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 < 1,0 x 109/l for > 7 days or an ANC < 0,5 x 109/l for > 3 days or platelet count < 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.

Treatment with Bendamustine, Thalidomide and Prednisolone (BPT) in Patients with Refractory or Relapsed Multiple Myeloma after Autologous Stem Cell Transplantation or Conventional Chemotherapy: Results of a Phase I Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3564-3564 ◽  
Author(s):  
Wolfram Poenisch ◽  
Marta Rozanski ◽  
Hartmut Goldschmidt ◽  
Franz-Albert Hoffmann ◽  
Thomas Boldt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dose Level ◽  
Single Agent ◽  
Fixed Dose ◽  
Maximal Response ◽  
High Dose ◽  
Conventional Chemotherapy ◽  
Who Grade ◽  
Treatment Regimens

Abstract Thalidomide is an active single agent in advanced relapsed or refractory multiple myeloma (MM). The combination of low dose thalidomide with bendamustine and prednisolone might maintain or increase efficacy of the drug while avoiding dose limiting toxicity (DLT). Patients and Methods: The treatment consists of a fixed dose of bendamustine (60mg/qm) day 1, 8, and 15 with prednisolone (100 mg) day 1, 8, 15, and 22. In addition, thalidomide is given in three escalating doses, starting with 50 mg to a maximum of 200 mg daily. At each dose level 8 to 12 relapsed or refractory patients, half of them after conventional chemotherapy and half after high dose therapy with stem cell support, were enrolled. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles either until a maximal response was achieved, or until a DLT or a disease progression were observed. Between March 2004 and May 2006, 28 patients were enrolled: 8 in the first dose level with 50 mg thalidomide; 8 in the second dose level with 100 mg and 12 in the third dose level with 200 mg. All patients had received a minimum of 2 prior treatment regimens. Seven patients had been refractory to the last treatment. Median age was 67 years (range: 40 – 78). All patients completed 2 cycles of BPT-treatment and are therefore evaluable. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). Results: Twentyfive of 28 patients responded after at least 2 cycles of chemotherapy with 3 CR, 1 nCR, 5 VGPR, 15 PR and 1 MR. Two patients had stable disease and one patient was refractory. With a median follow up of 15 months, EFS and OS at twelve months were 34 % and 92 %, respectively. The most common side effects were constipation (11 patients WHO grade 1, 8 patients WHO grade 2), polyneuropathy (15 patients WHO grade 1, 3 patients WHO grade 2) and somnolence (4 patients WHO grade 1). None of the 28 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. Transient neutropenia was reported in 9 patients (WHO grade 3 and 4) but no thrombocytopenia was observed. Conclusion: BPT with a dose between 50 and 200 mg thalidomide daily is well tolerated in patients with relapsed or refractory MM.

Bendamustine in Combination with Thalidomide and Prednisolone (BPT) in Patients with Refractory or Relapsed Multiple Myeloma (MM): Preliminary Results of a Phase I Clinical Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4901-4901
Author(s):  
Wolfram Poenisch ◽  
Marta Rozanski ◽  
Sabine Leiblein ◽  
Hartmut Goldschmidt ◽  
Almut Wegner ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Fixed Dose ◽  
Hematological Toxicity ◽  
Newly Diagnosed ◽  
Significant Treatment ◽  
Who Grade ◽  
Myeloma Protein

