Elotuzumab In Combination with Lenalidomide and Low-Dose Dexamethasone In Patients with Relapsed/Refractory Multiple Myeloma: Interim Results of a Phase 1 Study

Abstract Abstract 1936 Background: Elotuzumab is a humanized monoclonal IgG1 antibody targeting CS1, which is highly and uniformly expressed on multiple myeloma (MM) cells, and important to myeloma cell survival. Elotuzumab exerts significant antitumor activity against primary myeloma cells via NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), regardless of sensitivity or resistance to conventional therapies. In preclinical studies, the activity of elotuzumab is independently enhanced by lenalidomide and dexamethasone. We present the results of an ongoing phase 1 study evaluating the maximum tolerated dose (MTD), safety, clinical response, and pharmacokinetics of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory MM. Methods: Entry criteria included patients who had measurable disease, had experienced at least 1 relapse, and had not received lenalidomide for at least 6 weeks before the first dose of elotuzumab. The study enrolled 3 escalating dose cohorts of elotuzumab (5, 10, and 20 mg/kg IV), administered on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles, and then days 1 and 15 of each subsequent cycle, along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. At each dose level, dose-limiting toxicities (DLTs) were assessed during cycle 1 and clinical responses were evaluated with International Myeloma Working Group (IMWG) criteria during each cycle. The first 5 patients received up to 6 cycles of therapy before a protocol amendment allowed subsequent patients to be treated until disease progression. Results: Twenty-nine patients with advanced MM (median stage III) who had received a median of 3 prior MM therapies, including bortezomib (69%), thalidomide (59%), or lenalidomide (21%), were enrolled. Of these, 28 received elotuzumab; 3 patients each were treated with 5 and 10 mg/kg and 22 with 20 mg/kg. Patients received a median of 8.5 treatment cycles and 20.5 doses of elotuzumab. Sixteen patients have permanently discontinued study treatment. No DLTs were observed up to 20 mg/kg during the escalation phase and hence no MTD was established. The most frequent grade 3/4 toxicities were neutropenia (36%) and thrombocytopenia (21%); 2 patients experienced 3 serious infusion-related reactions (1 patient with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events) during the first treatment cycle. Objective responses (partial response or better) were obtained in 82% (23/28) of treated patients and 96% (21/22) of lenalidomide-naïve patients. ORRs were also high in patients who had received prior thalidomide 94% (15/16) or whose disease was refractory to the most recent therapy 82% (9/11). The median time to response was 7 weeks. The proportion of patients without disease progression (Kaplan-Meier estimate) at 16 months is 53% for total patients and 66% for patients in the 20 mg/kg elotuzumab cohort, who are being treated until disease progression. The median time to progression was not reached. Conclusions: The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging overall response rates in patients with relapsed/refractory MM who had received multiple prior therapies. A larger phase 2 study is ongoing to confirm the rate and durability of the responses observed in this phase 1 trial. Disclosures: Lonial: Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding. Vij:Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Celgene, Bristol-Myers Squibb: Speakers Bureau. Harousseau:Bristol-Myers Squibb, Celgene, Janssen-Cilag, Novartis, Onyx: Honoraria; Celgene, Janssen-Cilag: Speakers Bureau. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Moreau:Celgene, Facet Biotech, Bristol-Myers Squibb: Honoraria. Leleu:Janssen-Cilag, Celgene, Chugai Pharmaceutical, Roche, Amgen, Novartis, Leo Pharma: Consultancy, Honoraria, Research Funding. Kaufman:Celgene, Millennium: Consultancy; Celgene, Merck: Research Funding. Westland:Facet Biotech: Employment. Tsao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium, Takeda Pharmaceutical Company, Janssen-Cilag: Honoraria.

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ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study

Blood ◽

10.1182/blood.v118.21.1860.1860 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1860-1860 ◽

Cited By ~ 5

Author(s):

Jatin J Shah ◽

Jeffrey Zonder ◽

Adam Cohen ◽

Robert Z. Orlowski ◽

Raymond Alexanian ◽

...

