A Randomized Phase II Trial of High-Dose Melphalan, Ascorbic Acid and Arsenic Trioxide with or without Bortezomib in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2309-2309
Author(s):  
Manish Sharma ◽  
Peter Thall ◽  
Xuemei Wang ◽  
Chitra Hosing ◽  
Floralyn L Mendoza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
High Dose ◽  
Randomized Phase Ii ◽  
Preparative Regimen ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Abstract 2309 Poster Board II-286 Background There is a role for novel preparative regimens in multiple myeloma to improve the outcome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto HCT). Bortezomib is an active agent in newly diagnosed or relapsed multiple myeloma, and has synergistic activity with melphalan. We conducted a randomized phase II trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA) and melphalan. Methods auto HCT, with preparative regimen melphalan 100 mg/m2 IV on days -4 and -3, AA 1000 mg/day IV on days -9 to -3 and ATO 0.25 mg/kg IV on days -9 to -3. Patients were randomized to 3 arms; no bortezomib (arm 1), bortezomib 1 mg/m2 on days -9, -6 and -3(arm 2), and bortezomib 1.5 mg/m2 on days -9, -6 and -3 (arm 3). Primary endpoints were complete response (CR), NCI grade 4 toxicity, and overall survival (OS). Results In arms 1, 2 and 3, median intervals between diagnosis and auto HCT were 12.2, 9.6 and 8.8 months; median follow up in all surviving patients was 20 months (range 10 to 31). CR+near CR rates in arms 1, 2 and 3 were 35%, 30% and 25%. Grade 3–4 toxicity was seen in 6 patients in arm 1 (mucositis 3, dyspnea 1, acute renal failure 1, pleural effusion 1), 6 patients in arm 2 (mucositis 3, diarrhea 1, pneumonia 1 and hydronephrosis 1) and 6 patients in arm 3 (pulmonary edema 2, mucositis 1, intestinal obstruction 1, low back pain 1, elevated transaminases 1). The most common adverse events were nausea, diarrhea and pedal edema. Grade 1–2 weight gain due to fluid retention was seen in 84%, 70% and 95% of patients in arms 1, 2 and 3. Median time to neutrophil engraftment (ANC >500/dl) was 10 days in each arm. Median OS has not been reached in any of the 3 arms. Median progression-free survival (PFS) times were18.6, 13.2 and 17.5 months. OS was significantly shorter in patients with relapsed disease (0.00001) and cytogenetic abnormalities at auto HCT (0.0002). Conclusions Adding bortezomib to a preparative regimen of ATO, AA and high dose melphalan is safe and well tolerated in patients with multiple myeloma. There was no significant impact of adding bortezomib at either dose on the CR rate, grade 3-4 toxicity or OS. Disclosures: Shah: Celgene, Amgen, Novartis, Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Qazilbash:Cephalon: Speakers Bureau.

A Randomized Phase II Trial of High-Dose Melphalan, Ascorbic Acid and Arsenic Trioxide with or without Bortezomib in Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3320-3320 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Rima M. Saliba ◽  
Matteo Pelosini ◽  
Chitra M Hosing ◽  
Floralyn L Mendoza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Phase Ii Trial ◽  
High Dose ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Preparative Regimen ◽  
High Dose Melphalan

