scholarly journals A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4774-4774
Author(s):  
James R. Berenson ◽  
Laura V. Stampleman ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
Leonard M Klein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

a Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5383-5383 ◽  
Author(s):  
James Berenson ◽  
Laura Stampleman ◽  
Alberto Bessudo ◽  
Peter J Rosen ◽  
Leonard M. Klein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Safety And Efficacy ◽  
Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who previously received POM treatment were ineligible. POM was administered orally on days 1-21 of a 28-day cycle, while DEX (40 mg) and PLD (5mg/m2) were both infused on days 1, 4, 8, and 11. During phase 1 enrollment, three cohorts were enrolled at 2, 3 and 4 mg doses of POM, and DEX and PLD were both administered at fixed doses. Phase 2 enrollment commenced once the MTD was established from the phase 1 portion of the study. Results As of August 1, 2015, 70 pts were screened, 68 were enrolled in the trial (with the pre-planned enrollment goal reached) and had received study drug, and a total of 50 pts were evaluable for safety and efficacy. Among all enrolled pts, 60pts discontinued treatment and 8 remain active. Pts had received a median of 4 prior treatments (range 1-18). Median number of cycles for all pts was 4 (range 1-8), with a median follow-up time of 5.5 months (range 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 57 pts enrolled in phase 2, 53% percent were refractory to LEN and steroids with or without other agents and 31% had previously received PLD. A median of 4 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Fifty-five pts were evaluable for response as 2 pts are active but have not yet had any post-baseline disease assessment. Among all evaluable pts (n=55) enrolled in phase 2, the overall response rate (ORR) was 33% (CR= 5%, VGPR= 5% and PR=23%) and clinical benefit rate (CBR) was 47% with 11 pts (26%) showing stable disease and 5 pts (12%) demonstrating progressive disease. For all evaluable pts enrolled in phase 2, the median follow-up time was 3.6 months (range 0-12 months) and the median PFS was 4.2 months (range 0.3- 29.0+). ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (36% and 51%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (49 pts; 72.0%), lymphopenia (36 pts; 52.9%), leukopenia (33 pts; 48.5%), hyponatremia (27 pts; 39.7%), and hypokalemia (26pts; 38.2%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures No relevant conflicts of interest to declare.

Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin For Patients With Relapsed/Refractory Multiple Myeloma: Results From a Phase 1/2 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3218-3218 ◽  
Author(s):  
James R. Berenson ◽  
James D. Hilger ◽  
Leonard Klein ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Effective Treatment Option ◽  
Recent Trial

Abstract Background Thalidomide and its immunomodulatory drug (IMiD) derivatives such as lenalidomide (LEN) have shown great promise as treatment options for multiple myeloma (MM) patients (pts). Pomalidomide (POM) is a newer IMiD with high in vitro anti-MM potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM pts. Recent data has shown POM to be effective in combination with dexamethasone (DEX), even for patients who are refractory to bortezomib and lenalidomide (Richardson et al, 2012). It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM pts (Offidani et al, 2006; 2007). Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). These results imply that the combination of POM, DEX and PLD may be an effective regimen for treating R/R MM pts. We conducted a phase 1/2 trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using our modified dose, schedule, and longer 28-day cycle for pts with R/R MM. Methods For enrollment into the phase 1 portion of the study, eligible pts had to show progressive MM at the time of enrollment. For participation in the phase 2 portion, pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving this IMiD or relapsed within 8 weeks of their last dose. Pts who received previous POM treatment were ineligible. During the phase 1 part of the trial, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX (40 mg intravenously over 30 min) and PLD (5 mg/m2infused over 30-90 min) both were given on days 1, 4, 8, and 11 of each cycle. POM doses were escalated per cohort until maximum tolerated dose (MTD) was reached. Phase 2 patients were all enrolled at what was established as the MTD. Results As of July 9, 2013, 33 pts were registered: 11 and 22 enrolled in the phase 1 and 2 portions, respectively. Fifteen patients have discontinued treatment thus far and 18 remain active. Pts had received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimen (range, 0-2) and 1 prior IMiD regimen (range, 0-4). Pts have completed a median of 4 cycles (range: 0-8) with a median of 3.2 months of follow up (range: 0-9.7). During the phase 1 portion, no dose-limiting toxicities were identified, so the highest administered dose of 4 mg was initially established as the MTD. However, neutropenia ≥ G3 was observed in 10/17 phase 2 pts (58.8%) at this dose; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all phase 2 pts beyond the 29thpt (n = 4). Thirty-two pts have received study drug. Twenty-nine pts were evaluable for response at data cutoff as 3 were active but had not yet had any post-baseline disease assessments. Of the 29 considered evaluable, overall response rate and clinical benefit rates were 34.5% and 48.3%, respectively, Six pts (20.7%) showed stable disease while 8 (27.6%) pts exhibited progressive disease. There was ≥ grade 3 (G3) neutropenia in 12 (37.5%) pts. Two pts experienced this toxicity during the phase 1 portion (3 mg and 4 mg doses- 1 each) whereas the other 10 pts experienced this side effect at the 4 mg dose during phase 2 enrollment. Following the lowering of the MTD to 3 mg due to this issue, neutropenia (≥ G3) has not been observed to date. Other treatment-emergent AEs ≥ G3 occurring in more than 1 pt were leukopenia in 12 (37.5%), lymphopenia in 8 (25%), anemia in 3 (9.4%), hyponatremia in 3 (9.4%), thrombocytopenia in 2 (6.3%), and duodenal ulcers in 1 (3.4%) pts. One pt died during treatment due to sepsis. Conclusions Results from this phase 1/2 trial demonstrate that the combination of pomalidomide with dexamethasone and PLD using a 28-day cycle shows efficacy for MM pts with progressive disease who are refractory to lenalidomide. Notably, less neutropenia has been observed at the 3 mg dose of pomalidomide, with 4 mg POM dosing associated with a high incidence of ≥ G3 neutropenia when used in this three-drug combination. Disclosures: Berenson: Celgene: Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vescio:Celgene: Speakers Bureau.

