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 A Phase 1/2 Study to Assess Safety and Dose of Ixazomib in Combination with Cyclophosphamide and Dexamethasone in Newly Diagnosed Patients with Light Chain (AL) Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3128-3128 ◽  
Author(s):  
Larysa Sanchez ◽  
Heather J Landau ◽  
Cara A. Rosenbaum ◽  
Alex Abrahams ◽  
Cindy Chin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Phase 1 ◽  
Primary Study ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

Introduction: 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. Although the combination of bortezomib, cyclophosphamide and dexamethasone (CyBorD) has activity, better tolerated treatment approaches are needed. 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 according to standard criteria. 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 May 2019, 18 pts have been enrolled; 16 in phase 1 and 2 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 pts (44%) have been taken off study prior to completing 6 cycles due to no response in 5 (28%) after a median of 3.5 cycles (2-5), grade 4 hyperbilirubinemia unrelated to study drug in 1 (6%), cardiac decompensation in 1 (6%), and 1 death attributed to advanced disease. 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). Conclusion: 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. Disclosures Landau: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health. Ozbek:Viracor: Patents & Royalties: Biomarker Patent. Hassoun:Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding.

A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1732-1732
Author(s):  
Philippe Moreau ◽  
Arnaud Jaccard ◽  
Lotfi Benboubker ◽  
Bruno Royer ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Response Rate ◽  
Standard Dose ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Open Label ◽  
Dose Escalation Study

Abstract A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

A Phase 1 Study of Concomitant High Dose Lenalidomide and 5-Azacytidine Induction in the Treatment of Acute Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3616-3616
Author(s):  
Giridharan Ramsingh ◽  
Peter Westervelt ◽  
Amanda Cashen ◽  
Geoffrey L. Uy ◽  
Keith Stockerl-Goldstein ◽  
...  
Keyword(s):  
Complete Remission ◽  
Progressive Disease ◽  
Phase 1 ◽  
Hematological Toxicity ◽  
High Dose ◽  
Phase 2 ◽  
Elderly Aml ◽  
Grade 3 ◽  
Induction Cycle ◽  
Refractory Aml

Abstract Abstract 3616 Novel therapies for elderly and relapsed AML are needed. We recently published an institutional phase 2 trial using high dose (50mg/day × 28 days) single agent lenalidomide (HDL) followed by maintenance of 10 mg daily for 12 months in responders in elderly untreated AML patients (≥ 60 years) showing a complete remission (CR)/complete remission with incomplete blood count recovery (CRi) of 30% (Fehniger et al, Blood, 2011). Azacitidine (AZA) given IV or SC has also shown significant response in patients with MDS and AML. Recently Pollyea et al (JCO 29: 2011 (suppl; abstr #6505) reported on a phase 1 trial combining AZA and escalating doses of lenalidomide repeated sequentially in 6 week cycles in patients with untreated AML. Here, we report on a phase 1 single institutional study to evaluate the toxicities and feasibility of combining HDL and AZA concurrently as induction followed by a less intensive lenalidomide and AZA maintenance schedule in untreated elderly AML (≥60 years) or relapsed/refractory AML ≥18 years. Treatment schedule: 2 cycles of induction (each 28 days) of lenalidomide 50 mg PO days 1–28 and AZA at 3 dose cohorts 25 mg/m2 (cohort 1), 50 mg/m2 (cohort 2) and 75 mg/m2 (cohort 3) given IV days 1–5. Thereafter patients were given maintenance cycles (every 28 days) with lenalidomide 10 mg PO days 1–28 and AZA 75 mg/m2 days 1–5 for a total of 12 cycles. The median age was 74 (range 63–81); 7 males, 8 females; 6 with newly diagnosed elderly AML and 9 with relapsed or refractory AML. The median WBC count was 2600 (range 300–13100). The median bone marrow blast percentage was 22% (range 2–90%),with normal cytogenetics in 7 (63.6%), monosomy 7 in 3 (20%), trisomy 8 in 1 (6.7%), and other in 4 (26.6%). 8 patients were enrolled in cohort 1, 4 patients in cohort 2 and 3 patients in cohort 3. 2 patients in cohort 1 and 1 patient in cohort 2 who received less than 1 induction cycle (2 withdrew consent and 1 had progressive disease) were replaced. 11 (73.3%) of patients completed 1 induction cycle and 7 (46.7%) of patients completed 2 induction cycles and 5 (30%) patients went on to maintenance therapy. Patients remained on therapy for a median of 2 months (range 0.5–13 months). Dose limiting toxicities (DLT) observed included grade 3 rash in cohort 1 leading to expansion of the cohort to include 3 additional patients. To date grade 3/4 non-DLT hematological toxicity was seen in 6/11 (54.1%) patients. The most common 3/4 non-DLT non-hematological toxicity was neutropenic fever seen in 5/11 (45.4%). The most common grade 1/2 toxicity was fatigue in 7/11 (63.6%). 40% (6/15) of patients died, all due to progressive disease. Of the 11 evaluable patients 7 (63.6%) responded to treatment with CR/CRi in 3 (27.3%) and partial remission (PR) in 4 (36.4%) with the median duration of response of 3 months (range 0.5–11 months). In summary combination of lenalidomide with AZA appears to be a feasible regimen with acceptable toxicities. A phase 2 multicenter extension of this study with untreated elderly AML at the maximum tolerated dose of AZA and HDL will be initiated soon. Disclosures: Off Label Use: Here we discuss the use of lenalidomide and azacytidine in relapsed refractory or elderly AML. Stockerl-Goldstein:Celgene: Speakers Bureau. Vij:Celgene: Consultancy, Research Funding, Speakers Bureau.

Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: Results of an interim analysis of the German DSMM Xia trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8516-8516 ◽  
Author(s):  
S. Knop ◽  
P. Liebisch ◽  
H. Wandt ◽  
M. Kropff ◽  
W. Jung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interim Analysis ◽  
Standard Of Care ◽  
Dose Finding ◽  
Optimum Dose ◽  
Primary Study ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Study Objective ◽  
Grade 3

8516 Background: Cytoreductive induction followed by HD-MEL and ASCT is considered standard of care for younger patients (pts) with multiple myeloma (MM). The success of this combined procedure partially depends on the efficacy of induction treatment. Bortezomib-containing induction regimens have already been shown to be superior to standard VAD. In order to further improve the efficacy of induction treatment we combined Vel with intravenous (IV) cyclophosphamide (C) and dexamethasone (D). Methods: This trial is an open, prospective, multicenter, uncontrolled phase II/III study with a planned recruitment of 400 pts. The first 30 pts were included in the dose finding study to determine the optimum dose of IV C in conjunction with Vel and D. The following 170 pts up to 60 years of age with untreated MM were enrolled to receive 3 cycles of induction with Vel 1.3 mg/m2 IV d1, 4, 8, 11; D 40 mg/d d1, 2, 4, 5, 8, 9, 11, 12; and C 900mg/m2 IV d1. Primary study objective is response rate (≥ PR) to VelCD according to the EBMT criteria. Results: Data from the first completed 200 pts (mean age: 52 years; 74% stage III) from 36 German centers were analyzed as ITT population. Response rates are given in Table and were documented in 82% of the subjects with 13q-, in 94% with t(4;14) and in 70% with 17p-. SAEs (n=84) occurred in 24.5% of the pts and were related to Vel, C or D in 16%, 14.5% or 9.5% respectively. The mortality rate of 1% is low, 53% of the patients experienced grade 3 + 4 AEs, infections of grade 3 and 4 were reported in 2% and grade 3 paraesthesia occurred in 2%. Conclusions: This interim analysis demonstrates that bortezomib combined with dexamethasone and intravenous cyclophosphamide (VelCD) is a highly effective induction regimen for pts ≤ 60 years with newly diagnosed MM regardless of cytogenetic risk factors. [Table: see text] [Table: see text]

Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9014-9014 ◽  
Author(s):  
Tara C. Gangadhar ◽  
Bryan J. Schneider ◽  
Todd Michael Bauer ◽  
Jeffrey S. Wasser ◽  
Alexander I. Spira ◽  
...  
Keyword(s):  
Phase 1 ◽  
Phase 2 ◽  
Test Results ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase ◽  
History Of ◽  
Grade 3 ◽  
Preliminary Phase ◽  
Clinical Trial Information

