A Phase I/II Trial Evaluating the Combination of Arsenic Trioxide, Bortezomib and Ascorbic Acid for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2565-2565 ◽  
Author(s):  
James Berenson ◽  
Jeff Matous ◽  
Delina Ferretti ◽  
Regina Swift ◽  
Russell Mapes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Phase I ◽  
Arsenic Trioxide ◽  
In Vivo Studies ◽  
Current Phase ◽  
Refractory Multiple Myeloma ◽  
Early Results ◽  
Dose Levels

Abstract Background: Both arsenic trioxide and bortezomib as single agents have shown efficacy for patients with relapsed/refractory multiple myeloma (MM). Recently, we have demonstrated synergistic anti-MM effects when these two agents are combined to treat human MM in SCID mice and evaluated in in vitro studies. In addition, we and others have also shown that the addition of ascorbic acid (AA) sensitizes MM cells to the cytotoxic effects of arsenic trioxide both through in vitro and in vivo studies. Thus, the objective of the current Phase I clinical trial was to assess the safety and tolerability of bortezomib + arsenic trioxide + AA treatment for patients with refractory/relapsed MM. Methods: A treatment cycle comprised of intravenous injections of arsenic trioxide, bortezomib and AA on days 1, 4, 8, and 11 followed by a 10-day rest period every three weeks. Bortezomib was given at one of three dose levels (0.7, 1.0, or 1.3 mg/m2), followed by arsenic trioxide at one of two doses (0.125 or 0.25 mg/kg) intravenously followed by AA (1000 mg). Patients were treated for a maximum of eight cycles and were eligible for maintenance therapy with the same treatments given once every other week. Results: Eighteen patients have been enrolled to date, with three patients enrolled in each of the six cohorts. Patients had received a median of three prior therapies (range, 1–6), and five patients had received prior bortezomib therapy. Fifteen patients are evaluable for efficacy to date, and response data are summarized in Table 1. Overall, among the 15 evaluable patients, seven patients responded (2 PR, 5 MR), three patients showed stable disease, and five patients progressed. Among the six patients (in cohorts 1 and 4) enrolled at the lowest (0.7 mg/m2) bortezomib dose level, only one achieved a MR whereas among the nine evaluable patients enrolled at the higher (1.0 and 1.3 mg/m2) bortezomib dose levels six patients responded (2 PR, 4 MR). In general, the regimen was well tolerated. One patient in cohort 3 was removed from study during the first cycle because of the development of an asymptomatic arrhythmia which resolved spontaneously. Other serious adverse events included pneumonia in two patients, chest pain, and abdominal pain (one patient each). Conclusion: These early results from this Phase I/II study indicate that the combination of bortezomib, arsenic trioxide and ascorbic acid has efficacy and is well tolerated in a heavily pretreated population of patients with relapsed or refractory MM. Because of these encouraging clinical results, we plan to further evaluate this combination in a larger group of patients with relapsed/refractory myeloma. Table 1. Dose escalation scheme Cohorts Arsenic trioxide Bortezomib No. of evaluable pts Response *one patient in cohort 3 went off study during cycle 1 (see above), and the other two patients (one each in cohorts 3 and 6) are too early for response evaluation Cohort 1 0.125 mg/kg 0.7 mg/m2 3 1 MR, 2 PD Cohort 2 0.125 mg/kg 1.0 mg/m2 3 1 PR, 1 SD, 1 PD Cohort 3 0.125 mg/kg 1.3 mg/m2 1* 1 PR Cohort 4 0.25 mg/kg 0.7 mg/m2 3 1 SD, 2 PD Cohort 5 0.25 mg/kg 1.0 mg/m2 3 3 MR Cohort 6 0.25 mg/kg 1.3 mg/m2 2* 1 SD, 1 MR

A Multicenter Phase II Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2564-2564 ◽  
Author(s):  
James Berenson ◽  
Ralph Boccia ◽  
David Siegel ◽  
Marek Bozdech ◽  
Alberto Bessudo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Vitamin C ◽  
Arsenic Trioxide ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response ◽  
In Vivo Studies

