Genzyme and Relational Investors: Science and Business Collide?

The chairman and CEO of the Genzyme Corporation, one of the country's top five biotechnology firms, has received a phone call requesting a meeting with the cofounder and principal of a large activist investment fund that now has a 2.6% stake in his company. Before meeting with him, the CEO is aware that he needs a strategy for dealing with this “activist” investor with a track record of forcing out CEOs.

Phase I Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy in Relapsed or Relapsed/Refractory Multiple Myeloma

Abstract 1874 INTRODUCTION: This study aimed to determine the safety and activity of plerixafor (CXCR4 inhibitor) in combination with bortezomib as a chemosensitization strategy in multiple myeloma (MM). This was based on our preclinical studies showing that plerixafor (Mozobil, Genzyme Corporation, MA) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. METHODS: Eligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with 1–5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib), 2) measurable disease, 3) not receiving chemotherapy > 3 weeks, or biological therapy for MM > 2 weeks prior to study treatment. Eight cohorts with different doses and two treatment schedules were planned. In cohorts 1–5, patients received plerixafor at the recommended dose sq on days 1–6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. To test the hypothesis that higher doses and a different schedule might induce better chemosensitization, in cohort 5b–7 plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Bortezomib was given 60–90 minutes after plerixafor. Patients were assessed after every cycle by modified EBMT/UC criteria. Patients who had a response or stable disease went on to receive a total of 8 cycles with maintenance therapy for patients with at least a minimal response (MR). To examine the in vivo effect of plerixafor and bortezomib on de-adhesion of MM cells and other accessory cells of the bone marrow, peripheral blood samples were obtained from the patients at 0, 1, 2, 3, 4 and 24 hours post-dose on days 1 and 3, and time points 0, 2, and 4 hours post-dose on days 6, 10 and 13 of cycle 1. RESULTS: Twenty-five patients were enrolled in this phase I trial from June 2009 to May 2011. Median age was 60 years (range, 44–85) and median lines of prior therapy were 2 (range, 1–4) with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 3 (1–11). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). To further explore the safety of maximum tolerated dose, three additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). Overall, the combination proved to be well tolerated. There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). One patient came off treatment due to grade 2 painful neuropathy at cycle 5. Twenty-three patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR) and 3 (13%) MR, with an overall response rate (including MR) of 5 (22%) in this relapsed and refractory population. In addition, 15 (65%) patients achieved stable disease (SD), with just 3 (13%) having progressive disease (PD) as their best response. We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. Similar results were observed on days 1 and 3, but less mobilization occurred on the following days. Hematopoietic stem cell mobilization occurred at 4 hours on days 1 and 3, and was less observed with subsequent doses of plerixafor consistent with prior studies. CONCLUSIONS: The combination of plerixafor and bortezomib is generally well tolerated with minimal neuropathy or other toxicities seen to date. The responses observed are encouraging in this relapsed and refractory population. The ability to demonstrate transient de-adhesion of MM cells and accessory cells in vivo in most of the patients indicates that chemosensitization can potentially be achieved in patients with MM using this approach. Further studies are warranted and a phase 2 trial is underway. This study was supported by R01CA133799-01, and by Genzyme Corporation. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Plerixafor in myeloma. Munshi:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium: Consultancy; Celgene: Consultancy. Anderson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Preliminary Results From A Phase I Dose Escalation Study to Determine the Maximum Tolerated Dose of Plerixafor In Combination with Rituximab In Patients with Relapsed Chronic Lymphocytic Leukemia