Abstract Background: There is a role of novel preparative regimens to further improve the outcome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) in multiple myeloma. Arsenic trioxide (ATO) has synergistic activity with melphalan and ascorbic acid (AA) both in vitro and in vivo, and this 3-drug combination was found to be safe and feasible in both conventional and high-dose settings. Bortezomib, a proteasome inhibitor, is an active agent in newly diagnosed or relapsed multiple myeloma in conventional therapy setting. We conducted a randomized phase II trial to determine the safety and efficacy of a combination of ATO, AA and melphalan with or without bortezomib as preparative regimen in patients with myeloma. Methods: Sixty patients were enrolled and 58 patient received ASCT between October 2006 and September 2007. One patient developed respiratory failure and another developed extensive pulmonary embolism after enrollment and did not proceed to ASCT. All 58 evaluable patients received melphalan 100 mg/m2 IV on days -4 and -3, AA 1000 mg/day IV on days -9 to -3 and ATO 0.25 mg/kg IV on days -9 to -3. Patients were randomized to 3 arms; no bortezomib (arm 1), bortezomib 1 mg/m2 on days -9, -6 and -3 (arm 2), and bortezomib 1.5 mg/m2 on days -9, -6 and -3 (arm 3). Patients were also asked to fill out a standardized Quality of Life (QOL) questionnaire at enrollment and at 6 months post-ASCT. Results: Median age of patients in arms 1, 2 and 3 were 61, 59 and 64 years, respectively (p=0.08). Median interval between diagnosis and ASCT were 12.2, 9.6 and 8.8 months, respectively (p=0.3). Cytogenetic abnormalities were detected in 2, 5 and 8 patients in arms 1, 2 and 3, respectively (p=0.08). With a median follow up of 11.4 months (range 5 to 20) post ASCT in surviving patients, cumulative non-relapse mortality was1.7%. Grade 3–4 toxicity was seen in 6 patients in arm 1 (mucositis 3, dyspnea 1, acute renal failure 1, pleural effusion 1), 6 patients in arm 2 (mucositis 3, diarrhea 1, pneumonia 1 and hydronephrosis 1) and 6 patients in arm 3 (pulmonary edema 2, mucositis 1, intestinal obstruction 1, low back pain 1, elevated transaminases 1) (p=0.9). The most common adverse events were nausea, diarrhea and pedal edema. Grade 1–2 weight gain due to fluid retention was seen in 84, 70 and 95% of patients in arms 1, 2 and 3, respectively (p= 0.1). Median time to neutrophil engraftment (ANC >500/dl) was 10 days in each arm. Complete response rates in arms 1, 2 and 3 were 26, 10 and 16%, respectively (0=0.4). Kaplan-Meiers estimates of progression-free survival (PFS) and overall survival (OS) are shown in Figures 1 and 2. Median PFS and OS have not been reached. There was no significant difference in CR, PFS or OS between the 3 arms (p = 0.4, 0.62 and 0.4, respectively). Relapsed disease at ASCT (p=0.003), >12 months interval between diagnosis and ASCT (p=0.05), and cytogenetic abnormalities at diagnosis (p=0.005) predicted a shorter PFS. On a subset analysis, there was no significant difference in PFS or OS between the 3 arms in patients undergoing ASCT in first remission. Fifty-patients submitted their responses to the QOL questionnaire. More patients at 6-month post ASCT reported better overall health (56% vs.12%, p=0.0001). In contrast, more patients at study enrollment reported moderate to severe pain (44% vs. 27%, p=0.09) and debilitating emotional problems (42% vs. 23%, p=0.07). Conclusions: Adding bortezomib to ATO, AA and high dose melphalan is safe and well tolerated as preparative regimen for ASCT in patients with multiple myeloma. Patients with chromosomal abnormalities were predominantly treated in the bortezomib arms without an adverse impact on PFS or OS. Overall QOL indicators showed improvement at 6-month post ASCT. Longer follow up is needed to assess the efficacy of this combination. FIGURE 1 FIGURE 1. FIGURE 2 FIGURE 2.

Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan Is Safe and Effective for Autotransplantation for Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 942-942 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Rima M. Saliba ◽  
Gaurav Parikh ◽  
Chitra Hosing ◽  
Floralyn Mendoza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Response Rate ◽  
Hematopoietic Progenitor Cell ◽  
High Dose ◽  
Preparative Regimen ◽  
Relapsed Disease ◽  
High Dose Melphalan

Abstract Background: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a randomized phase II trial to determine the safety and efficacy of a combination of ATO, melphalan, and ascorbic acid (AA) as a preparative regimen in patients undergoing autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact of ATO levels on melphalan pharmacokinetics, engraftment, and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age, 54; range 35–70) were treated between 4/04 and 8/05. All patients received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms: no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2), and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had received a prior autograft, with a median 4.5 x 106/kg (range 2.3–10.9) CD34+ cells infused. Results: Patients in all 3 arms were evenly matched. Twenty-nine patients (60%) were transplanted for consolidation of first remission and 19 patients (40%) for relapsed disease. With a median follow-up of 26 months (range 10–37) post-autograft, no dose-limiting toxicity, or nonrelapse mortality was reported. Toxicity was limited to grade 1 or 2 nausea, vomiting, and diarrhea and was comparable in all 3 arms. Melphalan pharmacokinetics was not altered by ATO pretreatment. Median time to neutrophil engraftment (absolute neutrophil count >500/dL) was 9 days, with no engraftment failures or delays in either the control or ATO arms. The complete response (CR) rate for all patients was 25% (12/48), and the partial response rate was 60% (29/48) for an overall response rate (ORR = CR + PR) of 85%. Progression-free survival (PFS) and overall survival (OS) after 24 months of follow-up were 59% and 91%, respectively. Median PFS was 29 months; median OS has not been reached. There was no significant difference in CR, ORR, PFS, or OS among the 3 arms (P =.9, .9, .5, and .6, respectively). PFS and OS were comparable among patients with chromosomal abnormalities or relapsed disease at transplant and patients undergoing a second autotransplant for salvage. Conclusions: Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for autotransplants in patients with MM, including high-risk patients. There was no adverse impact of ATO on engraftment. Longer follow-up is necessary to assess the efficacy of this combination on PFS and OS.