9014 Background: ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of epacadostat (a potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus pembrolizumab (E + P) in patients (pts) with advanced tumors. We report preliminary efficacy and safety outcomes for the phase 1/2 NSCLC cohort. Methods: Adult pts with prior platinum-based therapy (tx) and no prior checkpoint inhibitor tx were eligible. Phase 1 dose-escalation tx was E (25, 50, 100, 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 cohort expansion. Efficacy was evaluated by tumor proportion score (TPS [% viable tumor cells, PD-L1 staining]: < 50% and ≥50%) and by prior lines of tx in RECIST 1.1 evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: As of 29OCT2016,43 pts (phase 1, n = 12; phase 2, n = 31) were evaluated. Median age was 65 years, 58% of pts were women, 12% were EGFR-positive, and 23% were KRAS-positive. Most pts had a history of smoking (84%), ≤2 prior lines of tx (84%), and no prior TKI tx (93%). For the 40 efficacy-evaluable pts, ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. PD-L1 TPS test results were available in 28/40 efficacy-evaluable pts. ORR and DCR for pts with TPS ≥50% and ≤2 prior tx were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for pts with TPS < 50% and ≤2 prior tx, ORR and DCR were 35% (6/17; all PR) and 53% (9/17; 3 SD). Among the 40 efficacy-evaluable pts, 12/14 responses were ongoing (range, 1+ to 519 days) at data cutoff. PFS and biomarker analyses are ongoing. Across all 43 pts, most frequent TRAEs were fatigue (19%), arthralgia (9%), and increased AST (9%); 16% of pts had grade ≥3 TRAEs, and increased lipase (asymptomatic) was the only grade ≥3 TRAE that occurred in > 1 pt (n = 2). Two pts discontinued due to TRAEs (grade 3 increased AST, grade 2 increased ALT [n = 1]; grade 2 brain edema [n = 1]). Conclusions: E + P was generally well tolerated and associated with promising responses in pts with NSCLC. A phase 3 NSCLC study is planned. Clinical trial information: NCT02178722.

scholarly journals Treatment withα-Lipoic Acid over 16 Weeks in Type 2 Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Hector Garcia-Alcala ◽  
Celia Isabel Santos Vichido ◽  
Silverio Islas Macedo ◽  
Christelle Nathalie Genestier-Tamborero ◽  
Marissa Minutti-Palacios ◽  
...  
Keyword(s):  
Lipoic Acid ◽  
Phase 1 ◽  
Treated Group ◽  
Diabetic Patients ◽  
High Dose ◽  
Phase 2 ◽  
Open Label ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Effective treatment of diabetic sensorimotor polyneuropathy remains a challenge. To assess the efficacy and safety ofα-lipoic acid (ALA) over 20 weeks, we conducted a multicenter randomized withdrawal open-label study, in which 45 patients with type 2 diabetes and symptomatic polyneuropathy were initially treated with ALA (600 mg tid) for 4 weeks (phase 1). Subsequently, responders were randomized to receive ALA (600 mg qd;n=16) or to ALA withdrawal (n=17) for 16 weeks (phase 2). During phase 1, the Total Symptom Score (TSS) decreased from 8.9 ± 1.8 points to 3.46 ± 2.0 points. During phase 2, TSS improved from 3.7 ± 1.9 points to 2.5 ± 2.5 points in the ALA treated group (p<0.05) and remained unchanged in the ALA withdrawal group. The use of analgesic rescue medication was higher in the ALA withdrawal group than ALA treated group (p<0.05). In conclusion, in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose (600 mg tid) administration of ALA, subsequent treatment with ALA (600 mg qd) over 16 weeks improved neuropathic symptoms, whereas ALA withdrawal was associated with a higher use of rescue analgesic drugs. This trial is registered with ClinicalTrials.gov Identifier:NCT02439879.

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.

G-CSF Priming, Clofarabine and High Dose Cytarabine (GCLAC) for Relapsed or Refractory Acute Myeloid Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2068-2068 ◽  
Author(s):  
Pamela S. Becker ◽  
Elihu Estey ◽  
Stephen Petersdorf ◽  
Barry E Storer ◽  
Frederick R Appelbaum
Keyword(s):  
Phase 1 ◽  
Initial Therapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Platelet Recovery ◽  
Neutrophil Recovery ◽  
Oncology Research ◽  
Pediatric All ◽  
Grade 3 ◽  
Age Range