Abstract 2450 Background: Dose intense rituximab in previously-treated patients (pts) with CLL has demonstrated modest activity. Preclinical data indicate that the CXCR4/CXCL12 axis plays a key role in CLL cell homing and retention in tissue microenvironments, such as the bone marrow. Disruption of this axis using the small-molecule CXCR4-antagonist, plerixafor, may abrogate stroma-mediated drug resistance, and enhance sensitivity of CLL cells to rituximab. To test this hypothesis, we initiated a phase 1 trial of plerixafor + rituximab in previously-treated pts with CLL. Aims: The primary objective was to determine the maximum tolerated dose (MTD) and safety of plerixafor when combined with rituximab. Methods: Adult pts with WBC≤ 50×109/L, intermediate/high risk CLL not refractory to rituximab, and with active disease by NCI criteria were eligible in this ongoing study. Pts were treated with 3x/week rituximab, as a 100mg flat dose on Day 1, and subsequently 375mg/m2 IV for 12 total doses (i.e. for 4 weeks). Plerixafor was given SC prior to rituximab starting at the 4th rituximab dose (Day 8) for 9 total doses. Cohorts of pts were treated at 1 of 4 dose levels with plerixafor (0.08mg/kg, 0.16mg/kg, 0.24mg/kg and 0.32mg/kg). Pts were observed for dose-limiting toxicities (DLT) from the first plerixafor dose (Day 8) through Day 29 and cohort advancement followed dose escalation rules using a 3+3 design. Peripheral blood (PB) CD34+ and CLL cells were enumerated on Days 8 and 26 by flow cytometry; PB samples were obtained at baseline pre-plerixafor treatment and at 2, 4, 6, 10, and 24 hours post-plerixafor. Responses were assessed as defined by Cheson et al (Blood, 1996). Results: 17 pts (median age 64 years; 88% male; Rai Stage IV: 53%) were enrolled, 3 pts each in the 0.08 and 0.24 mg/kg cohorts, 4 pts in the 0.16mg/kg cohort and 7 pts in the 0.32mg/kg cohort (Table 1). No DLTs were reported. Of 14 evaluable pts, 5 (36%) had partial response, 3 (21%) had stable disease for ≥2 months and 6 (43%) had progressive disease. Treatment-emergent, plerixafor-related adverse events (AEs) were seen in 5 pts and included diarrhea, vomiting, nausea, appetite loss, headache, hypoaesthesia and paraesthesia. All AEs were grade 1 except nausea (n=1) that was grade 2. Treatment-emergent serious AEs were seen in 2 pts (0.16mg/kg dose; grade 3 EBV infection, grade 2 gastrointestinal reflux disease and grade 2 dyspnea); all unrelated to plerixafor. On Day 8, there was a median 3.8-fold increase in PB CLL cells (range: 1.2 –15.0-fold), indicating CLL cell mobilization. On Day 26 fewer PB CLL cells were detected with a median fold increase of 1.5 (range, 0.9–8.0). Conclusions: The combination of plerixafor + rituximab in CLL pts with WBC < 50×109/L was well tolerated. CLL cells were mobilized following plerixafor, and partial remissions were seen in a proportion of pts. In some cases, maximum responses were seen several months after completion of rituximab, consistent with single agent therapy. This suggests that continued follow up may show additional responses in recently treated pts. Disclosures: Andritsos: Genzyme Corporation: Research Funding. Off Label Use: Plerixafor (Mozobil®), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Byrd: Genzyme Corporation: Research Funding. Jones: Genzyme Corporation: Research Funding. Hewes: Genzyme Corporation: Employment. Kipps: Genzyme Corporation: Research Funding. Hsu: Genzyme Corporation: Employment, Equity Ownership. Burger: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Efficacy and Safety of Hematopoietic Stem Cell Remobilization with Plerixafor (Mozobil®) + G-CSF In Adult Patients with Non-Hematologic Malignancies

Abstract 2249 Background: Although high dose chemotherapy followed by autologous hematopoietic stem cell (HSC) transplantation is a potentially curative procedure for patients with hematologic and non-hematologic malignancies, a significant number are unable to mobilize sufficient cells to proceed to transplant. While the safety and efficacy of plerixafor + G-CSF is well established for front-line and salvage mobilization in patients with myeloma and lymphoma, data are limited for patients with non hematological malignancies. We now report on the safety and efficacy of remobilization with plerixafor + G-CSF in patients in this setting. Methods: This is a retrospective analysis of patients >18 years with non hematological malignancies enrolled in the US plerixafor compassionate use program (CUP). In the CUP, patients with previous mobilization failure (defined as the inability to collect ≥2 ×106 CD34+ cells/kg or achieve an adequate peripheral blood (PB) count, typically ≥10 CD34+ cells/μl) were remobilized with plerixafor + G-CSF with the goal of collecting 2 × 106 CD34+ cells/kg to proceed to transplant. G-CSF (10μg/kg SC) was given every morning for 5 days. Plerixafor (0.24 mg/kg SC) was given in the evening on Day 4, ~11 hours prior to apheresis the next day. Plerixafor, G-CSF and apheresis were repeated daily until patients collected ≥2×106 CD34+ cells/kg. Results: The analysis included 32 patients (median age 32.5 years) with germ cell tumor (n=21), medulloblastoma (n=4), sarcoma (n=3), breast cancer (n=2), cervical cancer (n=1) or chordoma (n=1). Previous mobilization regimens included growth factor alone in 22 patients and growth factor + chemotherapy in 10 patients; 25 patients failed to collect the minimum transplantable cell dose (median yield: 1.27 ×106 CD34+ cells/kg); 7 patients did not undergo apheresis due to low PB CD34+ cells. Remobilization with plerixafor + G-CSF resulted in a median yield of 2.8 × 106 CD34+ cells/kg; the median number of apheresis days was 2 (range 1–4). Twenty-two (69%) patients collected ≥2 × 106 CD34+ cells/kg; the median time to collect the target cell dose was 2 days (range 1–3 days). The median CD34+ cell yield for patients with germ cell tumors was 3.16 × 106 cells/kg. Twenty-four (75%) patients proceeded to transplant; 8/21 patients with germ cell tumors received tandem transplants. Median time to neutrophil and platelet engraftment was 11 and 20 days, respectively. Drug-related adverse events were observed in 12 (38%) patients; most were mild and commonly included injection site reactions (n=6), diarrhea (n=3), nausea (n=2) and bone pain (n=2). None of the patients experienced serious adverse events. Conclusions: Mobilization with plerixafor + G-CSF facilitates collection of an adequate number of HSC in the majority of adult patients with non-hematologic malignancies who have failed prior mobilization with growth factor ± chemotherapy. Using this salvage approach 75% of patients who otherwise would not have had the option could successfully undergo autologous transplantation. Disclosures: Horwitz: Genzyme Corporation: Honoraria, Research Funding. Off Label Use: Plerixafor (Mozobil®), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Huebner: Genzyme Corporation: Employment, Equity Ownership. Mody: Genzyme Corporation: Employment, Equity Ownership. Schriber: Genzyme Corporation: Speakers Bureau.