Transplant Outcomes after Topotecan-Melphalan-Cyclophosphamide (TMC) Conditioning for Autologous Stem Cell Transplantation for Multiple Myeloma. Comparison to Melphalan 200 mg/M2 (MEL200).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1177-1177
Author(s):  
Michele Donato ◽  
Ana Aleman ◽  
Donna Weber ◽  
Michael Wang ◽  
Muzaffer Qazilbasch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
High Dose ◽  
Transplant Outcomes ◽  
Transplant Program ◽  
Preparative Regimen

Abstract Background: Topotecan at modest doses has activity in multiple myeloma (MM). The combination of high-dose topotecan, melphalan, and cyclophosphamide (TMC) has been used as a conditioning regimen for autologous SCT in patients with MM. We report the results of a phase II trial with this combination and perform a retrospective analysis comparing TMC to a standard preparative regimen of melphalan 200 mg/m2 (MEL200). Patients and Methods: Between 10/99 and 3/04, 55 patients with newly diagnosed MM were treated on a Phase II trial of topotecan 3.5 mg/m2 daily for 5 days in combination with cyclophoshamide 1 gm/m2 daily for 3 days, and melphalan 70 mg/m2 daily for 2 days followed by autologous SCT. Patient characteristics are summarized in table 1. In brief, median age was 55 (range, 37–67), median time to transplant was 6 months (range, 2-59); median B2M @diagnosis 3.3 (range, 1.4–17.2); 76% of patients had chemosensitive disease prior to transplant. Results: No treatment related deaths were observed, the regimen was well tolerated with grade 2 Bearman mucositis and diarrhea the most common toxicities, and no grade 3 or 4 toxicities observed. When compared to a group of patients who received MEL 200 the overall response rate was lower 75% vs 82% and a lower CR rate 11% vs 36%, but a similar median time to disease progression (14 m vs 13 m), with a trend towards a better 3 yr overall survival (87% vs 77%; p=.05) (Table 2 and Figure 1). Conclusion: TMC is a well tolerated conditioning regimen for myeloma, our results suggests that although no more effective than MEL200 as a single preparative regimen for MM, it warrants exploring as part of a tandem transplant program. Patient Characteristics TMC MEL200 N 55 157 Median Age (range) 55(37-67) 56(29-75) Median B2M @Dx 3.3 (1.4 - 17.2) 4 (0.5 - 49.8) % Abn Cytogenetics 15% 22% CR/PR @ SCT 4%/73% 10%/89% % 1ry Refractory 24% 27% Transplant Outcomes TMC MEL200 p ORR/CR conversion 75%/11% 82%/36% Non Relapse Mortality 0 2 Median OS NR 52 months .05 Figure Figure

Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3090-3090 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Rima M. Saliba ◽  
Marilyn S. Davis ◽  
Floralyn L. Mendoza ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Cell Transplantation ◽  
Hematopoietic Progenitor Cell ◽  
High Dose ◽  
Significant Difference ◽  
Preparative Regimen ◽  
The Impact

Abstract Backround: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as preparative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age: 54, range: 3570) were treated between 4/04 and 8/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2) and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had disease progression or relapse after a prior autograft. Median CD34 cells dose infused was 4.5 x 106/kg (range 2.3–10.9). Results: Patients in all 3 arms were evenly matched. With a median F/U of 14.0 months (range 6–25) post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Toxicity was limited to grade I or II nausea, vomiting and diarrhea. Median ATO levels on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Melphalan PK was not altered by ATO pretreatment. Median time to neutrophil engraftment (ANC >500/ dl) was 9 days. There were no engraftment failures or delays in the ATO arms. CR rate for the entire group was 23%, and total response rate (CR + PR) was 75%. 1-year Progression-free survival (PFS) and overall survival (OS) were 75% and 95%, respectively. There was no significant difference in CR, RR, PFS or OS between the 3 arms (p = 0.9, 0.9, 0.4 and 0.6, respectively). A prior autologous transplant (p = 0.02) and abnormal cytogenetics at transplant (p = 0.04) were associated with a significantly shorter remission. Conclusions: ATO + melphalan + ascorbic acid is a safe, effective and well tolerated preparative regimen for patients with multiple myeloma undergoing an autotransplant. A longer follow up is needed to assess the impact of ATO on progression-free and overall survival.