Abstract Background: Despite the recent increase in treatment options for patients with multiple myeloma (MM), the disease remains largely incurable. Both arsenic trioxide (ATO) and melphalan have shown clinical activity in MM. Recent in vitro and in vivo studies in our laboratory have shown that arsenic trioxide sensitizes chemoresistant MM cells to melphalan-induced cytotoxicity; the addition of ascorbic acid (AA) further improves this effect. We conducted a multi-center clinical trial to evaluate the safety and efficacy of this steroid-free combination, melphalan, ATO and vitamin C (MAC), for patients with relapsed/refractory MM. Methods: MM pts who relapsed after responding to 1st-line therapy and/or were refractory to prior treatment were enrolled. During week 1 of each 6-week cycle, pts received ATO, 0.25 mg/kg IV, followed by ascorbic acid (AA), 1 g IV, days 1–4. ATO followed by AA was given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) was administered orally for the first 4 days of each cycle. Pts received a maximum of 6 cycles followed by weekly maintenance treatment with ATO and AA. The primary objectives of this study were to determine response rate and safety and tolerability of MAC therapy. Results: 65 patients have been enrolled and 51 are currently evaluable for response. 26 (1 CR, 10 PR, 15 MR) of the 51 evaluable patients (51%) had an objective response and an additional 14 patients achieved stable disease, resulting in a total of 40 patients (78%) with disease control. Among patients with elevated serum creatinine levels at baseline, renal function improved for those with responsive or stable disease. 20 of the 26 responding patients had failed ≥ 2 prior therapies: 19 pts had received prior thalidomide or lenalidomide therapy and 8 pts had received prior bortezomib. The regimen was well-tolerated with few significant side effects reported. Mild cytopenias occurred infrequently and were reversible. Conclusions: The results from this large multi-center phase II trial show that the MAC regimen is active in a group of MM patients who had either relapsed or were refractory to standard and/or investigational MM treatments. The regimen was well-tolerated even in this heavily pre-treated patient population. These findings are consistent with preclinical studies that showed the efficacy of this combination from both in vitro and in vivo studies.

scholarly journals A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma

2007 ◽  
Vol 13 (6) ◽  
pp. 1762-1768 ◽  
Author(s):  
James R. Berenson ◽  
Jeffrey Matous ◽  
Regina A. Swift ◽  
Russell Mapes ◽  
Blake Morrison ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Combination Therapy ◽  
Phase I ◽  
Arsenic Trioxide ◽  
Refractory Multiple Myeloma

A Phase I/II Multicenter, Safety and Efficacy Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2398-2398 ◽  
Author(s):  
James R. Berenson
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Stable Disease ◽  
Low Dose ◽  
Objective Response ◽  
Multicenter Trial ◽  
In Vivo Studies