Extended follow-up of outcome measures and analysis of prognostic factors in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7617-7617 ◽  
Author(s):  
S. E. Biehn ◽  
D. T. Moore ◽  
P. M. Voorhees ◽  
R. A. Garcia ◽  
M. J. Lehman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Liposomal Doxorubicin ◽  
Cox Regression ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Rank Test ◽  
Significant Activity ◽  
Prior Therapy

7617 Background: Preclinical studies of bortezomib (bort) with pegylated liposomal doxorubicin (PLD) showed enhanced anti-tumor efficacy compared with either single agent. This led to a phase I trial in patients (pts) with advanced hematologic malignancies who received bort on days 1, 4, 8 and 11 at 0.9–1.5 mg/m2, and PLD on day 4 at 30 mg/m2, every three weeks (Blood 105:3058, 2005). Significant activity was seen, with 36% of relapsed/refractory multiple myeloma (MM) pts achieving a complete or near-complete response, while 73% attained at least a partial response. It was therefore of interest to define time to progression (TTP) and overall survival (OS) with this regimen. Methods: Additional follow-up was obtained on all 22 evaluable MM pts. TTP and OS were determined from day 1 of bort/PLD, and the Kaplan-Meier method was used to calculate time-to-event estimators. The log-rank test was used to compare TTP and time to retreatment (TTR) on bort/PLD vs. the prior therapy. Cox regression was used to evaluate covariates for association with TTP and OS. Results: Median TTP with bort/PLD was 9.3 months (mos)(95% confidence interval (CI) 8.3–22.4) versus 3.8 mos (95% CI 2.3–10.0) on the pt’s prior therapy (p=0.04). Similarly, the median TTR after bort/PLD was prolonged (p=0.04) compared with TTR after the prior regimen, with 3 pts having not yet received their next therapy. With a median follow-up of 36 mos, 13 of these patients (59%) remain alive, and the median OS has not yet been reached. Karnofsky performance status was significantly associated with TTP (p=0.02), while the hematocrit (hct; p=0.06) and IgA subtype (p=0.08) had borderline significance. Hct was significantly associated with OS (p=0.03), while the number of prior regimens (p=0.07) and the platelet count (p=0.06) had borderline significance. Conclusions: Bort alone induced a median TTP of 6.6 mos and OS of 16 mos in MM (N Engl J Med 348: 2609, 2003). The current results support the possibility that the bort/PLD regimen may improve upon TTP, and especially OS, compared with bort alone. This hypothesis is being studied in a randomized, international phase 3 trial ( NCT00103506 ) comparing bort and bort/PLD. No significant financial relationships to disclose.