SUPER- BEAM (SB): Incorporation of Bortezomib, Thalidomide, Dexamethasone, Cisplatin and Rapamycin Into the BEAM Regimen for Multiple Myeloma (MM).

Abstract 3421 Poster Board III-309 Introduction While the prognosis of patients with MM has been drastically improved with the introduction of novel agents into the treatment armamentarium, relapse management remains a difficult task, especially in the post-transplant and high-risk MM setting, as defined by the presence of cytogenetic abnormalities (CA) and gene expression profiling (GEP). Patients and Methods We have explored the efficacy and safety of SB in 95 patients with MM. The regimen comprised BCNU at 300mg/m2 on day 1, etoposide 200mg/m2 on days 1-4; cytarabine 400mg/m2 on days 1-5; melphalan 140mg/m2 on day 5 plus: bortezomib 1.0-1.3mg/m2 on days 1+4, thalidomide 100-200mg on days 1-5, dexamethasone 20-40mg days 1-5, cisplatin 10-12.5mg/m2/d by continuous infusion on days 1-5, rapamycin 3mg on day 1 and 1mg on days 2-5; followed by autotransplant (AT) on day 6. Results Patient characteristics included age >=65, 19%; LDH>ULN, 43%; CA, 67%; GEP high-risk, 44%; GEP MF, 15%; GEP delTP53, 22%; prior AT, 75% including 46% with 2AT and 12% with 3 AT. CR and near-CR status was documented in 50%; TRM occurred within 100 days in 6%. Three-year estimates of overall survival (OS) and event-free survival (EFS) were 34% and 18%; OS/EFS were superior: (a) without CA – 60%/50% versus 15%/5% with CA (p=0.003/0.0005); (b) with GEP low-risk – 55%/20% versus 10%/15% with high-risk MM (p=0.009/0.01); (c) with GEP Hyperdiploidy and Low Bone disease molecular subgroups – 70%/35% versus 20%/10% in the remainder (p=0,001/0.002); and (d) absence of progression prior to SB – 52%/35% versus 16%/5% for the remainder (p=0.002/0.0006). Univariately significant adverse variables for OS and EFS included low albumin, B2M>=3.5mg/L, CA, GEP high-risk and relapse just prior to SB, of which B2M, CA and pre-SB survived on multivariate analysis for the 78 patients with all variables; among the 57 with GEP data, OS was inferior with GEP high-risk MM (HR=3.55, p=0.007) whereas EFS was inferior with high LDH (HR=3.44, p=0.004), CA (HR=2.79, p=0.02) and pre-SB relapse (HR=2.94, p=0.035). Conclusions We conclude that SB is a safe salvage regimen that was well-tolerated for the majority in the outpatient setting. Although beneficial to patients lacking CA and GEP high-risk status, the poor outcome also with SB in the presence of these adverse features emphasize the urgent need to discover agents/strategies effective in this setting. Disclosures van Rhee: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.