A Phase II Clinical Trial of the Anti-EGFR Antibody Cetuximab in Patients with Refractory or Relapsed Multiple Myeloma: Final Results,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3965-3965
Author(s):  
Bastian von Tresckow ◽  
Boris Böll ◽  
Dennis A. Eichenauer ◽  
Denissa Peine ◽  
Stefan Knop ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Side Effects ◽  
Partial Response ◽  
Stable Disease ◽  
Clinical Benefit ◽  
Single Agent ◽  
Acneiform Rash ◽  
Grade 3 ◽  
Egfr Antibody

Abstract Abstract 3965 INTRODUCTION: So far, monoclonal antibodies have not yielded convincing therapeutic success in multiple myeloma (MM). Therefore, the discovery of an effective targeted antibody against MM would open new perspectives for patients with relapsed or refractory MM and for the combination with established therapies. Cetuximab is an anti-epidermal growth factor receptor (EGFR) antibody. EGFR is also expressed on multiple myeloma (MM) plasma cells and bone marrow stromal cells. Recently, the inhibition of EGFR by small molecule inhibitors has been shown to induce apoptosis in primary myeloma cells revealing a synergistic effect with dexamethasone. Therefore, the anti-EGFR antibody cetuximab might be of clinical benefit in the treatment of MM, especially in combination with dexamethasone. Here we show the final results of the first clinical trial with an anti-EGFR antibody in MM. METHODS: Cetuximab was administered once weekly in standard dose to patients with refractory or relapsed MM who had previously received at least one line of prior treatment including autologous stem cell transplant (ASCT). Patients who still were candidates for ASCT were not included. Dexamethasone 20 mg on day 1–3 of each cycle was added starting week 5 in case of tumor progression or week 9 if no partial response (PR) or complete response (CR) was achieved with cetuximab alone. Planned treatment duration was 16 weeks (primary endpoint) with the possibility to prolong treatment in case of stable disease (SD) or response. RESULTS: In total, 15 patients have been enrolled. Seven patients were treated for a minimum of 16 weeks and 5 of those patients received cetuximab for at least 28 weeks. One patient received cetuximab treatment as single agent for more than one year. Thrombocytopenia, hyponatremia and acneiform rash were the most common CTC grade 3 or 4 side effects. Acneiform rash CTC grade 1 occurred in all patients and 3 patients suffered from acneiform rash CTC grade 3. After 16 weeks (primary endpoint) cetuximab in combination with dexamethasone induced 4 responses (3 minimal responses (MR) and 1 partial response (PR)) and achieved stable disease (SD) in 1 patient. Cetuximab as single agent induced SD in 2 patients. This results in an intention-to-treat overall response rate (ORR; CR+PR+MR) of 27% and a clinical benefit rate (at least SD) of 47%. Five of the 15 patients included did not receive the planned 16 weeks of treatment due to progressive disease (PD); three patients stopped treatment due to intolerable side effects. Six patients were treated more than 16 weeks: 1 patient received cetuximab as single agent and had SD more than a year and 5 patients continued treatment with cetuximab and dexamethasone in combination. CONCLUSIONS: Cetuximab is feasible and safe in MM patients. It demonstrated moderate efficacy in highly pre-treated patients, especially in combination with dexamethasone. Due to its unique mode of action and favorable side effect profile, cetuximab should be evaluated as combination partner for established substances such as bortezomib or lenalidomide to increase response rates both in therapy naive and in refractory patients. Disclosures: No relevant conflicts of interest to declare.

Anti-EGFR Antibody Cetuximab in Refractory or Relapsed Multiple Myeloma: Preliminary Results and Evaluation of Response Prediction in a Phase II Clinical Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3686-3686
Author(s):  
Bastian von Tresckow ◽  
Denissa Peine ◽  
Boris Böll ◽  
Dennis A Eichenauer ◽  
Elke Pogge von Strandmann ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Plasma Cells ◽  
Single Agent ◽  
Response Prediction ◽  
Study Medication ◽  
Acneiform Rash ◽  
Grade 3 ◽  
Egfr Antibody

