ALBERT

Description: Background Hypercalcemia of malignancy (HCM) is a serious complication in patients with advanced cancer, including those with hematologic malignancies. HCM is commonly treated with intravenous (IV) bisphosphonates, but HCM may persist or relapse despite bisphosphonate therapy. Denosumab (XGEVA®) is a fully human monoclonal antibody that binds to RANK ligand (RANKL) to inhibit osteoclast-mediated bone resorption. Methods In this single-arm, open-label study, patients with solid tumors or hematologic malignancies who had HCM (corrected serum calcium [CSC] 〉12.5 mg/dL) despite IV bisphosphonate treatment ≥7 and ≤30 days before screening received subcutaneous denosumab 120 mg on days 1, 8, 15, and 29, then every 4 weeks thereafter. The primary endpoint was the proportion of patients who had a treatment response (defined as CSC ≤11.5 mg/dL) within 10 days of denosumab initiation. Key secondary endpoints included the proportion of patients with a treatment response at each study visit and the proportion of patients with a complete response (defined as CSC ≤10.8 mg/dL) by day 10 or at each study visit. This ad hoc analysis summarizes results for patients with hematologic malignancies. Results The study enrolled 33 patients, of whom 9 had hematologic malignancies (5 myeloma, 2 non-Hodgkin lymphoma, 2 chronic lymphocytic leukemia [CLL] with Richter's transformation). Key baseline characteristics are shown in the Table. By day 10, 21 of the 33 patients in the study (64%) had a treatment response. Also by day 10, all 9 patients (100%) with hematologic malignancies had a treatment response, and 5 of 9 (56%) had a complete response. Eight of the 9 hematologic malignancy patients (89%) had a complete response over the course of the study. The most frequently reported serious adverse events (SAEs) in the overall study population were worsening of hypercalcemia (n=5, 15%) and dyspnea (n=3, 9%). In patients with hematologic malignancies, disease progression was reported in 2 patients (22%), and worsening of hypercalcemia was reported in 1 patient (11%); all other SAEs occurred in only 1 patient each. Two patients, including 1 with CLL, had isolated episodes of CSC levels ≤8.0 mg/dL; none had CSC

Description: Abstract 3057 Background: Multiple myeloma (MM) is an aggressive and incurable disorder with an eventual fatal outcome bringing urgency to the identification of effective treatments for patients who have exhausted standard chemotherapy. New agents, such as lenalidomide and bortezomib have led to a rapid increase in therapeutic options as single agents and in combination with other agents. However, despite this progress nearly all patients will relapse and require additional therapeutic options. Bendamustine is a unique chemotherapeutic agent that combines an alkylating group with a purine-like benzimidazole ring that is approved in the US for the treatment of CLL and refractory indolent B-cell NHL. Bendamustine is approved in Europe for the treatment of MM. Bortezomib is a proteasome inhibitor (PI) that is approved for the treatment of MM and the combination of this PI with alkylating agents including melphalan and cyclophosphamide has proven highly effective in the treatment of MM. Thus, the combination of bortezomib with bendamustine which also possesses alkylating agent properties may enable patients that were previously treated with bortezomib to have additional therapeutic options. In addition, this combination may allow use of lower doses of bortezomib to be used potentially reducing the incidence of peripheral neuropathy as has been observed in other combinations involving bortezomib with other alkylating agents. This study is being conducted to assess the safety and efficacy of bendamustine in combination with bortezomib for the treatment of relapsed/refractory MM. Methods: This open-label, Phase 1/2 study, will enroll up to 40 patients (pts), age ≥18 years, with measurable MM that has relapsed following or is refractory to at least 1 previous treatment. Patients received bendamustine infused intravenously over 1 hour on days 1 & 4 in 3-dose cohorts of 50, 70, or 90 mg/m2 and bortezomib on days 1, 4, 8, & 11 at a fixed dose of 1.0 mg/m2 for up to eight 28-day cycles. Three pts were initially enrolled at each dose cohort. Up to 5 pts were allowed to enroll in each initial cohort if they were all in screening prior to the 3rd pt being enrolled. After the first 3 pts completed cycle 1 of each dose, the cohort was assessed for dose-limiting toxicities (DLT). In this study, a DLT was defined as any study drug related grade 3 or grade 4 non-hematologic toxicity, grade 4 hematologic toxicity, grade 3 thrombocytopenia with grade 3 or 4 hemorrhage, grade 3 febrile neutropenia, grade 3 or grade 4 nausea and vomiting