Weekly bortezomib in the treatment of patients (pts) with previously treated multiple myeloma: A phase II trial of the Minnie Pearl Cancer Research Network

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7547-7547 ◽  
Author(s):  
F. A. Greco ◽  
D. R. Spigel ◽  
J. H. Barton ◽  
C. Farley ◽  
M. T. Schreeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Research Network ◽  
High Dose ◽  
Weekly Schedule ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Previously Treated ◽  
Grade 3

7547 Background: Bortezomib, administered on a twice-weekly schedule, is now a standard part of treatment for patients with multiple myeloma. Weekly bortezomib schedules have shown activity in other cancer types, and are more convenient than twice weekly schedules. In this multicenter, community-based phase II trial, we evaluate the feasibility, toxicity, and efficacy of weekly bortezomib in pts with previously treated multiple myeloma. Methods: Eligibility criteria included a diagnosis of multiple myeloma treated with 1 or 2 previous systemic regimens (only 1 if first-line therapy included high-dose therapy); ECOG PS 0–2; creatinine < 2.0 mg/dL; WBC ≥ 3000/μL; ANC > 1000/μL; platelets ≥ 50,000/μL; no peripheral neuropathy > grade 1; informed consent. All pts received bortezomib 1.6mg/m2 IV on days 1, 8, 15, and 22 of each 5-week cycle. Pts were reevaluated at 10-week intervals; treatment continued for 8 cycles (40 weeks) or until myeloma progression. Results: Between 5/04 and 12/05, 37 pts entered this trial. Pt characteristics: median age 70 years; male/female, 20/17; 24 pts (65%) had received 2 previous regimens (previous high dose therapy, 2 pts); elevated β-2 microglobulin, 27 pts (73%). Of 26 pts evaluated, 13 pts (50%) had major responses, 11 pts (42%) stable disease, and 2 pts (8%) had progression. After a median follow-up of 7 months, projected median PFS is 9.6 months; overall survival at 1 year is 81%. Weekly bortezomib was well tolerated by most pts. Grade 3/4 toxicities included fatigue (21%), diarrhea (11%), neutropenia (7%), thrombocytopenia (4%), all others < 5%. No grade 3/4 neuropathy occurred. Only 1 pt required bortezomib dose reduction during treatment, and 2 pts discontinued treatment because of toxicity (myelosuppression, 1; fatigue/dehydration, 1). Conclusions: Weekly bortezomib is a convenient, well tolerated treatment for pts with previously treated multiple myeloma. Overall response rates with this schedule are similar to those previously reported with the standard twice-weekly schedule. Further followup is necessary to better evaluate the duration of response and the incidence of cumulative toxicities. [Table: see text]

Relapsed and Refractory Acute Myeloid Leukemia (AML) Treated with AS1411 and Cytarabine: A Randomized Phase II Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1935-1935 ◽  
Author(s):  
Robert Kenneth Stuart ◽  
Gary Acton ◽  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Cytogenetic Response ◽  
High Dose ◽  
In Vivo Models ◽  
Randomized Phase Ii ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
To Receive ◽  
Refractory Aml