Abstract Abstract 2068 Poster Board II-45 Background: Clofarabine is active in both relapsed and newly diagnosed AML. Clofarabine in combination with ara-C at a dose of 1 g/m2 daily for 5 days resulted in 52% complete remission (CR) in newly diagnosed patients age 50 or older. (Faderl et al Blood 108:45, 2006), Addition of low dose cytarabine (ara-C) improved efficacy as compared to clofarabine alone in untreated patients age 60 or older (Faderl et al Blood 112:1638, 2008). As high dose ara-C has considerable efficacy in AML, we combined clofarabine with higher dose ara-C (HiDAc) and granulocyte colony-stimulating factor (G-CSF) priming for patients with relapsed AML or AML that failed to respond to initial therapy. GCLAC is based on the FLAG regimen, substituting clofarabine for fludarabine, given the former's greater anti-AML effect. Methods: We initially conducted a phase 1 trial in 19 pts and identified 25 mg/m2 daily days 1-5 as the MTD of clofarabine when combined with ara-C 2 g/m2 daily days 1-5 and G-CSF 5 mcg/kg subcutaneously, beginning 1 day before chemotherapy and continuing daily until neutrophil recovery. A phase 2 expansion was then conducted at the MTD. Results: We have treated 38 patients (pts), age range 19-66 years, median 51, 22 at the MTD. Twenty pts received GCLAC as 1st salvage, 15 at the MTD. Seven of the 20 had relapsed after a median 1st CR duration of 6 mos while 13 had not responded to initial 3+7 induction therapy, including 4 who were refractory to > 1 course. The CR rate for all patients or all patients at the MTD was 45% and the CR +CRp rate at the MTD was 64%. These rates are 50% CR (95%CI 27-73%) and 65% CR+CRp among 1st salvage pts (95% CI 41-85%), respectively, and 70% CR + CRp excluding pts who relapsed after allogeneic SCT. Median time to neutrophil recovery (ANC>500) was 21 days (range 13 to 39), and to platelet recovery (platelet count >100,000), 29 days (range 21-42). Four of 22 pts had serious infections and/or asymptomatic grade 3 LFT elevations, a rate not in excess of that seen with other ara-C-containing salvage therapies. Sixty percent of the first salvage patients had poor risk cytogenetics, and 80% of CRs were observed after the first course of therapy. Median overall survival was 7.4 months, and event free survival, 4.3 months. Using a prognostic model that derives expected CR rates with HiDAc or FLAG based on 1st CR duration and number of prior salvage therapies (Blood 1996;88:756), the ratio of observed (with GCLAC) to expected CR was 2.5:1. Conclusion: Based on its efficacy, formal comparisons of GCLAC with other salvage regimens are warranted and the combination should also be investigated in untreated pts. Disclosures: Becker: Genzyme Oncology: Research Funding. Off Label Use: Clofarabine is approved for relapsed or refractory pediatric ALL .

Dasatinib In Children and Adolescents with Relapsed or Refractory Leukemia: Results of the CA180018 Phase 1 Dose-Escalation Study of the Innovative Therapies for Children with Cancer (ITCC) Consortium

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2265-2265 ◽  
Author(s):  
C. Michel Zwaan ◽  
Carmelo Rizzari ◽  
Francoise Mechinaud ◽  
Donna L Lancaster ◽  
Pamela R. Kearns ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Maximum Concentration ◽  
Phase 1 ◽  
Molecular Response ◽  
Cell Transplant ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Grade 3

