 553 mg/L (range 49-2823). Apart from the heart, the median number of other organs involved was 1 (range 0-5), with nervous system (n=8, 47%) and kidneys (n=7, 41%) most commonly affected. The median number of daratumumab infusions was 13 and the median duration of therapy with daratumumab therapy was 3.7 months. Overall, 5 patients (29%) started additional treatment with bortezomib after completion of 3 cycles of daratumumab monotherapy. All 17 patients had at least one treatment-emergent adverse event. Eleven patients (65%) had a serious adverse event (SAE); 9 (53%) had at least one cardiac-related serious adverse event, and one SAE (fatigue) was related to bortezomib. Six patients (35%) suffered a fatal SAE: sepsis (n=1), sudden death (n=3), and cardiac failure (n=2). Most common grade 3 or 4 non-serious AEs were peripheral edema (n=4, 24%), dyspnea (n=3, 18%), and atrial fibrillation (n=2, 12%), and only one non-serious neutropenia grade 3 was related to daratumumab. The overall response rate was 71%, with 3 patients (18%) achieving CR, 6 (35%) VGPR, and 3 (18%) a PR, with a combined CR+VGPR rate of 53% (9/17). One-, two-, and three-month overall response rates were 65% (n=11), 71% (n=12), and 71% (n=12), and the median time to first response was 7 days while the median time to at least VGPR was 14 days. The 6-month and 12-month OS rate were 70% and 53% respectively (median OS has not been reached). Conclusions: In this prospective phase 2 study, in patients with high-risk AL amyloidosis (stage 3B), daratumumab monotherapy shows a favorable safety profile and induced very rapid and deep hematologic responses with a median time to first response of 7 days, with 53% of the patients achieving VGPR or better and a 6-month OS of 70%. Figure 1 Figure 1. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria. Minnema: Jansen-Cilag: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy; Celgene: Other: Hospitality; BMS: Honoraria. Dimopoulos: Amgen: Honoraria; Beigene: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Huart: Janssen: Honoraria. Leonidakis: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Sonneveld: Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees.

Updated Results of a Phase 2 Study of Bendamustine in Combination with Dexamethasone (Ben/Dex) in Patients with Previously-Treated Systemic Light-Chain (AL) Amyloidosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3041-3041 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Raymond L. Comenzo ◽  
Jeffrey A Zonder ◽  
Keren Osman ◽  
Miao Susanna ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Nyha Class ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
Cardiac Events ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Phase 2 Study