A Phase 1/2 Study of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2979-2979 ◽  
Author(s):  
James R. Berenson ◽  
James D. Hilger ◽  
Leonard M. Klein ◽  
Shahrooz Eshaghian ◽  
Youram Nassir ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Effective Treatment ◽  
Treatment Option ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Study Drug ◽  
Great Promise ◽  
Effective Treatment Option ◽  
Minor Response

Abstract Abstract 2979 Background: Thalidomide and its immunomodulatory (IMiD) derivatives such as lenalidomide have shown great promise as a treatment option for multiple myeloma (MM) patients. Pomalidomide is a newer IMiD with high in vitro potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM patients. Recent data has shown pomalidomide to be effective in combination with dexamethasone, even for patients who are refractory to bortezomib and lenalidomide. It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM patients. Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the dose and schedule of these drugs. These data imply that the combination of pomalidomide, dexamethasone, and PLD for R/R MM patients may be an effective regimen. We conducted a phase 1/2 trial investigating the safety and efficacy of pomalidomide in combination with IV dexamethasone and (PLD) using a modified dose and longer 28-day schedule for patients with R/R MM. The combination of PLD, dexamethasone and lenalidomide without bortezomib has not been previously evaluated. Methods: For enrollment into the phase 1 dose-escalation portion of the study, eligible pts had to have progressive MM at the time of enrollment that has relapsed following stabilization to at least one anti-myeloma regimen or is refractory defined as progressed while receiving anti-myeloma treatment. For enrollment into the planned phase 2 portion of the study, eligible pts have to be refractory to lenalidomide (singe-agent or in combination) demonstrated by progressive disease while receiving lenalidomide or relapse within 8 weeks of the last dose of lenalidomide. Patients who have received previous pomalidomide treatment were not eligible. Patients must not have received chemotherapy, corticosteroids, immunotherapy, antibody therapy, or treatment with thalidomide, lenalidomide, or bortezomib within 3 weeks of receiving study drug, nor extensive radiation therapy within 4 weeks of receiving study drug. During the phase 1 part of the trial, pomalidomide was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 patients each on days 1–21 of each 28-day cycle. Dexamethasone was administered intravenously at 40 mg over 30 min on days 1, 4, 8, and 11 of each cycle. PLD was administered at 5 mg/m2 as an IV infusion over 30–90 min on days 1, 4, 8, and 11 of each cycle. Pomalidomide doses were escalated until maximum tolerated dose (MTD) was reached. Once MTD was reached, all subsequent patients will be enrolled at that dose. Results: Ten of 40 planned patients have been enrolled to date, all during the phase 1 portion of the trial. Pts received a median of 4 prior treatments (range, 1–8) with a median of 1 prior PLD regimens (range, 0–1). Pts have completed a median of 1 cycle (range: 0–12) with a median of 1.2 months of follow up (range: 0.2–3.6). To date, the trial has enrolled all three cohorts in phase 1 (1 patient in cohort 1 chose to withdraw during Cycle 1 and was replaced). MTD has not yet been reached with no dose limiting toxicities (DLTs) in the first 2 cohorts. The 3 patients in cohort 3 are currently in Cycle 1. Seven patients are currently evaluable for efficacy and the 3 patients in cohort 3 have not yet had response assessment. Best response for evaluable patients is as follows: 3 patients have shown partial response, 2 patients have shown minor response, 1 is exhibiting stable disease (SD) but shows a decreasing monoclonal protein, and 1 has progressed. The incidence of reported adverse events (AEs) so far is low. Only 1 grade 3 or 4 (G3, G4) AE has been observed. The most common AEs were lymphopenia, which occurred in 6 pts (G1: 3; G2: 2; G3: 1), elevated urea nitrogen occurred in 4 pts (all G1), neutropenia occurred in 4 pts (all G1), and leukopenia occurred in 4 pts (all G1). Conclusions: The combination of pomalidomide with dexamethasone and PLD on a 28-day cycle may be an effective treatment option with acceptable tolerability for relapsed/refractory MM patients. Disclosures: Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Oral Clofarabine for Relapsed/Refractory Non-Hodgkin Lymphomas: Final Results from a Phase 1-2 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4423-4423
Author(s):  
Jeremy S. Abramson ◽  
Eric D. Jacobsen ◽  
Robert Allyn Redd ◽  
Tak Takvorian ◽  
David C. Fisher ◽  
...  
Keyword(s):  
T Cell ◽  
Progressive Disease ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Median Number ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Grade 3