Keyword(s):

Multiple Myeloma ◽

Febrile Neutropenia ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Phase 1 ◽

Phase 1 Study ◽

Acceptable Safety Profile ◽

Heavily Pretreated ◽

Grade 3

Abstract Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

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Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study

Blood ◽

10.1182/blood.v116.21.3023.3023 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3023-3023

Author(s):

Andrzej J Jakubowiak ◽

Don M Benson ◽

William Bensinger ◽

David S Siegel ◽

Todd M Zimmerman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Median Time ◽

Phase 1 ◽

Objective Response ◽

Time To Progression ◽

Phase 1 Study ◽

Advisory Committees ◽

Ortho Biotech ◽

Grade 3

Abstract Abstract 3023 Background: Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surface glycoprotein, CS1, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against MM cell lines. In vitro pretreatment with bortezomib enhanced elotuzumab-mediated autologous ADCC, and in a murine xenograft model of MM the combination of elotuzumab and bortezomib exhibited synergistic antimyeloma activity. We present updated results of a phase 1 study that evaluated the maximum tolerated dose (MTD) of elotuzumab and the overall safety and clinical responses of the combination of elotuzumab and bortezomib in patients with relapsed/refractory MM. Methods: The study enrolled patients with MM and measurable serum and/or urinary M protein who had received 1 to 3 prior therapies. A 3+3 dose escalation design evaluated 4 escalating doses of elotuzumab (2.5, 5, 10, and 20 mg/kg IV) administered on days 1 and 11 in combination with bortezomib (1.3 mg/m2 IV) administered on days 1, 4, 8, and 11 of a 21-day cycle. Dexamethasone 20 mg PO was added for patients with disease progression after cycle 2 or 3 on days 1, 2, 4, 5, 8, 9, 11, and 12 of subsequent cycles. Patients with stable disease or better after 4 cycles continued treatment until disease progression or unexpected toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and responses were assessed during each cycle using European Group for Bone Marrow Transplantation (EBMT) criteria. Results: The 28 enrolled patients had a median time since MM diagnosis of 3.5 years and had received a median of 2 prior therapies; 11 patients (39%) had received prior bortezomib, 4 (14%) were refractory to bortezomib, and 12 (43%) were refractory to their last therapy. Three patients each received the 2.5, 5, and 10 mg/kg doses of elotuzumab and 19 received 20 mg/kg. No DLTs were observed during cycle 1 and the MTD was not reached. After a median of 6 cycles of therapy (range, 1–25 cycles), 2 patients remain on therapy. Serious adverse events related to elotuzumab were 1 grade 3 chest pain and 1 grade 3 gastroenteritis. The most frequent grade 3/4 AEs were lymphopenia (25%), fatigue (14%), thrombocytopenia, neutropenia, hyperglycemia, peripheral neuropathy, and pneumonia (11%), and leukopenia and anemia (7%). Twenty-seven patients completed at least 2 cycles of therapy or progressed earlier and were therefore evaluable for response (Table). An objective response (≥ PR) was observed in 13/27 (48%) evaluable patients, including 7% CR and 41% PR. A clinical response (≥ MR) was seen in 17/27 (63%) evaluable patients. Notably, a partial response was seen in 2 (50%) of 4 patients refractory to prior bortezomib. The objective response rate (ORR) was 60% (6/10), 50% (6/12), and 20% (1/5) in patients who had received 1, 2, or 3 previous lines of therapy, respectively. Analysis of bone marrow plasma cells indicated that 10 and 20 mg/kg elotuzumab doses resulted in complete or near complete saturation of CS1 sites by elotuzumab. Median time to progression was 9.46 months in the overall population as well as in the bortezomib-naïve population. Conclusions: The combination of elotuzumab and bortezomib had a manageable safety profile. Key toxicities attributable to elotuzumab appeared to be related to infusion reactions. The combination showed promising efficacy with an ORR of 48% and a clinical response rate of 63%. Notably, activity was seen in bortezomib-refractory patients (ORR = 50%). The median time to progression was 9.46 months for both the overall and the bortezomib-naïve populations. Disclosures: Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson, Centocor Ortho Biotech: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor Ortho Biotech: Speakers Bureau. Off Label Use: Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study. Bensinger:Millennium Pharmaceuticals, Celgene Corp., Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board. Zimmerman:Millennium, Celgene: Speakers Bureau. Mohrbacher:Millennium: Speakers Bureau. Richardson:Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Afar:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Millennium, Celgene, Novartis, Onyx, Merck, Bristol-Myers Squibb: Consultancy; Acetylon: Stock Options; Acetylon: Membership on an entity's Board of Directors or advisory committees.

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Phase 1/2 Study of Elotuzumab in Combination with Lenalidomide and Low Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma: Interim Results.