Abstract Background: An urgent need exists for new treatments to overcome chemoresistance in MM patients. Recent in vitro and In vivo studies in our laboratory show that arsenic trioxide (ATO) can sensitize chemoresistant MM cells to melphalan-induced cytotoxic effects. Pre-clinical studies also show the most profound anti-MM effects when ATO, ascorbic acid and melphalan are used in combination compared with the effects observed when the drugs are used alone or combinations of any two of these agents. Based on encouraging results from a pilot study1, a larger, multicenter trial was recently started. Methods: MM patients who showed relapse after responding to first-line chemotherapy and/or having proved to be refractory to chemotherapy are enrolled. Patients received a loading dose of ATO at 0.25 mg/kg IV followed by ascorbic acid 1 g IV days 1–4 of week 1 of each six-week cycle. ATO/ascorbic acid was given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) was administered orally for the first 4 days of each cycle. Patients received a maximum of 6 cycles followed by weekly maintenance treatment with weekly ATO followed by ascorbic acid. The primary objectives of this study are to determine response rate and safety and tolerability of MAC therapy. Results: Twenty patients have received at least one treatment cycle. Preliminary data show that eight (4 PR, 4 MR) of the 14 evaluable patients (57%) had an objective response, an additional three patients achieved stable disease, resulting in a total of 11 patients (79%) with disease control. Since responses were seen after 2 to 5 treatment cycles, it is possible that some patients with stable disease may experience additional disease response. Seven of the eight responding patients had failed two or more treatments: five patients had received prior thalidomide therapy, two had received melphalan and bortezomib, and two patients had undergone autologous peripheral stem cell transplantation. Of the six patients who have now completed the maximal numbers of cycles, four achieved PR, one MR, and one SD. The regimen was well tolerated with few significant side effects reported; mild cytopenias were reported as reversible. Conclusions: These preliminary results in this treatment group of heavily pre-treated MM patients who had either relapsed or were refractory to standard and/or investigational multiple myeloma treatments suggests that the MAC treatment regimen (1) shows efficacy using a low dose of melphalan supporting the preclinical evidence that ATO can sensitize tumors to chemotherapy; (2) is well tolerated; (3) may require multiple cycles before response.

A Phase I Study of Arsenic Trioxide (Trisenox), Ascorbic Acid, and Bortezomib (Velcade) Combination Therapy in Patients with Relapsed/Refractory Mulitple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5129-5129
Author(s):  
Lauren Held ◽  
Jon P. Gockerman ◽  
Louis F. Diehl ◽  
Carlos Manuel de Castro ◽  
Joseph O. Moore ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Phase I ◽  
Arsenic Trioxide ◽  
Patient Population ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Dependent Manner ◽  
Refractory Multiple Myeloma

Abstract Abstract 5129 Purpose: Bortezomib is a well recognized standard therapy, however it is not curative for multiple myeloma. New agents and approaches are needed to overcome resistance in multiple myeloma. Arsenic trioxde (ATO) induces apoptosis of plasma cells through a number of mechanisms, including down regulation of gene overexpression, activating cell cycle arrest by inducing p21 cyclin-dependent kinase inhibitor protein, and by triggering apoptosis through caspase-3 in a dose dependent manner. This phase I study assessed the feasibility and tolerability of concomitant administration of arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (VelcadeÔ) (AAV) in patients with relapsed/refractory multiple myeloma. Experimental Design: A standard dose of ATO (0.25 mg/kg IV infused over 1–2 hours) and AA (1g IV infused over 15 minutes after infusion of ATO) were given once weekly × 2 with an escalating dose of bortezomib (cohort 1: 1 mg/m2 or cohort 2: 1.3 mg/m2 IV bolus on days 1, 8) of a 21 day cycle). ATO was given at least 1 hour prior to bortezomib and patients were allowed up to a maximum of 6–8 cycles. Results: A total of ten patients (median age, 62 years old) were enrolled with a median follow up of survivors of 25 months. Patients had an average of 4 prior failed therapies. Seven (70%) patients were refractory to bortezomib when previously administered. Despite our patient population being heavily pre-treated, objective responses were observed, with one partial response (Cohort 2), two minimal response (Cohort 1 and 2), and one stable disease (Cohort 2). To date, three of the 10 patients are continuing maintenance therapy 13–43 months from initiating this study. Conclusion: Of the patients that completed the treatment, objective responses were observed despite suboptimal dosing and previous bortezomib treatment failure. Tolerability was observed in most patients as discontinuation was not due to treatment toxicities, but due to aggressiveness of disease. Further studies are warranted with a larger patient population to effectively determine the effectiveness of AAV in relapsed/refractory multiple myeloma. Disclosures: Rizzieri: Cephalon: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Long:Millennium: Speakers Bureau. Gasparetto:Millennium: Speakers Bureau.

