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-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone for Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3536-3536 ◽  
Author(s):  
Donna E. Reece ◽  
Giovanni Piza ◽  
Suzanne Trudel ◽  
Mariela Pantoja ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Response Rates ◽  
Median Number ◽  
Weekly Schedule ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Dose Levels

Abstract Bortezomib (btz) has established efficacy in relapsed/refractory multiple myeloma (MM) patients (pts). Combinations of btz and other agents can produce even higher response rates. We have reported that oral cyclophosphamide (CY) + prednisone (P) produced partial remissions (PR) in 41% and a median progression free survival (PFS) of 18.6 mos in MM pts who had progressed after ASCT. We now report a phase I trial adding btz to CY + P in 27 patients with relapsed/refractory MM. CY was given p.o. once weekly on days 1, 8, 15, and 22 of a 28 day cycle while P 100 mg was given every other morning. CY was given before btz on appropriate days. A total of 8 cycles was planned. The median age was 59 yrs (48–74); 16 were male. Ig subtypes were: IgG (19 pts), IgA (4 pts), kappa light chain (4 pts). The median number of prior regimens was 2 (1–6); all had undergone prior ASCT and 59% had received thalidomide and/or lenalidomide. The median pretreatment β2-microglobulin was 228 nm/L (114–875), albumin 38 g/L (30–46) and creatinine 86 nmol/L (58–153). The dose escalation scheme and toxicity with cycle 1 is shown below: Table 1. Dose levels and toxicity Dose Level N CY dose (mg/m2) Btz dose (mg/m2) Gr 3–4 Toxicity (cycle 1) *Community acquired pneumonia without neutropenia; ** protocol amended to exclude G-CSF for 2 weeks before study entry. 1 6 150 0.7 d 1,8,15 2 CAP* 2 3 300 0.7 d 1,8,15 0 3 3 300 1.0 d 1,8,15 1 ↓ PO4 4 6 300 1.0 d 1,4,8,11 1 ↓ANC**; 1 ↑ AST/ALT 5 6 300 1.3 d 1,4,8,11 1 N/V 6 3 300 1.5 d 1,8,15 0 All the above toxicities above were gr 3 except for 1 transient episode of gr 4 hypophosphatemia. Dose limiting toxicity was not seen. The median number of protocol cycles given per pt was 7 (1–8); 1 pt chose to continue therapy and has received 15 cycles. Toxicities in cycles 2–8 were generally mild. Episodes of infection included shingles (5), gr 3 respiratory infection (6) and febrile neutropenia (2). A total of 168 cycles have been administered; the dose of CY was reduced in 5 cycles due to neutropenia (↓ANC) (3), thrombocytopenia (1) or increased AST/ALT (1), while the btz dose was decreased in 4 cycles due to gr 2 peripheral neuropathy (PN) (1) or ↓ANC (3). 12 pts have completed all 8 cycles, 5 are on therapy and 7 have progressed after a median of cycles 3 (1–7). 3 stopped protocol therapy (physician choice in 1 pt with minimal response, gr 2 PN in 2 pts (after 7 cycles at dose levels 2 and 5) including the pt with prior btz dose reduction. 14/15 pts treated at dose levels 4–6 (effective btz doses) were evaluable for response after receiving at least 2 cycles. Best response was CR/nearCR in 6 (43%) and PR in 7 (50%) for an overall response rate of 93%. The median follow-up is 12 mos (1–20). 6 pts have progressed after stopping therapy. The median PFS is 11 mos, while the median overall survival (OS) has not been reached. The actuarial 1 year OS and PFS are 83% (95% CI 61–93%) and 47% (95% CI 24–68%), respectively. 7 of 10 planned additional pts have entered the phase II portion of the trial at dose level 6. 3 have completed at least 2 cycles; 2 are in CR/near CR while one is in PR. We conclude: Btz 1.5 mg/m2 can be given safely on a convenient weekly schedule days 1, 8 and 15 of a 28 day cycle in combination with full dose oral CY + P in relapsed/refractory MM pts; preliminary response rates at this dose level include 4/6 (67%) CR/near CRs and 1/6 (17%) PR.