Blood ◽

10.1182/blood.v114.22.432.432 ◽

2009 ◽

Vol 114 (22) ◽

pp. 432-432 ◽

Cited By ~ 5

Author(s):

Sagar Lonial ◽

Ravi Vij ◽

Jean-Luc Harousseau ◽

Thierry Facon ◽

Jonathan Kaufman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Low Dose ◽

Phase 1 ◽

Advisory Board ◽

Advisory Committees ◽

Expansion Phase ◽

Grade 3

Abstract Abstract 432 Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces significant antibody-dependant cytotoxicity (ADCC) against primary myeloma cells in the presence of either autologous or allogeneic peripheral lymphocytes (PBMC), which is significantly enhanced when PBMC effector cells were pretreated with lenalidomide (Tai et al., Blood 112:1329, 2008). The primary objective of the phase 1 portion of the study is to evaluate the maximum tolerated dose (MTD) of elotuzumab in combination with lenalidomide and low dose dexamethasone in patients with relapsed MM. The study is also evaluating safety, pharmacokinetics (PK) and clinical response. Lenalidomide (25 mg PO) is given on Days 1-21 of a 28-day cycle. Elotuzumab in three escalating dose cohorts (5, 10 and 20 mg/kg) is administered by IV infusion on Days 1, 8, 15 and 22 of the 28-day cycle in the first two cycles and then on Days 1 and 15 of each subsequent cycle. Dexamethasone is given weekly at 40 mg PO. Initially, patients received 6 cycles of treatment unless withdrawn earlier due to disease progression or unacceptable. toxicity. The protocol was amended to allow for patients in the 10 and 20 mg/kg cohorts to receive treatment for up to 12 months following enrollment of the last patient. Key entry criteria: age ≥ 18 years; MM with at least one relapse; measurable disease M-protein component in serum and/or in urine; and prior lenalidomide treatment, if any, more than 6 weeks of first dose. To date, 24 patients with a median age of 60 years have been enrolled in the study and 23 patients have received study drug. The median time from initial diagnosis of MM was 5 years and patients had received a median of 3 prior MM treatments. Patients had been previously treated with thalidomide (58%), bortezomib (67%) or lenalidomide (21%) and 42% were refractory to their most recent MM therapy. Patients have been treated in the 3 cohorts; 3 patients each in the first two cohorts (5 and 10 mg/kg elotuzumab) and 17 patients (7 in dose-escalation phase and 10 in the expansion phase) in the third cohort (20 mg/kg). No dose limiting toxicities were identified during the dose-escalation phase of the study and no MTD was established. One patient discontinued in the first cycle due to grade 4 allergic reaction resulting from elotuzumab infusion in the expansion phase of the study. Additional SAEs (1 of each) included grade 2 atrial fibrillation (related to lenalidomide/dexamethasone) and unrelated grade 4 ruptured diverticulum, grade 3 neutropenic fever and grade 3 diarrhea.. Other common grade 3 or 4 AEs included neutropenia (25%) and thrombocytopenia (25%), which were managed by dose withholding or dose reduction of lenalidomide. Approximately 25% of patients experienced grade 1 or 2 chills and/or pyrexia associated with elotuzumab infusion. The best clinical response (IMWG criteria) in the 13 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis of elotuzumab suggests a serum half-life of 10-11 days at 10 and 20 mg/kg. Elotuzumab at all three doses resulted in near complete saturation of CS1 sites on plasma cells and NK cells in bone marrow and NK cells in the peripheral compartment. In conclusion, the combination of elotuzumab with lenalidomide and low-dose dexamethasone has a manageable adverse event profile and compared to historical data for lenalidomide and high-dose dexamethasone, the preliminary efficacy data (≥ PR of 92%) are very encouraging. Additional safety, efficacy and PK/PD data will be presented at the meeting. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Off Label Use: Lenalidomide/dexamethasone in combination with elotuzumab in patients with relapsed/refractory multiple myeloma. Vij:Celgene: Research Funding, Speakers Bureau. Harousseau:Celgene France: Advisory Board; Janssen Cilag France: Advisory Board; Celgene: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kaufman:Celgene: Consultancy, Research Funding; Millennium: Consultancy; Genzyme: Consultancy; Merck: Research Funding. Mazumder:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Leleu:Celgene: Research Funding, Speakers Bureau. Fry:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium: Advisory Board; Merck: Advisory Board.