Abstract Abstract 2265 Background: Pediatric relapsed/refractory leukemia portends a poor prognosis and more effective therapies are urgently needed. Dasatinib is a potent oral BCR-ABL inhibitor approved for treating adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to imatinib. Dasatinib also has activity against SRC-family kinases and KIT. A phase 3 trial of dasatinib vs imatinib in adults with newly diagnosed with CML in chronic phase (CP) showed superior efficacy of dasatinib with good tolerability (Kantarjian et al. NEJM 2010:362:2260). Methods: The CA180018 trial is a component of a European Medicines Agency-approved comprehensive Pediatric Investigation Plan for dasatinib aimed at improving outcomes in pediatric leukemias. This trial is being conducted via the ITCC consortium in 7 countries (15 centers) as a stratified phase 1 dose-escalation study. The primary aim is to establish a safe and effective phase 2 dose of dasatinib in children/adolescents with subtypes of relapsed/refractory leukemia. Secondary objectives include safety, pharmacokinetics (PK), and rates of hematologic, cytogenetic, and molecular response (cytogenetic/molecular responses in Ph+ only). Patients (pts) were stratified into 3 disease strata: Stratum 1, imatinib-resistant/intolerant Ph+ CML-CP; Stratum 2/3, advanced CML resistant to imatinib or Ph+ ALL relapsed/refractory after imatinib or Ph+ AML in ≥2nd relapse (original strata merged by protocol amendment due to slow enrolment); and Stratum 4, ≥2nd relapse of Ph– ALL or AML. Starting doses were 60, 80, 100, and 120 mg/m2 once daily, with dose escalations based on safety and efficacy. Intrapatient dose escalation was allowed for lack of response. Results: The study opened in March 2006 and closed to accrual in October 2009. 58 pts have been treated, of which 50 (86%) completed therapy by data cut-off of May 2010. No pts with Ph+ AML were enrolled. All pts had prior therapy, including imatinib in 59% (all Ph+ pts), anagrelide or hydroxyurea in 22%, interferon in 3%, other chemotherapy in 69%, radiotherapy in 43%, and stem cell transplant in 50%. Median age (yrs) was 11, including 2 pts (3%) aged <2, 32 (55%) aged 2–11, 23 (40%) aged 12–18, and 1 (2%) aged >18. 39 pts (67%) were male. No pt with Ph– AML had a KIT mutation. Median durations of therapy (range) were: Stratum 1, 11.3 mos (2.3–47.9); Stratum 2/3, 3.0 mos (0.5–24.6); and Stratum 4, 1.1 mos (<0.1–3.4). Dasatinib up to 120 mg/m2, including long-term therapy, was well tolerated. Common drug-related toxicities (≥10%) were: nausea (grade 1/2 in 16 pts [28%], grade 3 in 1 [2%]); headache (grade 1/2 in 11 [19%], grade 3 in 2 [3%]); diarrhea (grade 1/2 in 12 [21%]); vomiting (grade 1/2 in 9 [16%], grade 3 in 1 [2%]); rash (grade 1/2 in 9 [16%]); and pain in extremity (grade 1/2 in 6 [10%]). Pleural effusion occurred in 2 pts (3%) at grade 1 and 1 pt (2%) at grade 3. Two dose-limiting toxicities were seen in Stratum 4: grade 4 anaphylaxis 5 h after first dose (60 mg/m2) and grade 3 upper GI bleed on Day 6 (120 mg/m2) in a pt with platelet count of 16×109/L. Maximum tolerated dose has not been established. PK parameters, analyzed in 52 pts to date, showed high interpatient and intrapatient variability. Dasatinib was rapidly absorbed with median time to maximum concentration of 1.0 h irrespective of dose. Mean half-life ranged from 2.1–3.6 h. With dasatinib 60, 80, 100, or 120 mg/m2, area under the curve was 374, 530, 424, and 606 ng.h/mL and maximum concentration was 113, 138, 114, and 183 ng/mL, respectively. Treatment responses were seen in Ph+ pts who received dasatinib 60 or 80 mg/m2. In Stratum 1 (CML-CP; n=17), rates were complete hematologic response (HR) in 16 (94%), complete cytogenetic response (CCyR) in 14 (82%), major molecular response (MMR) in 6 (35%), and complete molecular response in 4 (24%). In Stratum 2/3 (advanced CML/Ph+ ALL; n=17), rates were major HR in 10 (59%), CCyR in 12 (71%), and MMR in 0/2 pts with advanced CML assessed to date. No pt in Stratum 4 responded (Ph– ALL/AML; n=24). Final data will be presented. Conclusions: This trial shows the safety and efficacy of dasatinib in pediatric pts with Ph+ leukemias and supports the feasibility of evaluating new agents in children with rare malignancies through cooperative group efforts. A phase 2 study is underway to further evaluate dasatinib in children/adolescents with Ph+ leukemias, including newly diagnosed CML. Disclosures: Zwaan: Bristol-Myers Squibb: Consultancy. Off Label Use: Dasatinib treatment of pediatric leukemias. Rosenberg: Bristol-Myers Squibb: Employment, Equity Ownership. Herdlicka: Bristol-Myers Squibb: Employment. Derreumaux: Bristol-Myers Squibb: Employment. Agrawal: Bristol-Myers Squibb: Employment.

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).

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