Abstract Background: Clofarabine is a second-generation purine analogue FDA-approved as an intravenous formulation for relapsed/refractory pediatric ALL. Purine analogues demonstrate significant clinical activity in non-Hodgkin lymphomas (NHL). Clofarabine may offer pharmacologic advantages over other nucleoside analogues including being a more efficient substrate for deoxycytidine kinase, more completely inhibiting ribonucleotide reductase and DNA polymerase α, and demonstrating improved activity in cells that are non-dividing or have a low proliferation rate. This phase 1-2 trial studied an oral formulation of clofarabine in relapsed or refractory NHL. Methods: Patients were eligible if they had relapsed or refractory NHL of any histologic subtype. All pts were required to have adequate organ function and performance status ≤2 as well as absence of CNS involvement. Patients were treated at 4 dose levels (1mg, 2mg, 4mg and ultimately 3mg) with oral clofarabine administered once daily on days 1-21 of a 28 day cycle for up to 6 cycles. Three to 6 pts were treated at each dose level in a traditional 3+3 design followed by a 10 patient dose expansion at the recommended phase 2 dose (RP2D). The phase 1 portion of this study has been published (Leuk Lymph 2013; 45:1915-1920). Phase 2 was designed to enroll 24 additional subjects. The primary endpoint in phase 2 was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A total of 50 patients were accrued on the phase 1-2 trial; 31 subjects were treated in phase 1 and 19 in phase 2. Phase 2 accrual was stopped prematurely due to discontinuation of the drug formulation used in the study. All patients treated at the RP2D (n=36) are included in the phase 2 efficacy analysis since there were no differences in treatment or follow-up for these patients. Results: The median age for all patients was 69 years (range 45-92). Eighty-two percent had advanced stage at study entry. The median number of prior regimens was 2 (range 1-7) and 4 patients had prior auto stem cell transplant. Histologies included follicular lymphoma (FL, 13 pts), small lymphocytic lymphoma (SLL, 8 pts), diffuse large B-cell lymphoma (DLBCL, 6 pts), marginal zone lymphoma (MZL, 11 pts), mantle cell lymphoma (MCL, 9 pts), T-cell lymphoma (TCL, 2 pts) and lymphoplasmacytic lymphoma (LPL 1 pt). The 3mg dose was declared the RP2D, as previously reported. The most common toxicities were anemia (78%), leukopenia (66%), neutropenia (64%), thrombocytopenia (62%) and fatigue (60%). Twenty-nine patients (58%) experienced at least one grade 3-4 toxicity. The most common grade 3-4 toxicities were leukopenia and neutropenia (48%), thrombocytopenia (30%), anemia (14%) and fatigue (6%). There were 2 deaths on study, both considered unrelated to study drug (cardiac arrest, progressive disease). The median number of cycles administered was 4, and 18 patients (36%) completed all 6 cycles of therapy. The most common reasons for discontinuing therapy were progressive disease (34%) and toxicity (16%). Of 50 patients on study, the ORR was 28% (95% CI: 16 - 42%) with complete response rate (CRR) of 10% (95% CI: 3 - 22%). An additional 36% had stable disease (SD). By histology, responses were seen in 5/11 MZL, 4/9 MCL, 3/8 SLL, 3/13 FL, and 1/1 LPL. No responses were observed in DLBCL or TCL, although an angioimmunoblastic T-cell lymphoma patient had SD with a 42% reduction in tumor volume, and a mycosis fungoides patient had significant reduction in cutaneous disease burden. Among 36 patients treated at the RP2D and included in the phase 2 analysis, the ORR was 28% (95% CI: 14 - 45%) with CRR of 8% (95% CI: 2 - 22%), and 44% of patients with SD. A higher proportion of patients treated at a non-RP2D experienced progressive disease on study (43% vs. 28% in the RP2D cohort). The median PFS was 5.5 months, and the one- and two- year PFS were 32% (95% CI: 20%, 45%) and 16% (95% CI: 7.5%, 27%), respectively. The median duration of follow-up was 3.8 years, with 26 patients alive and 22 deceased at last follow-up; two patients were lost to follow-up. The median OS was not reached, and the 3 year OS was 58% (95% CI: 43%, 71%). Conclusion: Oral clofarabine is generally well tolerated and produces disease control in a substantial proportion of patients with relapsed/refractory NHL, particularly in indolent histologies and MCL. Disclosures Abramson: Sanofi: Consultancy. Off Label Use: Clofarabine is not FDA-approved for non-Hodgkin lymphoma. Brown:Sanofi: Consultancy.