Phase I/II Study with Single Agent Everolimus (RAD001) in Patients with Relapsed or Refractory Multiple myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3850-3850 ◽  
Author(s):  
Andreas Guenther ◽  
Philipp Baumann ◽  
Renate Burger ◽  
Wolfram Klapper ◽  
Ralf Schmidmaier ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Research Funding ◽  
Cell Cancer ◽  
Single Agent ◽  
Study Drug ◽  
Fixed Dose ◽  
Bone Marrow Biopsies ◽  
Refractory Multiple Myeloma ◽  
Dose Levels

Abstract Abstract 3850 Poster Board III-786 Introduction The mammalian target of rapamycin (mToR) plays an important role in multiple myeloma (MM), since it is involved in the PI3K-AKT pathway which can be activated by stimulation with growth and survival factors such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) or the loss of the tumor suppressor PTEN. Inhibition of mToR blocked myeloma cell growth in vitro as well as in preclinical animal models. The mToR inhibitor everolimus (RAD001) is approved for immunosuppression and for the treatment of renal cell cancer. In an investigator-initiated phase I/II open label trial, patients ≥ 18 years with relapsed or refractory multiple myeloma (MM) were included after at least two lines of previous treatment. The patients received a fixed dose of oral everolimus for six months. The cohorts had 3 to 6 participants. The phase I part of the trial followed a classical dose-escalation design with three planned dose levels (5 mg, 7.5 mg and 10 mg). Patient benefiting from study drug were allowed to continue with treatment. To obtain insights into the biological activity of everolimus, serum dose levels were monitored and bone marrow biopsies and aspirates were performed three times (at screening, after four weeks and after six months of treatment). Results The primary endpoint of the phase I part was safety. Currently, 12 patients were screened and 11 enrolled in the trial (10 male and 1 female, age from 52 to 71 years). One patient withdrew his consent in the first four weeks of treatment and had to be replaced for safety and efficacy assessment. Since no DLT were observed, the intended final daily dose of 10 mg everolimus could be reached. Only one of four SAE during treatment was assessed to be possibly related to the study drug. Except for one grade 4 thrombocytopenia, no > grade 3 AE were observed during treatment. Remarkably, few infectious complications (≤grade 2) were seen despite the known immunosuppressive activity of everolimus. Anti-myeloma activity was documented in 5 out of 7 evaluable patients. One partial response in a heavily pre-treated patient and stable disease in four additional patients were seen. The observed rate of responses and clinical benefit fulfills the criteria defined in the protocol to enter the phase II part of the trial after completing phase I. The individual serum dose levels varied widely and response seemed to correlate to the achieved everolimus dose level. Conclusion Everolimus given orally at doses of 5 mg to 10 mg daily showed an acceptable safety profile in heavily pre-treated multiple myeloma patients and the observed responses even at suboptimal dose levels are promising. Further evaluation of everolimus, alone and in combination with other drugs, is warranted. Disclosures: Guenther: Novartis: Consultancy, Research Funding. Off Label Use: Everolimus is not approved for multiple myeloma. Baumann:Novartis: Consultancy, Research Funding. Schmidmaier:Novartis: Consultancy, Research Funding. Gramatzki:Novartis: Consultancy, Research Funding, Speakers Bureau.

Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone in Relapsed and Refractory Multiple Myeloma

2008 ◽  
Vol 26 (29) ◽  
pp. 4777-4783 ◽  
Author(s):  
Donna E. Reece ◽  
Giovanni Piza Rodriguez ◽  
Christine Chen ◽  
Suzanne Trudel ◽  
Vishal Kukreti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Overall Response Rate ◽  
Response Rate ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

PurposeThe combination of oral weekly cyclophosphamide and alternate day prednisone is a convenient regimen for relapsed/refractory multiple myeloma (MM), and we sought to improve its efficacy by adding bortezomib, a proteasome inhibitor with proven antimyeloma activity.Patients and MethodsWe conducted a phase I-II trial evaluating six dose levels to define the maximum tolerated dose (MTD) of this combination in relapsed/refractory MM. An additional 10 patients were evaluated at the highest dose level reached.ResultsThirty-seven patients were treated on this study. The MTD was not defined. Both of the highest dose levels of bortezomib tested (1.3 mg/m2on days 1, 4, 8, and 11 and 1.5 mg/m2on days 1, 8, and 15, each on a 28-day cycle) could be safely given with cyclophosphamide 300 mg/m2per week and prednisone. At these dose levels, the overall response rate was 95% (complete responses [CR] plus partial response plus minimal response), with CR observed in more than 50% of patients. The weekly bortezomib regimen resulted in fewer instances of grade 3 thrombocytopenia and grade 1 to 2 peripheral neuropathy; the 1-year progression-free and overall survival probabilities with this dose level were 83% (95% CI, 73% to 96%) and 100%, respectively.ConclusionWeekly bortezomib 1.5 mg/m2plus oral cyclophosphamide and prednisone produces an unprecedented response rate and encouraging 1-year survival in relapsed/refractory patients with MM. Further evaluation of this promising regimen is warranted both in relapsed and newly diagnosed disease.