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Bortezomib and Low-Dose Dexamethasone with or without Continuous Low-Dose Oral Cyclophosphamide for Primary Refractory or Relapsed Multiple Myeloma: Final Results of a National Multicenter Randomized Controlled Phase III Study

Blood ◽

10.1182/blood.v124.21.3470.3470 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3470-3470 ◽

Cited By ~ 3

Author(s):

Martin Kropff ◽

Martin Vogel ◽

Andrea Kreter ◽

Rudolf Schlag ◽

Lothar Müller ◽

...

Keyword(s):

Multiple Myeloma ◽

Sample Size ◽

Disease Progression ◽

Research Funding ◽

Low Dose ◽

Phase Iii ◽

Oral Cyclophosphamide ◽

Randomized Controlled ◽

Kaplan Meier ◽

Grade 3

Abstract Background Multiple myeloma (MM) typically follows a relapsing course and many patients require multiple lines of therapy. The combination of bortezomib and dexamethasone (VD), alone or with cyclophosphamide (VCD) has shown good efficacy and tolerability in patients with relapsed or refractory (rel/ref) MM in non-randomized trials (Mikhael Br J Haematol 2009, Kropff Br J Haematol 2007). This phase III, randomized, controlled study (NCT00813150) aimed to evaluate VCD vs VD in patients with rel/ref MM. Methods Adult patients with rel/ref MM (1st–3rd relapse) with Karnofsky performance status ≥60% were eligible for inclusion; patients with grade ≥2 peripheral neuropathy (PN) were excluded. Patients were randomized 1:1 to receive VD (up to 8 x 3-week cycles of intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus oral dexamethasone 20 mg on the day of bortezomib administration and the following day) or VCD (as VD with the addition of oral cyclophosphamide 50 mg daily). The study was designed with 80% power to detect a difference of 2.8 months in the primary endpoint of time to disease progression (TTP) at the 5% significance level (two-sided); a sample size of 270 patients was required. Secondary endpoints included overall survival (OS), response rate (RR), and safety. Disease progression was assessed per IMWG guidelines and adverse events (AEs) were assessed using NCI-CTCAE v3.0. TTP and OS were calculated using Kaplan-Meier methodology and compared using two-sided log-rank test. Results In total, 96 patients were randomized; 93 began study medication and were included in the safety population, and 90 received at least one dose of study drugs and one efficacy assessment and were included in the intention to treat (ITT) population. The planned sample size was not reached due to lack of recruitment and the study was stopped prematurely as a result of a joint decision of sponsor and coordinating investigator. The VD and VCD arms were well balanced in terms of baseline characteristics. Median age was 71 years (range 30–85) with most patients (97%) suffering from relapse of myeloma disease (3% refractory disease). One, 2, and 3 prior lines of therapy were reported by 57%, 30%, and 9% of patients, respectively; 14% had received prior bortezomib. In total, 19%, 24%, and 29% of patients were ISS disease stage I, II, and III, respectively. Patients in both VD and VCD arms received a median of 5 cycles of therapy. Reasons for premature termination of treatment included AEs (35% and 32% of patients in the VD and VCD arms, respectively) and progressive disease (2% in the VD arm only). After a median follow-up of 24 months, median TTP was 12.6 months in the VD arm vs 9.9 months in the VCD arm (p=0.192); the corresponding hazard ratio (HR) was in favor of the VD arm (HR 0.71, 95% CI 0.43–1.19), although this was not statistically significant (p=0.196). Median OS could not be determined in the VD arm vs 42 months in the VCD arm. The resulting Kaplan-Meier plots were superimposable with a HR of 0.85 (95% CI, 0.41–1.73; p=0.645). In total, 32 (74%) and 33 (70%) patients in the VD and VCD arms achieved ≥PR; 23 (54%) and 22 (47%) patients achieved ≥VGPR. The most common treatment-emergent non-hematologic AEs included PN (28% vs 47% in the VD vs VCD arms), fatigue (28% vs 40%), diarrhea (24% vs 36%), and constipation (22% vs 28%). Grade ≥3 PN occurred in 7 (15%) patients in the VCD arm vs 2 (4%) in the VD arm. Higher rates of grade ≥3 leukopenia (13% vs 0%) and grade ≥3 thrombocytopenia (34% vs 24%) were observed in the VCD arm; however, rates of clinically relevant infections were comparable (grade ≥3 infections 9 [19%] in the VCD arm vs 8 [17%] in the VD arm) and no clinically relevant bleeding events occurred. Conclusions These data indicate that both treatment regimens were similar in efficacy and safety. However, due to limited enrollment, the study is underpowered to draw firm conclusions. Further studies will be required to address the potentially enhanced neurotoxicity of VCD compared with VD. The dosing of cyclophosphamide also warrants further investigation, as other studies suggest that a dose intensified regimen may result in higher CR rates. Disclosures Kropff: Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Mundipharma: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Vogel:Janssen: Employment. Knauf:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fiechtner:Onkovis: Consultancy. Berdel:Janssen: Honoraria.