Abstract Background: AS1411 is an aptamer that binds to nucleolin, which is upregulated and overexpressed in the cytoplasm and on the cell surface of cancer cells. Combination of AS1411 with cytarabine produces synergistic effects on AML cell lines and in vivo models. A phase I trial of AS1411 monotherapy in 30 patients with various advanced cancers revealed no dose-limiting toxicities and showed evidence of activity, including 2 responses among 12 patients with metastatic renal cancer. This phase II study evaluates the addition of AS1411 to high-dose cytarabine in relapsed and refractory AML. Methods: This open-label randomized phase II trial compares AS1411 plus cytarabine with cytarabine alone in patients with primary refractory or relapsed de novo or secondary AML who have received up to 3 previous induction cycles. Patients in cohort I were randomized in a 1:2 ratio to receive cytarabine (3,000 mg/m2/day) for 4 days or AS1411 (10 mg/kg/day) on days 1–7 plus cytarabine on days 4–7. Following safety assessment, a second cohort was to be randomized 1:2 to receive cytarabine 3,000 mg/m2/day) for 4 days or AS1411 at a higher dose (40 mg/kg/day) on days 1–7 plus cytarabine on days 4–7. Key study objectives are comparison of response rates and safety and tolerability between treatment groups. Patients not achieving a CR after one cycle of single agent cytarabine are eligible for a subsequent cycle of AS1411 plus cytarabine. Results: Thirty-three patients had been randomized by July 2008, all to the first cohort. Safety findings were available for 27 patients (9 in the cytarabine arm and 18 in the combination arm). Numbers of grade 3 and 4 adverse events per patient were 19 among 9 patients on cytarabine alone and 35 among 18 patients on AS1411 plus cytarabine. The main grade 3/4 toxicities reported were blood and lymphatic system disorders, particularly febrile neutropenia, neutropenia and thrombocytopenia; and infections and infestations. Induction deaths were 1/9 and 0/18, respectively. Response data were available for 20 patients. In the cytarabine-alone group, 0/7 patients achieved a CR, CRp or cytogenetic response. In the cytarabine plus AS1411 group, 3/13 (23%) patients showed responses to treatment, with one CR, one CRp and one cytogenetic response. Three patients from the cytarabinealone group who failed to achieve remission with cytarabine alone crossed over to receive AS1411 plus cytarabine, one of whom experienced a 90% reduction in leukemic blast count. Conclusion: The combination of AS1411 at 10 mg/kg/day for 7 days with high-dose cytarabine 3,000 mg/m2/day over 4 days appeared to be well tolerated and showed signs of activity in patients with relapsed/refractory AML. Further patients are now being randomized to cytarabine or cytarabine plus the higher dose of 40 mg/kg/day AS1411.

scholarly journals Phase I/II Study of Lenalidomide and High Dose Melphalan As Preparative Regimen in Autologous Transplant in Myeloma: Report of Phase II Efficacy and Safety Data

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3193-3193 ◽  
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Rebecca Silbermann ◽  
Mary Cangany ◽  
Anita Rush-Taylor ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
High Dose ◽  
Disease Response ◽  
Preparative Regimen ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: High-dose melphalan and autologous hematopoietic stem cell transplantat (auto-HCT) is a standard consolidation therapy for eligible multiple myeloma (MM) patients due to superior survival outcome as compared to chemotherapy alone. However, patients remain at continuous risk of disease relapse following auto-HCT. Lenalidomide is active in newly diagnosed and relapsed MM and has synergistic activity with melphalan, but has not previously been incorporated into preparative regimen for auto-HCT. While high dose lenalidomide induces myelosuppression, the