scholarly journals A Phase I Study of Carfilzomib and Pegylated Liposomal Doxorubicin for Relapsed or Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4731-4731
Author(s):  
Jesse Keller ◽  
Mark A Fiala ◽  
Jeevan Sekhar ◽  
Connie Ceriotti ◽  
Melissa Allen ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Dose Level ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Median Number ◽  
Grade 3 ◽  
Abstract Submission

Abstract Background: Despite improvements in overall survival (OS) and progression free survival (PFS), the prognosis of patients with relapsed/refractory multiple myeloma (RRMM) remains poor. Carfilzomib (CFZ), a second generation proteasome inhibitor, is active as a single-agent or in combination with lenalidomide and/or dexamethasone (DEX) in RRMM. Pegylated liposomal doxorubicin (PLD) combined with bortezomib has been shown to prolong PFS and OS and is FDA approved as combination therapy in MM. We investigated the combination of CFZ with PLD in RRMM in a Phase I study. Objective: To determine the maximum tolerated dose (MTD) of CFZ combined with PLD. Patient/Methods: Patients with RRMM after ≥ 1 lines of therapy, with measureable disease, and good performance status, organ function and hematological reserve were eligible. Prior CFZ or PLD/doxorubicin exposure was not exclusionary. CFZ was given on days 1, 2, 8, 9, 15 and 16 at escalating doses of 27-56mg/m2 and PLD was given on day 8 in 28 day cycles at a dose of 30mg/m2. All dose levels included a lead-in dose of 20mg/m2 of CFZ on days 1 and 2 of cycle 1. Following 6 cycles of combination therapy, PLD was discontinued and patients were treated with maintenance CFZ (once weekly). Dose escalation was performed using a 3+3 design; MTD was defined as the highest dose level where dose limiting toxicity (DLT) occurred in less than 2 of 6 patients. Disease response was determined using International Myeloma Working Group (IMWG) criteria. Results: 16 patients were enrolled from May 2012-March 2014. Median age was 66 years (range 53-79) and 11 were female. Seven patients were ISS stage 3, 9 were stage 1. 3 patients had > 50% plasma cells present on bone marrow aspirate, 8 had < 20%. By mSMART criteria, 2 patients were high-risk, 2 were intermediate-risk, and 12 were standard-risk. Most patients were IgG Kappa subtype (12); while 3 patients had Kappa light chain subtype, and 1 had IgG Lambda subtype. Median number of prior therapies was 3 (range 1-12). Median time from diagnosis to start of protocol was 42 months (range 9-236). 100% had prior exposure to lenalidomide; 87.5% had prior exposure to bortezomib; 75% had undergone autologous transplantation; 6% had prior PLD or doxorubicin exposure; and 6% had prior CFZ exposure. No DLTs were observed in any cohort. Two patients were unable to complete the first cycle of treatment due to early progressive disease, and were replaced. Grade 3/4 non-hematologic adverse events were rare, but included: UTIs (3), sepsis (2), pneumonitis (2), dyspnea (2), syncope (1), pleural effusion (1). Grade 3/4 hematologic AEs were limited to: anemia (7), thrombocytopenia (4), neutropenia (5), lymphopenia (4), and hemolysis (2). Most of the neutropenia (60%) and thrombocytopenia (75%) occurred in the 56mg/m2 cohort. The median number of cycles completed was 3.5 (range <1-13). Disease progression caused discontinuation in 10 patients. Adverse events were the reason for 2; one patient had dyspnea after 2 cycles, one patient had hand-foot syndrome after 3 cycles. Four patients were on treatment at time of submission. 56% of patients had a partial response or better, including 80% treated at the maximum dose level. The median duration of response was 6.9 months. Individual patient responses are summarized in Table 1. Conclusion: Co-administration of CFZ and PLD is well tolerated and an MTD was not reached despite utilizing the approved single agent doses. Recommended dosage for further studies is: CFZ 56mg/m2 and PLD 30mg/m2. Subsequent phase I dose escalation of a 3 drug regimen CDD (CFZ-PLD-DEX) is ongoing at abstract submission and will be reported at the meeting. Table 1 ID Dose Level (CFZ;PLD) # of Prior Lines of Therapy Prior ASCT # of Cycles Best Response$ PFS (months) 1 1 (27mg/m2;30mg/m2) 3 Y 7 PR 6.2 2 1 (27mg/m2;30mg/m2) 7 N 7 SD 6.7 3 1 (27mg/m2;30mg/m2) 3 N 3 SD 1.8 4 2 (36mg/m2;30mg/m2) 4 Y 8 PR 6.9 5 2 (36mg/m2;30mg/m2) 12 Y <1 PD 0.8 6 2 (36mg/m2;30mg/m2) 3 Y 3 SD 2.1 7 2 (36mg/m2;30mg/m2) 1 N 2 PR 3.7 8 3 (45mg/m2;30mg/m2) 3 Y 3 SD 1.9 9 3 (45mg/m2;30mg/m2) 5 N <1 PD 0.2 10 3 (45mg/m2;30mg/m2) 1 Y 3 VGPR 3.4 11 3 (45mg/m2;30mg/m2) 1 Y 13* PR 12.8* 12 4 (56mg/m2;30mg/m2) 2 Y 4 PR 3.5 13 4 (56mg/m2;30mg/m2) 8 Y 11* VGPR 10.5* 14 4 (56mg/m2;30mg/m2) 1 Y 8* VGPR 8.4* 15 4 (56mg/m2;30mg/m2) 5 Y 2 PD 1 16 4 (56mg/m2;30mg/m2) 2 Y 5* PR 4.5* * Ongoing at abstract submission $ PR: partial response, SD: stable disease; VGPR: very good partial response; PD: progressive disease Disclosures Stockerl-Goldstein: Onyx: Speakers Bureau.