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A Phase I/II Trial of Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3542.3542 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3542-3542 ◽

Cited By ~ 6

Author(s):

Rakesh Popat ◽

Catherine Williams ◽

Mark Cook ◽

Charles Craddock ◽

Supratik Basu ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Median Time ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Chemotherapeutic Agents ◽

Time To Progression ◽

Overall Response ◽

Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (MR+PR+CR) of 46% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were classified by EBMT criteria. Results: To date 39 patients have been enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. 36 have now completed at least 1 cycle and are therefore evaluable for response. The overall response rate (CR+PR+MR) across all treatment levels was 75% rising to 81% (CR 11%; nCR 3%; VGPR 8%; PR 39%; MR 19%) with the addition of dexamethasone in 13 cases for suboptimal response. Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression is 10.1 months and the median overall survival has not yet been reached at a median follow-up of 7.4 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 13 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma where a response rate of 81% is seen with 14% achieving nCR/CR. The toxicity profile associated is predictable, manageable and predominantly haematological. Recruitment is ongoing to a total of 53 patients.

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Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma: Final Results of a Phase I/II Clinical Trial.

Blood ◽

10.1182/blood.v110.11.2713.2713 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2713-2713

Author(s):

Rakesh Popat ◽

Catherine Williams ◽

Mark Cook ◽

Charles Craddock ◽

Supratik Basu ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Phase I ◽

Median Time ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Time To Progression ◽

Overall Response ◽

Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (≥PR) of 43% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were defined by EBMT criteria. Results: 53 patients were enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. The overall response rate (≥PR) across all treatment levels (n=52) was 65% rising to 69% (CR 19%; nCR 4%; VGPR 6%; PR 40%; MR 15%) with the addition of dexamethasone in 27 cases for suboptimal response. Of the 32 patients treated at the MTD the overall response rate (≥PR) was 78% (CR 28%; nCR 6%; VGPR 6%; PR 38%; MR 9%). Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression was 10 months and the median overall survival has not yet been reached at a median follow-up of 17 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 19 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma with a response rate (≥PR) at the MTD of 78% including 34% nCR/CR. The toxicity profile is predominantly haematological.

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Clinical Safety and Activity In a Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v116.21.1777.1777 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1777-1777 ◽

Cited By ~ 44

Author(s):

Brad Kahl ◽

John C. Byrd ◽

Ian W. Flinn ◽

Nina Wagner-Johnston ◽

Stephen Spurgeon ◽

...

Keyword(s):