refractory to anti-emetic therapy, or any drug-related deaths. A standard 3+3 approach was used for determining the MTD. The MTD cohort will be expanded so that up to 40 total pts are enrolled. Results: Twenty-five pts with a median age of 62 (44-91) have been enrolled on the study and received at least 1 dose of study drug, and 52% of the pts are male. Patients had received a median of 4 (1-17) prior therapies. Notably, 80% (20/25) of pts had received at least one prior bortezomib-containing regimen. For the Phase 1 portion, 5 pts were enrolled into the 50 mg/m2 cohort, 4 pts were enrolled into the 70 mg/m2 cohort and 5 pts were enrolled into the 90 mg/m2 cohort. No DLTs were observed in the phase 1 portion of the study. The maximum dose (90 mg/m2) was well tolerated. Patients are currently enrolling into the Phase 2 portion of the study and receiving this dose of bendamustine in the combination treatment. To date, the most common grade 3 or 4 adverse events, occurring in more than 10% of pts, were neutropenia (36%), anemia, (24%), thrombocytopenia (24%), and renal failure (12%). A worsening of baseline peripheral neuropathy was reported in 20% of pts. Two (8%) pts were reported to have grade 1, treatment emergent peripheral neuropathy. To date, nearly one-third (8/25) of pts have achieved an MR or PR. To date, 16 pts have been enrolled at the 90 mg/m2 dose of bendamustine and 5 (31%) have achieved an MR or PR. Conclusions: The combination of bendamustine 90 mg/m2 on days 1 and 4 and bortezomib 1.0 mg/m2 on days 1, 4, 8, & 11 appears to be safe and effective in this heavily pre-treated patient population. The phase 2 portion of this study is ongoing. Disclosures: Berenson: Cephalon: Consultancy, Research Funding; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Bendamustine is approved for CLL and refractory NHL. It is being studied in combiantion with bortezomib for multiple myeloma. Siegel:Cephalon: Research Funding; Amgen: Research Funding; Incyte: Research Funding; Marmatech: Research Funding; Medivation: Research Funding; Caremark/CVS: Consultancy. Swift:Millennium: Speakers Bureau. Ehrman:Cephalon Inc.: Employment. Bensen-Kennedy:Cephalon Inc.: Employment.

Description: Background: Bendamustine hydrochloride (SDX-105; TreandaTM) is a multifunctional, alkylating agent with a purine-like ring system and novel mechanisms of action that exhibits impressive single-agent activity in multiple hematologic and solid tumors. In vitro data indicate that bendamustine induces cell death as a result of both apoptosis and mitotic catastrophe, resulting in potent cell-killing activity in cancer cells that are resistant to traditional chemotherapy (alkylating and fludarabine-containing regimens). In vitro data have also demonstrated a synergistic effect with rituximab for the treatment of non-Hodgkin’s lymphomas (NHL). A Phase II multicenter study (SDX-105-02) was conducted to determine the efficacy and toxicity of the combination of bendamustine with rituximab in relapsed NHL patients. Methods: The intent-to-treat (ITT) population consists of 54 patients with relapsed indolent CD20-positive B-cell or mantle cell NHL, enrolled from 22 sites in the US and Canada. Median age of the patients was 60 years (range 40–84); 59% had follicular NHL, 6% had small lymphocytic lymphoma, 4% had lymphoplasmacytoid lymphoma, 4% had marginal zone lymphoma, and 17% had mantle cell lymphoma; and 72% of all patients had Stage III/IV disease. Patients relapsed from a median of 1 prior therapy. Patients received rituximab, 375 mg/m2 IV on day 1, and bendamustine, 90 mg/m2 on days 2 and 3, every 28 days for 4–6 cycles. All patients received an additional dose of rituximab 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle. Results: Of the 54 ITT patients, 37% had prior treatment with rituximab. Forty-three patients are currently evaluable for response, as defined by the International Working Group. The overall response rate was 84%, with complete response in 21% and partial response in 63% of patients. The median duration of response has not yet been reached after a median follow up of 3.6 months. Minimal toxicity was observed. The most common nonhematologic toxicities included grade 1/2 gastrointestinal complications. The primary grade 3/4 hematologic toxicity was neutropenia (with no neutropenic fever), observed in 22% of patients. Grade 3/4 anemia and thrombocytopenia were observed in only 1 patient. No alopecia was observed. Conclusions: Bendamustine, administered in combination with rituximab, produced high objective response rates with minimal toxicity in patients with refractory indolent and mantle cell NHL, including patients that previously failed alkylating and fludarabine-containing regimens. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.