Abstract Thalidomide is an active single agent in advanced relapsed or refractory MM. Treatment, however, is associated with significant dose-dependent toxicity limiting his application. Combination of low dose thalidomide with bendamustine and prednisolone might be a way to maintain efficacy of the drug without dose limiting toxicity. The cytotoxic agent bendamustine combines a purine-like benzimidazol with a bifunctionally alkylating nitrogen mustard group. The drug is active in a variety of lymphoproliferative disorders with modest non-hematological and hematological toxicities. Previous clinical studies confirmed the efficacy of bendamustine monotherapy and in combination with prednisolone in patients with newly diagnosed and relapsed MM. In a phase III study of newly diagnosed patients, overall response rate for bendamustine and prednisone was 75% and shown to be superior to melphalan and prednisone in regard to progression free survival and quality of life. The purpose of this phase I study was to test the feasibility of the combination of BPT in advanced MM patients. The treatment consists of a fixed dose of bendamustine (60 mg/qm) i.v. day 1, 8, and 15 and prednisolone (100 mg) p.o. day 1, 8, 15, and 22. At the same time, thalidomide will be given orally in 4 patients cohorts with escalating doses, starting at 50 mg to a maximum of 200 mg daily. Cycles will be repeated every 28 days for a minimum of 2 and a maximum of 10 cycles until appearance of significant treatment-related toxicity or disease progression. Till now, four patients with stage IIIa MM were enrolled in the first dose level with 50 mg thalidomide daily. All patients had two prior treatment lines and three were refractory. Median age was 67 years (range 64 – 69 years). Results: All four patients completed at least 2 cycles of BPT-treatment (2 completed 6 cycles, 1 completed 3 cycles and 1 completed 2 cycles) and were evaluable for toxicity and efficacy. All patients responded after the first two cycles of therapy in three of them with decrease of the myeloma protein of more than 90%. One showed a reduction of the myeloma protein of 30%. Although median follow up is still short, no progression of disease was observed yet. Thalidomide in a dose of 50 mg daily given during 4.5 months median (range 2–6 months) was well tolerated. Most common site effects were constipation (three patients WHO grade 2) and somnolence (two patients WHO grade 1). None of the four patients developed dose-limiting hematotoxicity 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 1 patient (WHO grade 2) but no thrombocytopenia was observed. No grade 3 or 4 non-hematological toxicity was encountered and no dose modification was required. BPT with a dose of 50 mg thalidomide daily is well tolerated in patients with relapsed or refractory MM. The next cohort of patients is currently treated with Thalidomide 100 mg daily to evaluate the maximal tolerable doses of the BPT regimen.

Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

2015 ◽  
Vol 33 (7) ◽  
pp. 732-739 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Siegel ◽  
David H. Vesole ◽  
Peter Lee ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Concentration ◽  
Phase I ◽  
Phase I Study ◽  
Low Dose ◽  
Single Agent ◽  
Phase Iii ◽  
Maximum Plasma ◽  
Irreversible Inhibitor ◽  
Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

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 Study of XK469R (NSC 698215), a Quinoxaline Phenoxypropionic Acid Derivative, in Patients with Refractory Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1952-1952
Author(s):  
Wendy Stock ◽  
Samir D. Undevia ◽  
Stefan Faderl ◽  
Olotoyosi Odenike ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Acid Derivative ◽  
Dose Level ◽  
Phase I Study ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Clinical Activity

Abstract XK469R is a quinoxaline phenoxypropionic acid derivative which possesses broad activity against murine and human tumors (including leukemia) and high activity against multidrug-resistant tumors. COMPARE analysis of cytotoxicity data from the NCI cell line screen suggested a unique mechanism. Phase I studies in patients with advanced solid tumors indicated that the dose-limiting toxicity (DLT) was myelosuppression, without other significant toxicities noted, at a fixed dose of 1400 mg/dose when given on a day 1,3,5 schedule every 21 days. Therefore, we conducted a phase I study to establish the DLT and maximally tolerated dose (MTD) of XK469R in patients with refractory hematologic malignancies, as well as to study the pharmacokinetics of XK469R in this patient population. XK469R was given as a straight dose as an IV infusion over 30 minutes-1 hour on days 1, 3, and 5 of a 21 day cycle. Because significant interpatient variability in drug clearance (associated with toxicity) was noted in prior studies, each dose cohort included a minimum of six patients. The dose levels studied were 1400 mg (n=6), 1750 mg (n=12), 2200 mg (n=14), and 2750mg (n=14). A total of 46 patients with relapsed/refractory leukemia have been treated and are evaluable for toxicity; 41 patients with AML, 4 ALL, and 1 CML-BC. The group consists of 26 males and 20 females with a median age of 53 (range 20–85). ECOG PS included 0 (n=19), 1 (n=21), and 2 (n=6). Median number of cycles received was 1; 10 patients received 2 cycles and 2 patients received 3 cycles. DLT was defined as any clinically significant grade 3 or 4 adverse nonhematologic toxicity other than prolonged myelosuppression, as defined by NCI criteria specific for leukemia. DLTs of colitis and mucositis were observed at the 2200 mg dose level, and mucositis and elevated bilirubin at the 2750 mg dose level. Other possibly related grade 1 and 2 toxicities noted were SGOT/PT elevations, nausea/vomiting, diarrhea, anorexia, indigestion, rash, and alopecia. The MTD, defined as the dose level at which <2/6 patients experience a DLT, was 2200 mg. Forty-two patients were evaluable for response and include CR (n=1, in 1750 mg cohort), HI (n=5), SD (n=21), and PD (n=15). Preliminary pharmacokinetic analysis revealed that plasma concentrations of XK469R decline in a biphasic manner. Half-life was long with a mean value of 48 h. Mean clearance was 206 ml/h with a coefficient of variation of 32%. Patients with lower clearance did not appear to be at greater risk of DLT. In conclusion, the recommended phase II dose of XK469R in patients with advanced leukemia is 1750 mg (day 1,3,5). Due to its novel mechanism of action, reasonable toxicity profile, and clinical activity in these high-risk patients, further exploration of XK469R, possibly in combination with other established agents, is warranted in patients with relapsed/refractory acute leukemia.

Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of Bendamustine in Combination with Lenalidomide and Dexamethasone (BRD) in Patients with Relapsed Multiple Myeloma: A Multiple Myeloma Research Consortium Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2965-2965
Author(s):  
Shaji K. Kumar ◽  
Amrita Krishnan ◽  
Vivek Roy ◽  
Todd M Zimmerman ◽  
Morie Abraham A Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Expert Testimony ◽  
Research Funding ◽  
Phase 1 ◽  
Response Rates ◽  
Hematological Toxicity ◽  
Phase 2 ◽  
Dose Reductions

Abstract Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in >=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (>=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.

A phase I study of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1127-1127
Author(s):  
A. Kalykaki ◽  
S. Agelaki ◽  
A. Kotsakis ◽  
L. Vamvakas ◽  
V. Bozionelou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Treatment Delay ◽  
Hematological Toxicity ◽  
Oral Vinorelbine

1127 Background: The combination of capecitabine plus intravenous vinorelbine has shown substantial activity in anthracycline and/or taxane pretreated patients with metastatic breast cancer (MBC). The metronomic administration may be associated with reduced toxicity and enhanced efficacy. We conducted a phase I study to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of capecitabine plus oral vinorelbine administered metronomically in patients with MBC. Methods: Patients were treated with vinorelbine (30–60 mg total dose) p.o three times per week continuously and capecitabine (800–1250 mg/m2 twice a day) from day 1 to 14 in three week cycles. DLT was defined during the first cycle as grade (G) 4 neutropenia or thrombocytopenia, febrile neutropenia, any ≥ G 3 non-hematological toxicity, and any delay of treatment due to toxicity. Results: To date 27 patients have been enrolled on 7 different dose levels. Treatment was first line for 16 and second line for 11 patients. DLTs included G3 febrile neutropenia and treatment delay due to G2 neutropenia occurring in 1 patient each, at dose level 4 and G3 diarrhea and treatment delay due to G2 neutropenia in 1 patient each, at dose level 7. The MTD has not yet been reached. Hematologic and nonhematological toxicities were generally mild to moderate. Most common were myelosuppression, asthenia, nausea, and diarrhea. Nine objective responses were observed with 2 complete and 7 partial. Conclusions: Vinorelbine 60 mg three times a week in combination with capecitabine 1250mg/m2 twice a day, has been well tolerated. Enrollment is ongoing. Updated data will be presented at the meeting. No significant financial relationships to disclose.

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.

Abstract 178: Byvalson Fixed-Dose Combination for the Treatment of Hypertension: A Comprehensive Review

2017 ◽  
Vol 10 (suppl_3) ◽  
Author(s):  
Charles E Wight ◽  
Nicole Jara ◽  
Chelsea Harlan ◽  
Paul Petrillo ◽  
Mara N Poulakos
Keyword(s):  
Blood Pressure ◽  
Phase I ◽  
Phase I Study ◽  
Fixed Dose Combination ◽  
Phase Iii ◽  
Fixed Dose ◽  
Open Label ◽  
Phase Iii Trial ◽  
Treatment Of Hypertension ◽  
Dose Combination