Clinical Research ◽

Research Funding ◽

Phase 1 ◽

Selective Inhibitor ◽

Phase 1 Study ◽

Non Hodgkin Lymphoma ◽

Duration Of Response ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 1777 Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B-cell proliferation and survival. In non-Hodgkin lymphoma (NHL) cells, constitutive PI3Kδ-dependent PI3K pathway activation is frequently observed. CAL-101 is an isoform-selective inhibitor of PI3Kδ that inhibits PI3K signaling and induces apoptosis of NHL cell lines in vitro. Methods and Patients: This Phase 1 study evaluated the safety, pharmacokinetics and activity of orally administered CAL-101 in patients with relapsed or refractory hematologic malignancies. Sequential cohorts of patients were enrolled at progressively higher dose levels with cohort expansion based on toxicity profile and plasma exposure. CAL-101 was administered orally once or 2 times per day (QD or BID) continuously in 28-day cycles for up to 12 cycles (with the potential for more prolonged therapy on an extension protocol thereafter). Tumor response was evaluated based on standard criteria but without a requirement for PET imaging. Results: At data cutoff, the study had enrolled 55 patients with NHL; 28 patients had indolent NHL (follicular lymphoma n=15, small lymphocytic lymphoma n=6, Waldenstrom's macroglobulinemia n=4, marginal zone lymphoma n=3) and 27 had aggressive NHL (mantle cell lymphoma [MCL] n=18, diffuse large B-cell lymphoma [DLBCL] n=9). Patient characteristics included 69% males (38 vs 17 females), median age [range] of 68 [32-82] years, 44% with refractory disease and 56% with relapsed disease. The median [range] number of prior therapies was 5 [1-12]. The proportion of patients with specific prior therapies included: indolent NHL-rituximab 96%, alkylator 86%, anthracycline 50%, purine analog 36%; aggressive NHL-rituximab 100%, alkylator 100%, anthracycline/anthracenedione 96%, plus bortezomib 72% in MCL patients. CAL-101 dose levels were 50 mg BID (n=2), 100 mg BID (n=11), 150 mg BID (n=8), 200 mg BID (n=16), 350 mg BID (n=9) and 300 mg QD (n=9). The median [range] number of treatment cycles was 4 [1-16], with 16 (29%) patients continuing on treatment (11 on study and 5 on the extension protocol after 12 cycles). Symptomatic adverse events were infrequent, usually low-grade, and not clearly CAL-101-related. Grade ≥3 hematological laboratory abnormalities included neutropenia n= 5 (9%), lymphopenia n=3 (5%), and thrombocytopenia n=3 (5%) with uncertain relationship to CAL-101. Grade≥3 ALT/AST elevations occurred in 18 (33%) patients with onset 2–8 weeks after CAL-101 initiation and resolution 2–4 weeks after CAL-101 interruption; after resolution of ALT/AST changes, most patients were rechallenged at the same or a reduced dose of CAL-101 and the majority of these patients were able to resume treatment without recurrence of transaminase elevations. Partial responses were observed at all dose levels, with respective overall n/N (response rates) in evaluable patients of 15/24 (62%) for indolent NHL, 10/16 (62%) for MCL and 0/9 (0%) for DLBCL. Respective response rates by relapsed or refractory status were 9/13 (69%) and 6/11 (55%) for indolent NHL and 8/11 (73%) and 2/5 (40%) for MCL. The median duration of response had not been reached in indolent NHL patients; 5 patients have had response durations of ≥6 months with response durations ranging to >16 months. The median [range] duration of response was 3 months [1 month to 8 months] in MCL. Pharmacodynamic data have supported drug activity; plasma concentrations of chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases within 1 cycle of CAL-101 treatment (p<0.001 for both comparisons). An evaluation of pharmacokinetics indicated minimal increases in plasma Cmax and AUC at CAL 101 doses >150 mg BID; these data, taken together with the tumor regression results, have proved helpful in supporting Phase 2–3 dose selection. Conclusions: CAL-101, an oral PI3Kδ isoform-selective inhibitor, shows acceptable safety and promising pharmacodynamic and clinical activity in patients with indolent NHL and MCL. The high rate of tumor regressions and protracted durations of tumor control in heavily pretreated patients support advancing CAL-101 into additional studies, both as a single agent and in combination with chemo/immunotherapy. Disclosures: Kahl: calistoga: Consultancy, Research Funding. Off Label Use: CAL-101 for relapsed lymphoma. Byrd:Calistoga Pharmaceutical Inc.: Equity Ownership. Flinn:calistoga: Research Funding. Wagner-Johnston:calistoga: Research Funding. Spurgeon:calistoga: Research Funding. Furman:GlaxoSmithKline: Clinical research funding, Consultancy, Research Funding, Speakers Bureau; Genentech: Clinical Research Funding, Consultancy, Research Funding, Speakers Bureau; Cephalon: Speakers Bureau, Speakers bureau; Calistoga: Consultancy, Honoraria; Celgene: Clinical Research, Consultancy, Research Funding. Brown:Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Coutre:calistoga: Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Ulrich:Calistoga Pharmaceuticals: Employment, Equity Ownership. Webb:Calistoga Pharmaceuticals: Employment. Peterman:Calistoga Pharmaceuticals: Employment. Holes:Calistoga Pharmaceuticals: Employment.