Abstract Background: Melphalan in combination with dexamethasone is an active and the standard regimen in AL amyloidosis. Unfortunately very often patients relapse and other drugs are needed. Bendamustine is a bifunctional alkylating agent approved for the treatment of CLL, NHL, and MM in Europe and the US. But its safety and efficacy in AL amyloidosis is not known. In an effort to investigate the activity of Ben/Dex and improve the outcome of patients with relapsed AL we conduct a multi-center, Phase 2 study of Ben/Dex in AL (NCT01222260) and report data of an updated unplanned interim analysis. First data were reported at ASH 2014 (Abstr.3480). Methods: All patients had relapsed AL after a median of 2 prior therapies (range 1-4). Patients with very advanced cardiac involvement (NYHA Class IIIB/IV) were excluded. Patients with NYHA Class IIIA, NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI could be included after evaluation by cardiology to determine the risk associated with the treatment. Patients with a CrCl ³ 15 mL/min were considered for the trial if they were not in active renal failure. This Phase IIa clinical trial uses a two-stage optimal Simon design enrolling 13 patients in the first stage. Since at least three patients experienced hematologic PR or better, the trial proceeded to the second stage treating an additional 16 patients. If 9 or more patients out of the total of 29 patients evaluable for response experience a hematologic PR or better, the treatment will be considered worthy of further development. The primary objective is to determine the partial hematologic response rate (PR). Secondary objectives included overall hematologic response (OHR) rate, organ response rate (OrRR) (Palladini et al., JCO 2012), time to failure (TTF), toxicities (adverse events at least possibly related to treatment), overall survival (OS) and the assessment of expression of genes associated with ER stress. Patients were assigned to bendamustine according to CrCl: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle, CrCl 59-15 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle. The option to dose escalate was available to qualifying subjects including escalating to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) and 100 mg/m2 (if CrCl 59 - 15 mL/min at the time of inclusion into the study). Dexamethasone was started at 20-40mg weekly according to the performance status of the patient. The duration of each cycle was 28 days. Results: As of 7/15/15, 26 patients have received treatment and 28 patients have been enrolled. Median age of enrolled patients was 66 (range 44-77). Enrolled patients received a median of 1.5 prior regimens (range 1-4). Twelve of the enrolled patients received prior autologous stem cell transplant. Median number of cycles for treated patients is 3.5 (range is 1-12), with 4 patients still receiving treatment. Of note, only 2 patients discontinued treatment due to disease progression. Only 9 patients discontinued treatment due to AE. Most common drug-related AEs (all grades, >25%) included fatigue (39%), nausea (35%) and Anemia (27%),. No grade ≥3 drug-related AE occured in >20% of patients. Of note, no cardiac events were observed, including any increase in NT-proBNP.Of 24 patients eligible for response evaluation, 11 (46%) have responded hematologically, including (≥PR 42%, CR 4%). The median time to best response of treatment (partial response or better) was 1.57 months (range 0.97 to 15.1 months). The CR occurred in a patient after 5 cycles suggesting that this heavily pretreated patient population needs longer treatment to achieve response. Better responses were especially observed in less heavily treated patients. With a median follow-up of 13.4 months (range 1.5 to 30.3 months) the median OS has not been reached yet (Figure 1). The median PFS is 11.5 months (95% CI,1.5-29.1months) (Figure 2). Conclusions: In our updated unplanned interim analysis we found that Bendamustine in combination with dexamethasone is feasible and effective in pretreated AL amyloidosis with impaired organ function (NYHA IIIB and creatinine clearance of 30-15 mL/min were allowed). Cardiac events related to Bendamustine were not observed. Preliminary hematologic response rates are promising in this pretreated patient population, and organ assessments are ongoing. Further study of this approach is warranted. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Axiom: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Will discuss the use of Bendamustine and Dexamethasone under clinical trial NCT01222260. Comenzo:Takeda Millennium: Research Funding; Prothena: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Karyopharm: Research Funding. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support; Prothena: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Osman:Millennium / Takeda: Research Funding.

scholarly journals Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 4860-4867 ◽  
Author(s):  
Shaji K. Kumar ◽  
Suzanne R. Hayman ◽  
Francis K. Buadi ◽  
Vivek Roy ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Partial Response ◽  
Light Chain ◽  
Gastrointestinal Symptoms ◽  
Long Term Results ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Hematologic Response ◽  
Phase 2 Trial ◽  
Grade 3

Abstract Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).

Phase 2 Study of Bendamustine in Combination with Dexamethasone (Ben/Dex) in Patients with Previously-Treated Systemic Light Chain (AL) Amyloidosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3480-3480 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Raymond L. Comenzo ◽  
Keren Osman ◽  
Kevin Zikaras ◽  
Daniel Backenroth ◽  
...  
Keyword(s):  
Patient Population ◽  
Response Rate ◽  
Nyha Class ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
Cardiac Events ◽  
Pretreated Patient ◽  
Hematologic Response ◽  
Phase 2 Study ◽  
Heavily Pretreated