Final results from the phase Ib/II study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in patients with relapsed or progressive multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8529-8529 ◽  
Author(s):  
Michael Wang ◽  
Thomas Martin ◽  
William Bensinger ◽  
Melissa Alsina ◽  
David Samuel DiCapua Siegel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
The Us ◽  
Duration Of Response ◽  
Grade 3

8529 Background: Carfilzomib (CFZ) is approved in the US as single-agent treatment for patients with multiple myeloma (MM) who have progressed after bortezomib (BTZ) and an IMiD and are refractory to last line of treatment. We previously reported interim data from PX-171-006 (NCT00603447), a Ph 1b/2 study of CRd in relapsed or progressive MM (Wang et al. ASCO 2011). Herein we report final results. Methods: Patients (1–3 prior treatments) received CRd in 28-day (D) cycles—CFZ IV on D1, 2, 8, 9, 15, 16, lenalidomide (LEN) PO D1–21, and dexamethasone (dex) wkly. In phase 1, CFZ (15–27 mg/m2) and LEN (10–25 mg) doses were escalated to determine the maximum tolerated dose (MTD) with a maximum planned dose (MPD) of CFZ 20 mg/m2 D1, 2 of Cycle 1 and 27 mg/m2 thereafter, LEN 25 mg/d, and dex 40 mg/wk, followed by phase 2 expansion at MTD/MPD. Endpoints included IMWG overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled since June 2008. Overall, prior treatment included BTZ (77%/18% refractory) and LEN (70%/35% refractory); 20% had high-risk cytogenetics/FISH. MTD was not reached in Ph 1, supporting expansion at the MPD (n=52, 23% BTZ refractory and 42% LEN refractory). As of Nov 2012 (median follow-up 24.4 mo): ORR was 69% overall and 76.9% at MPD with very good partial response in 36.9% and 38.5% and stringent complete response in 3.6% and 3.8%, respectively; median DOR was 18.8 (95% CI 9.7–41.5) and 22.1 mo (95% CI 9.5–NE) respectively; median PFS was 11.8 (95% CI 7.6–20.7) and 15.4 mo (95% CI 7.9–NE), respectively. Seven responders at MPD pursued other therapy and were censored for PFS.A median of 8.5 (range 1−46) CFZ cycles were started; 4% required CFZ dose reductions; 15% discontinued CFZ due to adverse events (AEs). Grade 3/4 AEs were generally consistent with earlier studies in advanced MM that used similar doses of single-agent CFZ; grade 3/4 peripheral neuropathy was 1%. Conclusions: CRd was well tolerated, providing robust and durable responses in this pt population where 35% were LEN refractory. This combination is being further evaluated in several ongoing phase 2/3 trials. Clinical trial information: NCT00603447.