Bortezomib in Combination with Melphalan in the Treatment of Relapsed or Refractory Multiple Myeloma: A Phase I/II Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 209-209 ◽  
Author(s):  
James Berenson ◽  
H. Yang ◽  
R. Swift ◽  
K. Sadler ◽  
R. Vescio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
De Novo ◽  
Optimal Dose ◽  
Fixed Dose ◽  
Full Potential ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma

Abstract Introduction: Bortezomib (VELCADE®) is a proteasome inhibitor that has demonstrated durable responses as monotherapy for the treatment of pts with relapsed and refractory multiple myeloma. In vitro, bortezomib has been shown to restore melphalan sensitivity to melphalan-resistant cell lines (U266-LR7) and to synergize with melphalan in killing myeloma cells, thereby allowing the use of lower concentrations of melphalan (Ma et al, Clin Cancer Res.2003;9:1136). The objective of this dose-escalation phase I/II study was to determine an optimal dose of combination bortezomib + melphalan, starting with doses below those usually recommended for each agent for pts with refractory or relapsed multiple myeloma. Dose limiting toxicities, safety, tolerability, and activity were assesed in a dose-escalation study. Methods : Bortezomib 0.7 mg/m2 was administered by IV push on days 1, 4, 8, and 11 in combination with oral melphalan (0.025, 0.05, 0.1, 0.15, 0.25 mg/kg) on days 1–4 every 4 weeks for up to 8 cycles to 3-pt cohorts with active progressive disease. In the absence of dose-limiting toxicity (DLT), bortezomib was increased to 1.0 mg/m2 and melphalan co-administered using the original 5 escalating doses to subsequent cohorts. Results : Twenty six pts (50% male, median age 55 years, range 33–90 years) have been accrued to the study. The myeloma subtypes include IgG (16/26), IgA (4/26), IgM (2/26) and light chain only (4/26). The median ß2 microglobulin level was 5.0 mg/L (range 2.2–14 mg/L). In this heavily pretreated population (range 2–7 prior therapies), 12 patients received prior melphalan, 12 prior thalidomide, 7 prior CC-5013, 13 prior VAD, 2 prior bortezomib, and 8 prior autologous stem cell transplantation. Dose escalation has proceeded into the bortezomib 1.0 mg/m2 + melphalan 0.10 mg/kg cohort. Toxicities have been manageable. One DLT, grade 4 anemia, was observed at bortezomib 1.0 mg/m2 + melphalan 0.025 mg/kg, requiring expansion of that specific cohort. Grade 3 events were predominantly associated with myelosuppression (anemia, neutropenia, and thrombocytopenia) and were observed only among pts with baseline cytopenia. Among the 12 pts with baseline peripheral neuropathy (PN), symptoms worsened transiently in 1 pt, resolved in 1 pt, and remained stable in the other pts. Treatment-related PN (grade 1) developed de novo in 2 pts. Responses were observed in 67% (16/24 evaluable) of pts: 1 CR, 1 near CR, 6 PR, and 8 MR. The CR and near CR occurred in pts receiving bortezomib 1.0 mg/m2 in combination with melphalan .025 mg/kg. PR or better was independent of prior type of therapy and was also observed among pts who had previously received melphalan or bortezomib. Median time to progression was 1-18 mo. Six active pts out of 26 total pts remain progression-free for 2-8+ mo. Conclusion : Combination bortezomib plus oral melphalan is a promising regimen for the treatment of relapsed, refractory myeloma. The responses that were observed in pts who had previously received either drug serve as preliminary confirmation of preclinical evidence that the combination of low-dose bortezomib and melphalan has the capacity for chemosensitization and suggest possible synergy. Dose escalation with melphalan plus a fixed dose of bortezomib 1.0 mg/m2 is continuing in order to explore the full potential of this combination.