Phase I/II Study of Escalating Doses of Vinorelbine in Combination With Oxaliplatin in Patients With Advanced Non–Small-Cell Lung Cancer

2001 ◽  
Vol 19 (2) ◽  
pp. 458-463 ◽  
Author(s):  
Isabelle Monnet ◽  
Patrick Soulié ◽  
Hubert de Cremoux ◽  
Sabine Saltiel-Voisin ◽  
Mohammed Bekradda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Fixed Dose ◽  
Platinum Compound ◽  
Small Cell Lung ◽  
Dose Levels

PURPOSE: Oxaliplatin is a platinum compound active in non–small-cell lung cancer (NSCLC) patients, and vinorelbine (VNB) is an active reference agent. This phase I/II study was performed to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the recommended dose (RD) of a VNB/oxaliplatin combination given to previously untreated patients with advanced NSCLC. PATIENTS AND METHODS: Oxaliplatin was given at the fixed dose of 130 mg/m2 (2-hour intravenous [IV] infusion) on day 1. VNB was administered on days 1 and 8 (10-minute IV infusion), with doses starting at 22 mg/m2/d and escalated by 2 mg/m2 increments until MTD. Treatment was repeated every 3 weeks. No special hydration measures or prophylactic granulocyte colony-stimulating factors were used. RESULTS: Twenty-seven patients (20 men, 7 women) received 110 cycles total at six different VNB dose levels. Neutropenia was the DLT. Although no patient experienced DLT at the highest dose level (32 mg/m2/d), multiple treatment delays (54% of cycles) and dose reductions (34% of cycles) were required at this dose level. Others toxicities were mainly limited to grade 1 peripheral neuropathy and grade 1/2 nausea/vomiting. The relative dose-intensity of administered VNB from dose levels 3 to 6 (26 to 32 mg/m2) remained stable, whereas grade 3/4 neutropenia increased. All patients were assessable for activity; there were 10 objective responses, including one complete response (37% response rate). CONCLUSION: The present combination can be safely administered in an outpatient setting. The RD is VNB 26 mg/m2 days 1 and 8 with oxaliplatin 130 mg/m2 day 1 every 3 weeks.

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.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this 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 pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). 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 (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Bendamustine in combination with thalidomide and prednisolone (BPT) in patients with refractory or relapsed multiple myeloma: Results of a phase I clinical trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7620-7620
Author(s):  
W. Poenisch ◽  
M. Rozanski ◽  
F. Hoffmann ◽  
T. Boldt ◽  
A. Schwarzer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Single Agent ◽  
Fixed Dose ◽  
Maximal Response ◽  
Who Grade ◽  
Treatment Regimens ◽  
Grade 3 ◽  
Dose Limiting Toxicity

7620 Background: Thalidomide is an active single agent in advanced relapsed or refractory multiple myeloma (MM). Combination of low dose thalidomide with bendamustine and prednisolone might be a way to maintain efficacy of the drug without dose limiting toxicity (DLT). Methods: The treatment consists of a fixed dose of bendamustine (60mg/qm) day 1, 8, and 15 and prednisolone (100 mg) day 1, 8, 15, and 22. At the same time, thalidomide was given in patients cohorts with escalating doses, starting with 50 mg to a maximum of 200 mg daily. 8 patients (4 after conventional chemotherapy and 4 after APBSCT) were enrolled at each dose level. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles until a maximal response was achieved, a DLT or a disease progression were observed. 23 patients ( 8 in the first dose level with 50 mg thalidomide, 8 in the second dose level with 100 mg and 7 patients in the third dose level with 200 mg) are enrolled until now. The number of prior treatment regimens was 2 or more in all patients. 6 patients were refractory for the last treatment. Median age was 67 years (range: 40 - 78). Results: All patients completed 2 cycles of BPT-treatment and were hence evaluable. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). 20 of 23 patients responded after at least 2 cycles of chemotherapy with 3 CR, 5 VGPR, 11 PR and 2 MR. 2 patients had stable disease. With a median follow up of ten months, EFS and OS at twelfe months were 36 % and 85 %, respectively. Most common site effects were constipation (10 patients WHO grade 1, 8 patients WHO grade 2), polyneuropathy (14 patients WHO grade 1, 2 patients WHO grade 2) and somnolence (4 patients WHO grade 1). None of the 23 patients developed dose-limiting hematoxicity as defined by an ANC < 1,0 Gpt/l for > 7 days or an ANC < 0,5 Gpt/l for > 3 days or platelet count < 25 Gpt/l. Short neutropenia was reported in 8 patients (WHO grade 3 and 4) but no thrombocytopenia was observed. Conclusions: BPT with a dose between 50 and 200 mg thalidomide daily is well tolerated in patients with relapsed or refractory MM. No significant financial relationships to disclose.