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Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2936.2936 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2936-2936

Author(s):

Victor H Jimenez-Zepeda ◽

Donna E. Reece ◽

Suzanne Trudel ◽

Christine Chen ◽

Vishal Kukreti

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Research Funding ◽

Clinical Characteristics ◽

Phase 1 ◽

Prior Exposure ◽

Rank Test ◽

Continuous Variables ◽

Previously Treated ◽

Grade 3

Abstract Abstract 2936 Almost all patients (pts) with multiple myeloma eventually relapse and remission duration decreases with each regimen. The median Progression Free Survival (PFS) and Overall Survival (OS) in pts with relapsed myeloma refractory to lenalidomide (len) and bortezomib (btz) is poor at 5 and 9 months respectively. A phase 1 study of len plus btz in pts with relapsed or relapsed, refractory MM (RRMM) demonstrated favorable toxicity and promising response and survival further confirmed in a phase 2 study with len, btz and dexamethasone (dex) [RVD]. In this retrospective study, we assessed the efficacy and toxicity profile of RVD therapy for pts with advanced RRMM. We retrospectively reviewed the records of all pts with RRMM treated with RVD at Princess Margaret Hospital between 03/09 and 05/11. Relapse was defined according to the Uniform International Criteria. Pts were given RVD therapy as previous described by Anderson et al and must have completed at least one cycle of RVD therapy. Primary endpoints were response rate (RR), PFS, OS, and toxicity. Pts discontinued therapy if they experienced PD, no additional benefit or unacceptable toxicity. Definitions of response and progression were used according to the EBMT modified criteria with a category of very good partial response (VGPR). To examine variables independently prognostic for PFS and OS, multivariate Cox analysis was performed. Differences in continuous variables between groups were compared using Mann-Whitney or Kruskal-Wallis tests. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Thirty pts with RRMM received RVD therapy. Clinical characteristics are seen in Table 1. Median age at RVD initiation was 57 yrs (37–76 yrs), and 46.7% were male. Pts received a median of 3 prior therapies (1–6). In many instances, pts previously treated with len had len added to btz + dex at progression (n=6), or pts previously treated with btz had btz added to len + dex, at progression (n=5). Thalidomide (thal), len and btz containing regimens were previously used in 60%, 73.3% and 80% of pts respectively. PR or better was observed in 46.6%. After a median of 4.6 cycles (1–14), VGPR was seen in 4.8%, PR in 33% and SD in 14%. Pts who achieved PR or better experienced a significant improvement in PFS. There was no difference in terms of RR between those pts according to prior exposure to either btz or len (p=0.7 and 0.9 respectively). Eight pts experienced non-hematological grade 3/4 adverse events (26%), including muscle weakness, sepsis and pneumonia but there was no worsening of peripheral neuropathy. Grade 3–4 neutropenia and/or thrombocytopenia were commonly seen in 70% of pts (n=21). Disease progression was seen in 19 pts at a median of 3.9 months. Median PFS for pts previously exposed to len was 2.3 months vs 2.9 months for those with no prior exposure (p=0.75). On the other hand, median PFS for pts previously exposed to btz was 2.1 months vs 3.4 months for those with no prior exposure (p=0.9) In addition, median PFS for pts who achieved at least PR was significantly better at 5.9 vs 2.0 months for those who did not (p<0.005). (Figure 1) FISH cytogenetics studies were available in 19 out of 30 patients at relapse: 5 -normal, 4–13q deletion, 3-p53 deletion and 2 - t(4, 14). High-risk MM pts had a median PFS significantly lower of 0.6 months (CI 95%, 0–1.99) vs 4.7 months for those without high-risk features (CI 2.5–7.0) (p=0.008) (Figure 2) At the time of submission, 13 pts are alive (43.3%) and 7 pts (23%) continue on RVD therapy.Table 1.Clinical characteristics of patients with RRMM treated with RVDClinical characteristic N=30MedianRange%Age5737-76Male46.7%Female53.3%Hemoglobin (g/L)10571-155Creatinine (mmol/L)99.936-383Beta-2 microglobulin (mmol/L)280119-1440Lactate dehydrogenase (U/L)18189-255IgG56.6% (17)IgA23.3% (7)IgM3.3% (1)Light Chain16.6% (5)Kappa (mg/L)4005.3-346063.3% (19)Lambda (mg/L)5145.1-530036.7% (11)KappaLambda*BMPC57%6-95%M-spike serum (g/L)300-77M-spike urine (g/d)0.890-7.9Prior therapies31-6ASCT83.3% (25)Thal60% (18)Len73.3% (22)Btz80% (24)*BMPC, Bone marrow plasma cells In conclusion, RVD is active and well tolerated in pts with RRMM, including pts who have received prior len, btz, thal and ASCT but PFS is short at 3.9 months in this highly advanced disease group of patients. We question whether response is dependent on recognized risk factors such as adverse cytogenetics. Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Kukreti:Celgene: Honoraria.