anti-tumor activity of lenalidomide is dose-dependent. Methods: We conducted a single center, phase I/II study of lenalidomide and melphalan in patients with MM undergoing auto-HCT. The phase I portion included MM patients at all disease stages, including patients undergoing auto-SCT as salvage therapy. The phase II portion enrolled patients undergoing a first auto-SCT after achieving at least stable disease following their induction regimen. Phase I objectives included determination of side effect profile and recommended phase II dose (RP2D). Phase II objectives were disease response at day +100 and toxicity. Treatment: All patients received a standard melphalan dose of 200 mg/m2 (100 mg/m2 IV days -1 and -2). Phase I lenalidomide dose was escalated from 50 mg, 75mg, 100 mg, and 150 mg and administered orally daily from days -7 to +2. Phase I data were previously reported (Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 3146). Thirteen patients were treated and no MTD was reached. The RP2D lenalidomide dose (150 mg orally daily days -7 to +2) was further explored in the phase II portion of this study. Post-transplant lenalidomide maintenance therapy was started between days +100 and +120 in all responders. We now report the planned interim analysis of the efficacy and safety profile of the phase II study. Results: From 5/1/12 to 7/9/15, forty seven subjects were enrolled to the phase II portion of the study. Study accrual is complete. We report below on the 37 patients with at least 100 days follow-up (median duration of follow-up of 12 months). 36 patients were assessable for response. Responses are as followed: stringent CR 8 (22%), CR 3 (8%), VGPR 20 (54%), PR 3 (8%), progressive disease 2 (5%). Among responders, 34 were able to start maintenance lenalidomide on days +100 to +110 (two withdrew from the study to pursue tandem stem cell transplant). To date, 21 patients remain on the treatment. Of 13 who discontinued the therapy; 4 was due to progression, 4 due to physician/patient preference, 2 due to toxicities and 3 from other reasons. Median progression free survival has not been reached. Toxicities were considered treatment related if they occur after the initiation of study drugs. DLTs are defined as any AEs occurring from days -7 to -2 that cause delay or prevent subjects from proceeding to auto-SCTs, grade 3 or more non-hematologic toxicities that do not resolve to a grade 2 or less by day 30 after auto-SCT, or engraftment failure. No DLTs were observed. The median time for ANC and platelet engraftment was 12 and 15 days and no delayed engraftment was observed. Toxicities and posttransplant hematopoietic recovery rates were similar to historical data observed with single agent high dose melphalan. Lenalidomide related toxicities occurred more commonly during the maintenance phase. Common toxicities occurring in more than 10% of patients were diarrhea (24%), peripheral neuropathy (21%) and fatigue (10%). Grade 3-4 toxicities occurred in 16% percent of patients: fatigue (5%), neutropenia (5%) neuropathy (3%), and thrombocytopenia (3%). Conclusion The use of high dose lenalidomide in combination with high-dose melphalan as a preparative regiment for auto-SCT is well tolerated. High VGPR or better disease response rates, compared to historical control, suggest that the preparative combination regimen may improve the depth of response. Stem cell rescue likely overcome lenalidomide induced myelosuppression. The study is now closed to accrual. Updated data on primary endpoints from all subjects will be reported at the meeting. Disclosures Suvannasankha: Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Farag:Bristol Myers: Speakers Bureau; Millennium: Speakers Bureau; Teva: Research Funding; Celgene: Speakers Bureau. Silbermann:Amgen: Consultancy; Celgene: Research Funding. Abonour:Celgene: Research Funding, Speakers Bureau.