Arsenic Trioxide Shows Synergistic Anti-Myeloma Effects When Combined with Bortezomib and Melphalan In Vitro and Helps Overcome Resistance of Multiple Myeloma Cells to These Treatments in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2467-2467
Author(s):  
Richard A. Campbell ◽  
Haiming Chen ◽  
Daocheng Zhu ◽  
Janice C. Santos ◽  
Benjamin Bonavida ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Cell Lines ◽  
Combined Therapy ◽  
In Vivo Studies ◽  
Low Doses ◽  
Drug Resistant ◽  
Early Results ◽  
Post Implantation

Abstract Arsenic trioxide (ATO) induces apoptosis of plasma cells through a number of mechanisms including inhibiting DNA binding by NF-κB. These results suggest that this agent may be synergistic when combined with other active anti-myeloma drugs. To evaluate this we examined the effect of ATO alone and in combination with anti-myeloma treatments evaluated in vitro with MTT assays and using our severe combined immunodeficient (SCID)-hu murine myeloma models. First, we determined the effects of combining ATO with bortezomib or melphalan on the myeloma cell lines RPMI8226 and U266. Cell proliferation assays demonstrated marked synergistic anti-proliferative effects of ATO at concentrations ranging from 5x10−5M – 5x10−9M and melphalan concentrations ranging from 3x10−5M – 3x10−9M. Similar effects were observed when these cell lines were treated with bortezomib and varying concentrations of ATO (5x10−5 M – 5x10−10 M). We also investigated the potential of ATO to increase the efficacy of anti-myeloma therapies in our SCID-hu murine model LAGλ–1 (Yang H et al. Blood 2002). Each SCID mouse was implanted with a 0.5 cm3 LAGλ–1 tumor fragment into the left hind limb muscle. Mice were treated with ATO alone at 6.0 mg/kg, 1.25 mg/kg, 0.25 mg/kg, and 0.05 mg/kg intraperitoneally (IP) daily x5/week starting 19 days post-implantation. Mice receiving the highest dose of ATO (6.0 mg/kg) showed marked inhibition of tumor growth and reduction of paraprotein levels while there was no effect observed in all other treatment groups. Next, 27 days following implantation of our LAGλ–1 intramuscular (IM) tumor, LAGλ–1 mice were treated with ATO (1.25 mg/kg) IP, bortezomib (0.25 mg/kg), or the combination of both drugs at these doses in the schedules outlined above. ATO or bortezomib treatment alone had no anti-myeloma effects at these low doses consistent with our previous results whereas there was a marked decrease in both tumor volume (57%) and paraprotein levels (53%) in mice receiving the combined therapy. The combination of melphalan and ATO was also evaluated in this model. LAGλ–1 bearing mice received therapy with melphalan IP x1/weekly at 12.0 mg/kg, 6.0 mg/kg, 0.6 mg/kg, and 0.06 mg/kg starting 22 days post-implantation and showed no anti-myeloma effects. Twenty-eight days following implantation of LAGλ–1 tumor, mice received ATO (1.25 mg/kg) or melphalan (0.6 mg/kg) alone at doses without anti-myeloma effects, or the combination of these agents at these doses. The animals treated with these drugs alone showed a similar growth and increase in paraprotein levels to control mice whereas the combination of ATO and melphalan at these low doses markedly suppressed the growth of the tumor by >50% and significantly reduced serum paraprotein levels. These in vitro and in vivo studies suggest that the addition of ATO to other anti-myeloma agents is likely to result in improved outcomes for patients with drug resistant myeloma. Based on these results, these combinations are now in clinical trials with promising early results for patients with drug resistant myeloma.

A Multicenter Phase I/II Trial Evaluating the Safety and Efficacy of Lenalidomide [Revlimidä (R), CC-5013] in Combination with Doxorubicin and Dexamethasone (RAD) in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5136-5136 ◽  
Author(s):  
C. Gerecke ◽  
S. Knop ◽  
M.S. Topp ◽  
S. Kotkiewitz ◽  
H. Gollasch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Fixed Dose ◽  
Severe Toxicity ◽  
Refractory Multiple Myeloma ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Level 2 ◽  
Dose Limiting Toxicity