Description: We examined the IgM VH gene subgroup use-distribution in serial blood samples of 37 human immunodeficiency virus (HIV)-infected patients and a group of HIV-seronegative healthy adults. The IgM VH gene repertoires of healthy adults were relatively similar to one another and were stable over time. In contrast, individuals infected with HIV had IgM VH gene repertoires that were significantly more heterogeneous and unstable. Persons at early stages of HIV infection generally had abnormal expression levels of Ig VH3 genes and frequently displayed marked fluctuations in the relative expression levels of this VHgene subgroup over time. In contrast, persons with established acquired immunodeficiency syndrome (AIDS) had a significantly lower incidence of abnormalities in Ig VH3 expression levels, although continued to display abnormalities and instability in the expression levels of the smaller Ig VH gene subgroups. Moreover, the skewing and/or fluctuations in the expressed-IgM VHgene repertoire appeared greatest for persons at earlier stages of HIV infection. These studies show that persons infected with HIV have aberrant and unstable expression of immunoglobulin genes suggestive of a high degree humoral immune dysregulation and ongoing humoral immune responses to HIV-associated antigens and superantigens. © 1998 by The American Society of Hematology.

Description: Background: Bendamustine HCl (TreandaTM) is a multifunctional, alkylating agent with novel mechanisms of action. Unlike other commonly used chemotherapeutic agents, bendamustine in vitro induces durable cell damage resulting in rapid cell death in apoptosis-resistant cancer cell lines through the apoptosis independent pathway of mitotic catastrophe. European studies have reported single-agent activity in patients with relapsed/refractory NHL, chronic lymphocytic leukemia, multiple myeloma, and breast cancer. Aim: This study evaluated the efficacy and toxicity of bendamustine in patients with NHL who have relapsed or are refractory to previous chemotherapy regimens. Patients refractory to Rituximab had disease progression within 6 months of treatment. Methods: This Phase II multicenter trial enrolled patients with relapsed indolent or transformed rituximab-refractory B-cell NHL from 17 sites in the US and Canada. Indolent histologic phenotype was seen in 84% of patients, while 16% had transformed disease. Median age of patients was 63 years (range: 38–84) and 88% had Stage III/IV disease. Patients received bendamustine 120 mg/m2 IV over 30–60 minutes, days 1 and 2, every 21 days for up to 6 cycles. Response was measured using the International Working Group criteria. Results: The intent-to-treat (ITT) population consisted of 75 heavily pretreated patients with a median of 2 prior chemotherapies. The overall objective response rate (ORR) in the ITT population was 74%; 25% had a complete response, 49% had a partial response, 12% had stable disease, and 14% had disease progression. Of 15 patients who were refractory to prior alkylator treatment (patients who progressed after at least one prior alkylator-containing therapy), 10 (67%) experienced an objective response to bendamustine. The median duration of response was 6.6 months for all patients, 9.3 months for indolent patients, and 2.4 months for transformed patients. The most frequent nonhematologic adverse events were nausea (63%), fatigue (39%), vomiting (38%), fever (25%), and diarrhea (22%). Most of these events were grade 1 or 2; alopecia and hemorrhagic cystitis were not observed. Grade 3 or 4 reversible hematologic toxicities seen included neutropenia (47%), thrombocytopenia (24%), and anemia (11%). Conclusions: Single-agent bendamustine produced durable objective responses with acceptable toxicity, despite unfavorable prognostic features, in heavily pretreated rituximab-refractory indolent and transformed NHL patients. Durable response has been seen in alkylator-resistant patients. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.