Abstract Background: Melphalan is an alkylator and in combination with dexamethasone an active and standard regimen in AL amyloidosis. However these patients relapse and other drugs are needed. Bendamustine is a bifunctional alkylating agent with established efficacy in CLL, NHL, and MM but its safety and efficacy in AL amyloidosis is not known. In an effort to investigate the activity of Ben/Dex and improve the outcome of patients with relapsed AL we conduct a multi-center, Phase 2 study of Ben/Dex in AL (NCT01222260) and report data of an interim analysis. Methods: All patients had relapsed AL after a median of 2 prior therapies (range 1-4). Patients with very advanced cardiac involvement (NYHA Class IIIB/IV) were excluded. Patients with NYHA Class IIIA, NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI could be included after evaluation by cardiology to determine the risk associated with the treatment. Patients with a CrCl ≥ 15 mL/min were considered for the trial if they were not in active renal failure. This Phase IIa clinical trial uses a two-stage optimal Simon design enrolling 13 patients in the first stage. Since at least three patients experienced hematologic PR or better, the trial proceeded to the second stage treating an additional 16 patients. If 9 or more patients out of the total of 29 patients evaluable for response experience a hematologic PR or better, the treatment will be considered worthy of further development. The primary objective is to determine the partial hematologic response rate (PR) of patients who received at least 2 cycles of therapy. Secondary objectives included overall hematologic response (OHR) rate, organ response rate (OrRR) (Palladini et al., JCO 2012), time to failure (TTF), toxicities (adverse events at least possibly related to treatment), overall survival (OS) and the assessment of expression of genes associated with ER stress. Patients were assigned to bendamustine according to CrCl: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle, CrCl 59 – 15 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle. The option to dose escalate was available to qualifying subjects including escalating to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) and 100 mg/m2 (if CrCl 59 – 15 mL/min at the time of inclusion into the study). Dexamethasone was started at 20-40mg weekly according to the performance status of the patient. Results: As of 7/15/14, 15 patients have received treatment. Median age was 66.5 (range 43-76). Patients received a median of 2 prior regimens (range 1-4). Six patients received prior autologous stem cell transplant. Median number of cycles is 3.5 (range is 1-9), with 5 patients still receiving treatment. Of note, only 1 patient discontinued treatment due to disease progression. Only 3 patients discontinued treatment due to AE. Most common drug-related AEs (all grades) included fatigue (67%), nausea (53%), anemia, constipation and dyspnea (47% each), limb edema and increased creatinine (40% each). Grade ≥3 AE occurring in >25% of patients were only fatigue and chronic kidney disease (27% each). Of note, no cardiac events were observed, including any increase in NT-proBNP. No deaths have occurred in association with the treatment. Of 11 patients eligible for response evaluation, 5 (45%) have responded hematologically, including (≥PR 36%, CR 9%). Median time to PR was 2 cycles and the CR occurred in a patient after 5 cycles suggesting that this heavily pretreated patient population needs longer treatment to achieve response. With a median follow-up of 8.7 months (range 1.4 to 18.6 months) the median OS has not been reached yet (Figure 1). The median PFS is 11.2 months with a range of 0.4-15.7 months (Figure 2) Conclusions: Bendamustine in combination with dexamethasone is feasible and effective in heavily pretreated AL amyloidosis with impaired organ function (NYHA IIIB and creatinine clearance of 30-15 mL/min were allowed). Cardiac events were not observed. Preliminary hematologic response rates are promising in this heavily pretreated patient population, and organ assessments are ongoing. Further study of this approach is warranted. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Lentzsch: Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding. Off Label Use: Bendamustine treatment in amyloidosis .