Bortezomib in Combination with Pegylated Liposomal Doxorubicin and Thalidomide (VDT), An Effective Steroid Independent Regimen for Previously Untreated Multiple Myeloma Patients: Final Result of a Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 618-618
Author(s):  
Taimur Sher ◽  
Kena C Miller ◽  
Sikander Ailawadhi ◽  
Debbie Manfredi ◽  
Margaret Wood ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Pegylated Liposomal Doxorubicin ◽  
High Dose ◽  
Advisory Committees ◽  
Significant Toxicity ◽  
Grade 3

Abstract Abstract 618 Introduction: Steroids have been an important component of multiple myeloma (MM) therapeutics. High doses steroids as used in MM are associated with significant toxicity and morbidity. Development of steroid independent or steroid-lite regimens remains an important area of investigation in MM. Orlowski et al combined Doxil (D) with bortezomib (V) and showed enhanced anti-myeloma activity. In a phase II study in relapsed refractory MM patients, we observed further improvement in clinical efficacy with addition of thalidomide (T) to VD combination (VDT regimen). Encouraged by high response rates of this steroid sparing novel combination we investigated VDT regimen in treatment naïve MM patients. Final results of this phase II trial are reported here. Methods: Patients with previously untreated MM were eligible for this phase II trial. VDT regimen (V 1.3mg/m2 on days 1, 4,15,18; D 20mg/m2 on days 1,15 and T 200 mg daily continuously) given on a 4-week cycle for a maximum of 8 cycles. Acyclovir (400 mg BID) and weight adjusted low-dose warfarin (1 or 2mg for absolute body weight <70kg or ≥70kg, respectively) was given for prophylaxis of herpes zoster and deep vein thrombosis (DVT), respectively. Response was assessed using the modified Blade criteria. Results: Forty patients (26 males, 14 females; median age 60.5, range 40-80 yrs) were enrolled on this study. Among these 58%(n=23) had stage III (Durie-Salmon) disease with a median b2 microglobulin of 3.7 (range 1.6-16.5 mg/L) and median LDH of 443 (range 152-129 IU/L). Thirty-nine patients are eligible for response evaluation (1 too early for assessment). Overall response rate (CR/nCR+PR) was 79.4% (n=31) with 38% (n=15) patients achieving CR/nCR. The median progression free (PFS) and overall survival (OS) has not been reached. At 1 year the PFS and OS is 81% and 97%, respectively (1 patient died from disease progression to leukemic phase). Toxicity: Neutropenia was the most significant hematological toxicity with grade 3 and 4 neutropenia observed in 22.5% and 2.5% of the patients, respectively. Only 1 (2.2%) patient had febrile neutropenia. Clinically significant neuropathy (grade ≥2) was seen in 20% while grade ≥2 palmer planter erythrodysesthesia was seen in 15% (n=6) of the patients. Other grade 3 non-hematological toxicities included pneumonia (20%), pleural effusion (10%), pulmonary embolism (2%), DVT (2%), congestive heart failure (5%) and interstitial pneumonitis (2%). Conclusion Although effective, steroid based treatment regimen can be associated with significant toxicity especially among patients with concurrent co morbid conditions such as hypertension and diabetes mellitus. Furthermore, recent investigations demonstrate that decreasing steroid doses may actually improve PFS and OS despite a comparatively low initial ORR. In this clinical trial we hypothesized that rational combination of novel myeloma agents may actually preclude the need to rely on high-dose steroids without significantly compromising ORR. Consistent with our expectations, the VDT regimen has ORR comparable to some of the steroid-inclusive triple drug combinations. The toxicity profile of this combination was acceptable and the regimen was well tolerated. Thus we note that VDT is an effective and well tolerated steroid-independent induction regimen for MM patients. Disclosures: Off Label Use: A Phase II study of a novel combination in newly diagnosed myeloma patients. Miller:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Centocor Ortho Biotech: Research Funding. Sood:Celgene: Stock. Chanan-Khan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Randomized phase II trial of the nucleolin targeting aptamer AS1411 combined with high-dose cytarabine in relapsed/refractory acute myeloid leukemia (AML)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7019-7019 ◽  
Author(s):  
R. K. Stuart ◽  
K. Stockerl-Goldstein ◽  
M. Cooper ◽  
M. Devetten ◽  
R. Herzig ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Synergistic Effects ◽  
Response Rates ◽  
High Dose ◽  
Open Label ◽  
Randomized Phase Ii ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
And Control

7019 Background: Aptamers are small synthetic oligonucleotides that form stable nuclease-resistant 3D structures and bind target proteins with specificity and affinity similar to antibodies. These “chemical antibodies” represent a new class of therapeutics. The AS1411 aptamer binds nucleolin on the surface of cancer cells and induces apoptosis. AS1411 has synergistic effects in combination with cytarabine on AML cell lines in vitro and in vivo. A phase I trial of AS1411 monotherapy in 30 patients with advanced cancer showed objective responses without serious toxicities. Methods: This open-label randomized phase II trial compared AS1411 plus high-dose cytarabine (HiDAC) with HiDAC alone in patients with primary refractory or relapsed AML who had received up to 3 previous lines of chemotherapy. Patients in cohort I were randomized 2:1 to receive AS1411 10 mg/kg/day as continuous IVI on days 1–7 + HiDAC 1.5 g/m2/ twice daily on days 4–7 or HiDAC alone for 4 days. Following safety assessment, a second cohort was randomized in a similar manner, with AS1411 escalated to 40 mg/kg/day. Objectives were comparison of response rates (CR+CRp), safety and tolerability between treatment groups. Results: Accrual has been completed, with 71 patients randomized: 22 to AS1411 10 mg/kg/day + HiDAC (AS1411–10), 26 to AS1411 40 mg/kg/day + HiDAC (AS1411–40) and 23 to HiDAC alone (control). Safety findings are currently available for 44 patients (AS1411–10, 21; AS1411–40, 9; control, 14). The main grade 3/4 toxicities were hematologic, notably febrile neutropenia, neutropenia, and thrombocytopenia; and infections. Safety findings were similar across groups, except that grade 3 hypokalemia was more frequent with AS1411–40. Deaths within 28 days of treatment were: AS1411–10, 1/21; AS1411–40, 1/9; and control, 2/14. Response data are currently available for 39 patients; response rates were: AS1411–10, 16% (3/19); AS1411–40, 14% (1/7); and control, 0% (0/13). Conclusions: Data from this first phase II trial of an aptamer in oncology are encouraging. The combination of AS1411 at 10 or 40 mg/kg/day with HiDAC appears well tolerated and shows promising signs of activity in patients with relapsed/refractory AML. [Table: see text]

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