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

Bendamustine in Combination with Thalidomide and Prednisolone (BPT) in Patients with Refractory or Relapsed Multiple Myeloma after Conventional Chemotherapy: Final Results of a Phase I Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5154-5154
Author(s):  
Wolfram Poenisch ◽  
Marta Rozanski ◽  
Sabine Leiblein ◽  
Hartmut Goldschmidt ◽  
Franz A. Hoffmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Phase Iii ◽  
Fixed Dose ◽  
Hematological Toxicity ◽  
Conventional Chemotherapy ◽  
Who Grade

Abstract Thalidomide is a remarkably active agent in patients with advanced relapsed or refractory multiple myeloma (MM), but with a significant co morbidity due to side-effects such as neuropathy. We investigated whether lower doses of thalidomide in combination with weekly doses of bendamustine and prednisolone might be a more effective regimen with fewer side-effects especially in relation to neurotoxicity. Clinical studies in patients with newly diagnosed and relapsed MM have shown that bendamustine is effective as single agent as well as in combination with prednisolone. In a phase III study, overall response rate for bendamustine and prednisone was 75% as first line therapy. The purpose of this phase I study was the assessment of toxicity of the combination bendamustine, prednisolone, and thalidomide (BPT) in patients with advanced MM. The treatment consisted of a fixed dose of bendamustine (60 mg/qm) i.v. days 1, 8, and 15 and prednisolone (100 mg) p.o. days 1, 8, 15, and 22. Thalidomide was given to patient cohorts at escalating doses, starting with 50 mg up to a maximum of 200 mg daily. Four patients were enrolled at each dose level. If one dose limiting toxicity (DLT) occurred, additional two patients would be enrolled at that dose level. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles until maximum response, DLT, or progressive disease. Fourteen patients (4 in the first thalidomide dose level with 50 mg, 4 in the second dose level with 100 mg, and 6 patients in the third dose level with 200 mg) were enrolled. Median age was 69 years (range 61 - 78). The number of prior treatment regimens was 2 or more in all patients. Six younger patients were included who had failed VAD-like induction therapy (n=5) or stem cell mobilization (n=1). Six patients had been refractory to the last treatment. Results: All patients completed 2 cycles of BPT (1 completed 7 cycles, 4 completed 6 cycles, 3 completed 5 cycles, 3 completed 4 cycles, 2 completed 3 cycles, and 1 completed 2 cycles). Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). After at least 2 cycles of chemotherapy, 12 of 14 patients responded with 2 CR, 2 VGPR, 7 PR, and 1 MR (ORR 85%). Two patients had a stable disease. No DLT was observed at any dose level. Most common side-effects were constipation (7 patients WHO grade 1; 6 patients WHO grade 2), somnolence (4 patients WHO grade 1), and peripheral neuropathy (2 patients WHO grade 1; 2 patients WHO grade 2). None of the 14 patients developed dose-limiting hematological toxicity as defined by an ANC &lt; 1,0 x 109/l for &gt; 7 days or an ANC &lt; 0,5 x 109/l for &gt; 3 days or platelet count &lt; 25 x 109/l. Neutropenia was reported in 4 patients (WHO grade 4) but no thrombocytopenia was observed. No grade 3 or 4 non-hematological toxicity was encountered and no dose modification was required. BPT with daily thalidomide between 50 mg and 200 mg is well tolerated in patients with relapsed or refractory MM after conventional chemotherapy.

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