A phase I/II study to assess safety and dose of ixazomib in combination with cyclophosphamide and dexamethasone in newly diagnosed patients with light chain (AL) amyloidosis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8065-8065
Author(s):  
Keren Osman
Keyword(s):  
Light Chain ◽  
Phase 1 ◽  
Primary Study ◽  
High Dose ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Open Label ◽  
Study Objective ◽  
Grade 3

8065 Background: AL amyloidosis is an incurable clonal plasma cell disorder characterized by tissue deposits of immunoglobulin light chain fragments leading to organ dysfunction and death. Standard treatment for newly diagnosed patients (pts) has traditionally included oral melphalan + dexamethasone as well as high-dose melphalan + ASCT. Here we report preliminary results of a Phase 1/2, open-label, multi-institution study of ixazomib (I) in combination with cyclophosphamide (Cy) and dexamethasone (D) in newly diagnosed AL amyloidosis. Methods: Eligible pts are ≥18 years with newly diagnosed, untreated biopsy-proven AL amyloidosis. A total of up to 30 pts will be enrolled, with up to 18 in the dose escalation arm (phase 1) and 12 in the maximum tolerated dose (MTD) expansion arm (phase 2) according to a classical 3+3 design. Four dose levels were evaluated in phase 1. I and Cy are given orally (PO) on days 1, 8, 15, and D 20mg PO on days 1, 8, 15, 22 of each 28-day cycle. Treatment continues for a total of 6 cycles or until disease progression, significant toxicity or withdrawal. The primary study objective in phase 1 is to establish the MTD and in phase 2 is to determine hematologic/organ response rate. Results: As of February 2020, 120 pts have been enrolled; 16 in phase 1 and 4 in phase 2. The MTD was established at dose level 3 (I 4mg and Cy 500mg). Median age is 65 years (range 46-79), 12 (67%) are male. Light chain isotype is lambda in 14 (78%). Seven pts (39%) have cardiac, 10 (56%) renal, 4 (22%) gastrointestinal, 1 (6%) hepatic, 2 (11%) soft tissue involvement, with 22% having multi-organ involvement. Four pts (22%) completed 6 cycles of therapy and 6 (33%) remain on study with a median of 3 cycles completed. Eight of 16 pts (50%) had at least 1 drug-related adverse event (AE) (any grade), most commonly edema (19%), fatigue (19%), dizziness/lightheadedness (13%) and lymphopenia (13%). Grade 3/4 AEs were rare with grade 3 lymphopenia, anemia, and hyponatremia occurring in 13%, 6%, and 6% of pts, respectively. Of 18 evaluable pts, 7 (39%) achieved ≥VGPR with the median time to best response 2 cycles (1-5). Conclusions: The combination of ICyD for pts with newly diagnosed AL amyloidosis is safe and well tolerated. Phase 1 is completed and the recommended phase 2 dose has been established. Deep hematologic responses (≥VGPR) have occurred and time to response appears similar to standard of care induction regimens, ie CyBorD. Phase 2 response data will be updated at the meeting.

scholarly journals Cael-101 Is Well-Tolerated in AL Amyloidosis Patients Receiving Concomitant Cyclophosphamide-Bortezomib-Dexamethasone (CyborD): A Phase 2 Dose-Finding Study (NCT04304144)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Jason Valent ◽  
John Silowsky ◽  
Michael R. Kurman ◽  
Eileen Daniel ◽  
Janet Jobes ◽  
...  
Keyword(s):  
Light Chain ◽  
Dose Escalation ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
Open Label ◽  
Private Company ◽  
Phase 3 ◽  
Wide Range ◽  
Observation Period