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Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽

10.1182/blood.v120.21.3785.3785 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3785-3785 ◽

Cited By ~ 1

Author(s):

H. Jean Khoury ◽

Carlo Gambacorti-Passerini ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

David Marin ◽

...

Keyword(s):

Pleural Effusion ◽

Chronic Myeloid Leukemia ◽

Disease Progression ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115 CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110 MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41) CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119 PFS at 2 yc 70% 81% 79% 38% 75% OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

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Phase 1 Study of Tabalumab, a Human Anti-BAFF Antibody and Bortezomib in Patients with Previously-Treated Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.447.447 ◽

2012 ◽

Vol 120 (21) ◽

pp. 447-447 ◽

Cited By ~ 6

Author(s):

Noopur Raje ◽

Edward Anthony Faber ◽

Paul G. Richardson ◽

Gary J. Schiller ◽

Raymond J. Hohl ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Median Number ◽

Phase 1 Study ◽

Advisory Committees ◽

Baseline Serum ◽

Lower Baseline ◽

Previously Treated

Abstract Abstract 447 Background: Tabalumab, a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF), has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of multiple myeloma (MM). We initially conducted a Phase 1 study with the combination of tabalumab and bortezomib in previously-treated MM patients who were not refractory to bortezomib. The results from the dose escalation (Part A) have been previously reported, where a tabalumab dose of 100 mg was selected based on several factors, most notably the stabilization of the peak to trough concentration ratio. The cohort expansion (Part B) has since completed enrollment, and we now report the preliminary results for the entire study. Methods: The primary objective was to identify a safe and potentially efficacious dose of tabalumab to be combined with bortezomib. Bortezomib was given in a standard biweekly fashion, 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle, and tabalumab at 1, 10, 30, 100, or 300 mg (Part A) or 100 mg (Part B) IV (30 min) on day 1 in Cycles 1 – 3, 5, and 7. The study was later amended to include dexamethasone to assess safety, and 12 patients received dexamethasone in combination with bortezomib and tabalumab. Response was assessed per IMWG criteria and adverse events per CTCAE v3.0. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were obtained throughout the study, including BAFF, IL-1beta, IL-6, IL-10, VEGF, and TNF-alpha. Results: Forty-eight patients were enrolled to the study; 20 to dose escalation (Part A) and 28 to cohort expansion (Part B). The median age was 65.7 years and 56% were women. The median number of prior therapies was 3 (range 1–10). All patients received either bortezomib or an IMiD; 75% received prior bortezomib and 88% received prior IMiD therapy. The median number of cycles was 5.5 (range 1–28). Grade 3/4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, renal failure acute, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. Most patients discontinued treatment due to progressive disease or adverse events (neuropathy, neuralgia, fatigue, and thrombocytopenia). Two patients died during study participation - one during treatment from acute respiratory distress syndrome and another during follow-up from multiple myeloma. Confirmed responses included 2 complete responses, 4 very good partial responses, and 16 partial responses. Response associated with lower baseline serum BAFF or IL-6 levels, independent of the tabalumab dose. Also, response in patients treated with tabalumab 100 mg appeared to associate with lower baseline serum levels of IL-10 and undetectable TNF-alpha. With 14 patients censored, the TTP was 4.9 months (95% CI: 4 – 8). With 6 patients censored, the median response duration was 7.3 months (95% CI: 3.5 – 13.9). Conclusions: A 100 mg dose of tabalumab in combination with bortezomib was well tolerated; 22 patients achieved a PR or better despite prior bortezomib and/or IMiD therapy. Response correlated with lower baseline serum BAFF levels, supporting the hypothesis that a higher dose of tabalumab should be evaluated. A three-arm study randomizing patients to the combination(s) of bortezomib, dexamethasone, and tabalumab 100 mg vs. tabalumab 300mg vs. placebo is currently enrolling. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Schiller:Eli Lilly & Company: Research Funding. Cohen:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carpenter:Eli Lilly & Company: Employment. Cronier:Eli Lilly and Company: Employment. Kaiser:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

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