Relapsed Multiple Myeloma

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 303-309 ◽  
Author(s):  
Sagar Lonial
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Phase 1 ◽  
Treatment Options ◽  
Single Agent ◽  
Great Promise ◽  
New Agents ◽  
Ongoing Work ◽  
The Many

Abstract Advances in treatment options for patients with multiple myeloma have made a significant impact on the overall survival of patients and have helped achieve levels of response and duration of remission previously not achievable with standard chemotherapy-based approaches. These improvements are due, in large part, to the development of the novel agents thalidomide, bortezomib, and lenalidomide, each of which has substantial single-agent activity. In addition, a large number of second-generation agents are also in clinical development, such that the repertoire of available treatment options continues to expand. To better interpret clinical trials performed in the relapsed setting, it is important that definitions of relapse categories are used to help better pinpoint the specific benefit for a given therapy, especially in the combination therapy setting as it aids in determining if ongoing work should be continued or abandoned for a given new agent. Insights from preclinical modeling and in vitro work have identified several new combinations, new targets and second- or third-generation versions of existing targets that hold great promise in the setting of relapsed myeloma. Combinations of thalidomide, bortezomib, and lenalidomide with conventional agents or among each other have resulted in enhanced response rates and efficacy. Clinical trials of agents such as carfilzomib, pomalidomide, vorinostat, panobinostat, and elotuzomab are just a few of the many exciting new compounds that are being tested in phase 1 and phase 2 clinical trials for relapsed patients. Further clinical and translational testing are critical to better understanding how best to combine these new agents, as well as identifying patient populations that may best benefit from treatment with these developing new agents.

A Phase II Trial of Doxil, Vincristine and Reduced Schedule Dexamethasone (DVd) for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2415-2415 ◽  
Author(s):  
Paul Masci ◽  
Mary A. Karam ◽  
Luba Platt ◽  
Steven Andresen ◽  
Alan Lichtin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Liposomal Doxorubicin ◽  
Phase Ii Trial ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Response Rates ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Grade 3

Abstract Patients with newly diagnosed multiple myeloma (MM) typically have responses to initial cytotoxic or steroid based therapy. Disease relapse occurs in all patients. As high as 90% of patients with relapsed or refractory disease will have over-expression of the multi-drug resistance (MDR) gene. Pharmacokinetic data suggest that prolonged exposure to high concentrations of doxorubicin can overcome MDR. Pegylated liposomal doxorubicin can theoretically achieve this goal as the angiogenic activity of the MM bone marrow is significantly increased. We proceeded with a phase II trial to evaluate the response rate of patients with relapsed or refractory MM (R/R-MM) to the DVd regimen. Eligible patients had clinically active R/R-MM following at least one prior cytotoxic based treatment regimen. Patients received intravenous (IV) pegylated liposomal doxorubicin 40 mg/m2 day 1, vincristine 2 mg day 1 and oral or IV dexamethasone 40 mg daily days 1–4. Cycles were repeated every 28 days for a minimum of 6 cycles and 2 cycles after best response. Myeloma parameters were measured at the start of each cycle. SWOG criteria were used to determine response. Thirty-five patients (21 male and 14 female) with R/R-MM clinically active disease were enrolled. Median age was 59 years (range 43–87). Patients received a median of 2 (range 1–4) prior cytotoxic based treatments. All patients received at least one cycle of treatment (median=5; range 1–12) and were evaluable for response. Ten (29%) patients responded to therapy; 5 partial responses (PR &gt; 50%) and 5 responses (R &gt; 75%) were observed after a median of 2 cycles (range 1–9). Median progression free survival of responding patients (PR + R) was 4.5 mos. (range 0.67–44.8). Patients achieving R had a median progression free survival of 32.5 mos. (3.0–44.8). Thirteen (37%) patients had stable disease (SD) for a median of 1.4 mos. (range 0.8–9.9). Twelve (34%) patients had progressive disease after a median of 1 cycle (range 1–5). The most common toxicities were hematologic; there were four occurrences of febrile neutropenia. Three patients experienced grade 3 constipation and one grade 3 palmar-plantar erythrodysethesia was observed. This study suggests that in patients with R/R-MM, DVd alone yields response rates similar to bortezomib with patients achieving an R experiencing a durable plateau phase. Ongoing studies of DVd in combination with thalidomide or CC-5013 in patients with R/R-MM have resulted in higher and better quality response rates (comparable to autologous SCT) translating to a durable progression free survival. We would not recommend the DVd regimen in patients with R/R-MM without the addition of an immune modulator such as thalidomide.

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