Description: Abstract 4063 Background: Carfilzomib has shown promise in treating both newly diagnosed and relapsed/refractory MM patients. Recent data has suggested that single agent carfilzomib can produce a response for MM pts refractory to previous treatment regimens, including prior bortezomib-containing regimens. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of carfilzomib as a replacement for bortezomib in bortezomib-containing regimens to which pts have progressed. Methods: Eligible pts had to have progressed while receiving their most recent bortezomib-containing regimen after at least 4 doses of bortezomib at ≥ 1.0 mg/m2 in ≤ 4 weeks per cycle. Patients treated with bortezomib-containing combination regimens, including alkylating agents, anthracyclines, glucocorticosteroids, and/or immunomodulatory agents were eligible. Carfilzomib replaced bortezomib in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each 28 day cycle. For each pt, carfilzomib doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m2 or until maximum tolerated dose (MTD) was reached for that regimen. Aside from carfilzomib replacing bortezomib, regimens utilized the same dose(s) and schedule(s) of each drug administered in the most recent bortezomib-containing regimen to which the patient was refractory. Results: The trial has currently enrolled 32 of 45 planned patients. Pts received a median of 6 prior treatments (range, 1–18) and 2 different bortezomib-containing regimens (range, 1–13). Pts were treated with carfilzomib and 13 different combination regimens at varying doses and schedules. Agents in these combination regimens varied per patient, potentially including any of the following: ascorbic acid, bendamustine, clarithromycin, cyclophosphamide, dexamethasone, lenalidomide, melphalan, methylprednisolone, pegylated liposomal doxorubicin, and/or thalidomide. Six patients received a regimen containing IMiDs (thalidomide or lenalidomide). Pts have completed a median of 3 cycles (range: 0–12) with a median of 5.9 months of follow up (range: 0.4–14.1). To date, 1 regimen, carfilzomib + ascorbic acid + cyclophosphamide, has reached MTD with the maximum dose of carfilzomib (45 mg/m2) without any DLTs. Efficacy data stems from 24 of 32 enrolled pts who have completed at least 1 cycle of treatment. Clinical benefit was seen in 18 (75%) pts (complete response = 8.3%; very good partial response = 16.7%; partial response = 29.2%; minor response = 20.8%) with another 16.7% showing stable disease. Notably, response was achieved for each type of agent included in the trial across a variety of specific treatment combinations. Only 3 pts have progressed while on study, one with progressive disease after an initial response. Kaplan-Meier analysis reveals the median progression-free survival (PFS) at this point in the study to be 10 months (95% confidence interval: 8.6–11.2). The median time to progression (TTP) and duration of response (DOR) have not yet been reached. Safety data stems from all 32 enrolled pts. The most common grade 3/4 hematologic adverse events include: thrombocytopenia, occurring in 16 pts (G3: 5; G4: 2); lymphopenia occurring in 12 pts (G3: 6; G4: 1) and fever occurring in 2 pts (G3). The most common grade 3/4 non-hematologic adverse events include: fever, occurring in 8 pts (G3: 2); urinary tract infection, occurring in 3 pts (G3: 1); sepsis occurring in 1 pt (G4); pneumonia occurring in 2 pts (G3: 1); tumor lysis syndrome occurring in 1 pt (G3). Ten pts experienced a serious adverse event on study. Conclusions: These early results suggest that carfilzomib is an effective and tolerable replacement for bortezomib among pts who are refractory to bortezomib-containing combination regimens. These results appear to be applicable to a variety of combination regimens consisting of a wide array of therapeutic agents. Disclosures: Berenson: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: 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.