Abstract Introdution: Lenalidomide (Revlimid™) is Celgene’s lead clinical compound in a new group of drugs called IMiDs, which have immunomodularory properties. The drug has been evaluated in phase-I, II, and III clinical trials for the treatment of multiple myeloma (MM). Lenalidomide shows substantial anti-tumor activity in patients with refractory or relapsed MM and significantly prolongs time to tumor progression (TTP) compared to standard therapy in these patients. Lenalidomide was well tolerated in these trials, the only dose limiting toxicity in a phase-I trial was myelosuppression. In order to further improve therapeutic efficacy and to overcome drug resistance we are currently evaluating Lenalidomide (Revlimid™) in combination with doxorubicin and dexamethasone (RAD) for the treatment of patients with refracrory or relapsed MM in a phase-I/II trial. Methods: Patients with relapsed or refractory multiple myeloma recieve a fixed dose of either 10 mg or 15 mg Revlimid Revlimid™ given daily for 21 days (d 1–21) in combination with doxorubicin (adriamycin) and dexamethasone, to be repeated on day 29. Three dose levels of doxorubicin (adramycin) are planned: 4 mg/m2 day 1–4, 6 mg/m2 day 1–4 and 9 mg/m2 day 1–4. 40 mg dexamethasone is given orally day 1–4 and day 17–20 at a fixed dose. 3– 6 cycles are applicated unless severe toxicity or disease progression occurs. Results: RAD treatment was well tolerated at dose level 1 and dose level 2. Therefore, current dose escalation is continued. All patients treated at the first two dose levels (6/6) responded to RAD treatment. Further updated results on this trial will be presented.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

A Phase I, Multi-Dose, Dose Escalation Study of SGN-40 (anti-huCD40 mAb) in Patients with Refractory or Recurrent Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2413-2413
Author(s):  
Mohamad A. Hussein ◽  
Ruben Niesvizky ◽  
Nikhil Munshi ◽  
James C. Berenson ◽  
Kenneth C. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Transmembrane Protein ◽  
M Protein ◽  
Type I ◽  
Antitumor Effects ◽  
Grade 3 ◽  
Dose Levels

Abstract CD40 is a type I transmembrane protein that upon binding to CD40 ligand regulates important biologic effects in the immune system. CD40 is also highly expressed on hematologic tumors, which has raised interest in the potential for its use as a tumor target for antibody-based cancer therapy. SGN-40 is a humanized monoclonal antibody that selectively binds to human CD40 and induces apoptosis and growth inhibition of a wide variety of B-cell derived cancer cell lines in vitro. Our preclinical work has confirmed the in vitro cytotoxicity of SGN-40 against human multiple myeloma (MM) cells via several mechanisms. These include induction of cytotoxic ligands of TNF superfamily; suppression of IL-6-induced proliferative and anti-apoptotic effects, as well as antibody-dependent cell-mediated cytotoxicity (Tai, et al, Cancer Research64, 2846–2852, April 15, 2004). Since ≥ 90% of MM cells express CD40, targeting CD40 using SGN-40 presents a potential novel treatment strategy. Based on these preclinical data, a phase I study is being conducted to define the toxicity profile, characterize the pharmacokinetics (PK), and evaluate antitumor effects of SGN-40 in patients with refractory or recurrent MM. Four weekly doses ranging from 0.5 to 16 mg/kg are planned to be administered to groups of at least three patients per cohort. Patients will be followed for up to 6 weeks post their last dose. Currently, a total of seven patients have been treated with SGN-40 at dose levels of 0.5 and 1.0 mg/kg. No grade 3 or 4 non-hematologic dose limiting toxicities have been observed. One patient experienced a transient Grade 3 decrease in hemoglobin. Decrease in CD19 positive B-cells were noted for patients treated at both dose levels. Changes in serum and urine M protein levels were measured to estimate potential anti-tumor effects of SGN-40. Of the seven patients evaluated, one patient at 0.5 mg/kg dose had stable disease, based on serum M protein, over the 10 week study period. Clinical evaluation with dose escalation of this agent continues and updated safety, PK and antitumor data will be presented.

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