Immunoglobulin light Chain (AL) amyloidosis is the most common form of systemic amyloidosis, accounting for approximately 70% of the diagnosed cases in developed countries. There are no approved treatments for AL amyloidosis, and currently autologous stem cell transplants and/or chemotherapy targeted to eradicate the underlying plasma-cell dyscrasia (PCD) to stop the production of misfolded light chains are used. No therapies are available to remove existing amyloid deposits, improve and/or reverse organ dysfunction. CAEL-101 is a chimeric immunoglobulin G1 kappa isotype that reacts specifically with light chain fibrils, irrespective of their κ or λ isotype but, notably, not with the native forms. CAEL-101 was shown to bind to a cryptic epitope at the N-terminal of light chain proteins that adopt a non-native b-sheet structure, which is conserved in κ and λ mis-folded light chains. It is hypothesized that CAEL-101 will modify the disease course of AL amyloidosis by facilitating the removal of amyloid fibrils deposited in tissues. CAEL-101 was previously studied as monotherapy in an open label dose escalation Phase 1 study where it was shown to be safe, tolerable up to 500 mg/m2 and associated with an early organ response. No DLT were seen and the PK profile appeared not to reach linearity. The current multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo Stage I, II and IIIa AL amyloidosis patients was to define the safety and tolerability of CAEL-101 in combination with Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) as the standard of care (SOC) PCD therapy during a 27-day treatment period and to determine the recommended dose for the subsequent Phase 3 studies. Patients had measurable hematologic disease, as defined by at least one of:involved/uninvolved free light chain (FLC) difference (dFLC) > 5mg/dL orFLC >5mg/dL with abnormal ratio orserum protein electrophoresis (SPEP) m- spike > 0.5 g/dL Patients were seen in the clinic every week for 4 weeks to receive CAEL-101 2-HR IV infusions, and for safety and tolerability assessments. Subsequently, patients have been receiving CAEL-101 infusions approximately every other week. Actual dose was determined by patient body surface area in meters squared. When administered on the same day, CAEL-101 was administered first before CyBorD chemotherapy. The study employed a 3+3 dose escalation design, starting with a 500 mg/m2 dose. Patients were followed for dose-limiting toxicities (DLTs). The DLT observation period for the first cohort was through 14 days following the first infusion. For subsequent cohorts, this was through 27 days. At least 3 patients were enrolled in each dose cohort. Enrollment into a new cohort with the next higher dose of CAEL-101 did not begin until the DLT observation period had been completed for the last patient enrolled in the previous cohort, with further dosing cohorts at 750 and 1000 mg/m2. Safety assessment included vital signs, physical examinations, electrocardiograms (ECGs), clinical laboratory parameters (hematology, serum chemistry, urinalysis), and TEAEs. The pharmacokinetic (PK) profile of CAEL-101 was also assessed. The 13 patients averaging 65.2 years (range 47.6 to 79.6 years). The majority were male (76.9%), white (84.6%), and non-Hispanic (100%). Mayo staging I (7.7%), II (69.2%), and III (23.1%) reflected a wide range of disease severity in the patients enrolled. All patients were treated successfully through their 4th dose, the highest (1000 mg/m2) cohort enrolling 6 patients. No DLT was observed, and CAEL-101 was well-tolerated by all patients. The most common TEAEs were diarrhea and nausea (each 30.8%). Dose-normalized PK concentrations were best described by a linear two-compartment model, with terminal half-life of 28 days. This study demonstrated that CAEL-101 at doses up to 1000 mg/m2, given with CyBorD, was well-tolerated in the AL amyloidosis population. Two Phase 3 efficacy/safety studies, one enrolling Mayo Stage IIIa and the other Stage IIIb patients, have been initiated, and based on the findings from this Phase 2 study, the 1000 mg/m2 dose of CAEL-101 is being used for treatment in those studies. Figure 1 Disclosures Valent: Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau; Amgen Inc.: Other: Teaching, Speakers Bureau. Silowsky:Caelum Biosciences: Current Employment, Current equity holder in private company. Kurman:Caelum Biosciences: Consultancy. Daniel:Caelum Biosciences: Current Employment, Current equity holder in private company. Jobes:Caelum Biosciences: Current Employment, Current equity holder in private company. Harnett:Caelum Biosciences: Consultancy, Current equity holder in private company. Ziola:Caelum Biosciences: Consultancy. Roviwong:Caelum Biosciences: Current Employment, Current equity holder in private company. Spector:Caelum Biosciences: Current Employment, Current equity holder in private company. Sobolov:Caelum Biosciences: Current Employment, Current equity holder in private company.

Sign in / Sign up

Export Citation Format

Share Document