Purpose: Byvalson (nebivolol and valsartan), FDA approved in June 2016 for the treatment of hypertension, is the first combination beta blocker and ARB fixed-dose combination medication available. Two-thirds of patients with hypertension require more than one drug to achieve BP control. The combination of two antihypertensive medications has been associated with greater BP control, compliance, and reduced adverse effects. Nebivolol is a highly selective β1-adrenergic receptor antagonist with vasodilator properties and valsartan is an ARB. The objective of this study is to evaluate clinical efficacy and safety of this combination of BP-lowering medications in the treatment of hypertension. Methods: A comprehensive literature search was conducted to date utilizing MEDLINE and PUBMED with the following search terms: “nebivolol”, “valsartan”, and “hypertension” to retrieve clinical trials. The following three studies were found: a phase I randomized, open-label study investigating pharmacokinetic and pharmacodynamic interactions between nebivolol and valsartan; and two phase III studies evaluating the safety and efficacy of combination treatment: one is an open-label, single-arm study over 52 weeks and the other is a phase III randomized, placebo-controlled study comparing fixed-dose combination to nebivolol and valsartan alone over 8 weeks. Analysis of the study designs, methods, results, statistical analyses, and conclusions were properly conducted for appropriateness and validity. Results: The pharmacokinetic and pharmacodynamics parameters in the phase I study involving 30 patients had statistically significant steady-state PK interactions deemed not clinically significant, significant reductions in blood pressure (p≤0.005) and other PD interactions. A phase III trial (n=4161) showed significantly greater reductions from baseline at 8 weeks in DBP in the fixed-dose combination group than both nebivolol 40 mg (mean difference –1.2 mm Hg [95% CI, –2.3 to –0.1; p=0.030] and valsartan 320 mg (–4.4 mm Hg [95% CI, –5.4 to –3.3]; p<0.0001). SBP reductions were also significant (p<0.01). Another phase III trial (n=810) showed significant reductions from baseline at 52 weeks for SBP (-25.5±15.9 mm Hg) and for DBP (-19.0±8.7 mm Hg). 75.7% of nebivolol/valsartan and 57.8% of nebivolol/valsartan/HCTZ patients achieved a BP goal of <140/90. Conclusion: Both phase III trials evaluating the combination treatment of nebivolol and valsartan demonstrated long term safety, efficacy, and tolerability with significant reductions in systolic and diastolic blood pressure compared with monotherapy. The phase I study showed limited PK interactions, additive PD effects, and tolerability in healthy volunteers. As an initial therapy in patients with inadequately controlled blood pressure, Byvalson 5/80 mg taken orally once daily is a safe and effective treatment for the hypertension.

Combined Bendamustine, Prednisolone and Lenalidomide (RBP) In Refractory or Relapsed Multiple Myeloma. First Results of a Phase I Clinical Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1971-1971
Author(s):  
Wolfram Pönisch ◽  
Simone Heyn ◽  
Ina Wagner ◽  
Martin Mohren ◽  
Franz-Albert Hoffmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Single Agent ◽  
Hematological Toxicity ◽  
Maximum Tolerable Dose ◽  
Starting Dose ◽  
First Results ◽  
Grade 3 ◽  
Tolerable Dose

Abstract Abstract 1971 Introduction: While the role of lenalidomide monotherapy in the treatment of relapsed/refractory patients with multiple myeloma (MM) is established, combination therapies with Lenalinomide are still under investigation. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective in combination with steroids, thalidomide and bortezomib for the treatment of patients with MM. In the current trial, combination therapy of bendamustine, lenalinomide and prednisolone (RBP) was tested for feasibility and safety in patients with relapsed or refractory MM. Patients and Methods: This is a phase I trial examining dosing of lenalidomide in combination with bendamustine and prednisolone. The first cohort of patients received a starting dose of 10mg/d d1-21 lenalidomide, 60mg/m2/d d1-2 bendamustine and 100mg/d d1-4 prednisolone. Escalation steps in the next cohorts included 15, 20 and 25mg of lenalidomide followed by an escalation step of 75 mg/m2 bendamustine. Three patients were enrolled at each dose level and the first two cycles were evaluated for maximum tolerable dose. Patients received RBP in 4-week cycles for a maximum of 8 cycles in order to evaluate efficacy. Patients with stable or responding disease following 8 cycles of RBP received single-agent oral lenalidomide 10 mg once daily on days 1–21 of each 28-day cycle as maintenance. Results: : Nine patients (3 at each dose level of 10 mg, 15 mg or 20 mg lenalidomide) have been enrolled to date and 9 patients have completed at least 2 cycles. Response was assessed using modified EBMT criteria to include near complete remission (nCR) and very good partial remission (VGPR). 8 of 9 patients responded after at least 2 cycles with 2 VGPR, 4 PR, 1 MR and 1 stable disease. One patient experienced progressive disease. None of the 9 patients developed dose-limiting hematoxicity as defined by an ANC < 1,0 × 109/l with fever for > 3 days or an ANC <0,5 × 109/l for > 7 days or platelet count < 25 × 109/l for > 3 days. Neutropenia was reported in 4 patients (CTC grade ≥ 3) but no thrombocytopenia (CTC grade ≥ 3) was observed. No grade 3 or 4 non hematological toxicity was encountered and no dose modification was required. Conclusions: RBP with a dose of 20 mg lenalidomide d 1–21 and 60 mg/m2 bendamustine d 1–2 is well tolerated in patients with relapsed or refractory MM. Maximum tolerable dose was not reached. Further dose increase according to the protocol is in progress. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document