Abstract INTRODUCTION: Cetuximab (Erbitux©) is an anti-epidermal growth factor receptor (EGFR) antibody approved for the treatment of colorectal cancer and head and neck cancer. EGFR is also expressed on multiple myeloma (MM) plasma and bone marrow stromal cells (BMSC). Recently, the inhibition of EGFR by small molecule inhibitors has been shown to induce apoptosis in primary myeloma cells revealing a synergistic effect with dexamethasone. Therefore, the anti-EGFR antibody cetuximab might be of clinical benefit in the treatment of MM, especially in combination with dexamethasone. Here we show preliminary data of the first clinical trial with an anti-EGFR antibody in MM and discuss possible response predictors. METHODS: Cetuximab in a loading dose of 400 mg/m2 followed by 250 mg/m2 once weekly was administered to patients with refractory or relapsed MM who had previously received at least one line of prior treatment and were not eligible to undergo autologous stem cell transplantation. Responses were assessed according to the EBMT criteria. Dexamethasone 20 mg on day 1–3 of each cycle was added starting week 5 in case of tumor progression or week 9 if no partial response (PR) or complete response (CR) was achieved with cetuximab alone. Planned treatment duration was 16 weeks (primary endpoint). Patients achieving a response or stable disease after 16 weeks of treatment could continue study medication for up to 24 further weeks. In addition, patients who had responded could start treatment according to study protocol for a second time. To assess possible predictive markers for a response to cetuximab we collected patient plasma cells to perform toxicity assays and we analyzed BMSCs of patients for IL-6 secretion after treatment with cetuximab in vitro. RESULTS: Thirteen patients have been enrolled so far. Seven patients were treated for a minimum of 16 weeks and 5 of those patients received cetuximab for at least 28 weeks. One patient still continues cetuximab treatment as single agent for more than one year. Thrombocytopenia and hyponatremia were the most common CTC grade 3 or 4 side effects with grade 3 thrombocytopenia in one patient, grade 4 thrombocytopenia in 2 patients and grade 3 hyponatremia in 3 patients. Acneiform rash CTC grade 1 occurred in all patients and 1 patient suffered from acneiform rash CTC grade 2. Two serious adverse events (SAEs) with a possible relationship to the study medication were observed: Fever and shivering requiring hospitalization in 1 patient and dyspnea in 1 patient who suffered from chronic obstructive pulmonary disease, this patient was excluded from the study after the first application of cetuximab. Three SAEs with causal relationship not likely to study drug administration were noted: Septic shock resulting in death in 1 patient, fever due to infection requiring hospitalization in 1 patient and transient atrial fibrillation in 1 patient. After 16 weeks (primary endpoint) cetuximab in combination with dexamethasone induced 3 responses (2 minimal responses (MR) and 1 partial response (PR)) and led to stable disease (SD) in 3 patients, cetuximab as single agent led to SD in 1 patient. Five of the 13 patients included did not receive the planned 16 weeks of treatment due to progressive disease (PD). Six patients were treated more than 16 weeks: 1 patient still receives cetuximab as single agent and is SD since a year and 5 patients continued treatment with cetuximab and dexamethasone in combination. There was 1 PD after 21 weeks and 2 SDs and 2 MRs after 28 weeks in this cohort. In viability assays with patient plasma cells we could demonstrate that cetuximab is cytotoxic in some of the patient samples. Furthermore, cetuximab suppressed the production of growth stimulating IL-6 in BMSCs of the patient who still receives cetuximab and remains SD. To assess whether cytotoxicity of cetuximab in patient plasma cells in vitro or cetuximab-induced inhibition of IL-6 secretion might predict response to treatment, more samples will be evaluated. CONCLUSIONS: Cetuximab is safe and effective in MM patients. Because of its favourable side effect profile it should be evaluated in clinical trials in combination with other compounds. Analyzing the effects of cetuximab on patient plasma and BMSCs might become useful for response prediction of cetuximab in MM patients in the future.

scholarly journals 28-Day Metronomic Therapy for Relapsed Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Tarek H Mouhieddine ◽  
Julia Hieulle ◽  
Erin Moshier ◽  
Josh R. Richter ◽  
Hearn Jay Cho ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Clinical Benefit ◽  
Research Funding ◽  
Complete Response ◽  
Chemotherapeutic Agents ◽  
Metronomic Therapy ◽  
Grade 3

Background: The advent of novel therapies has led to tremendous progress in the treatment of multiple myeloma (MM). However, management of patients with high-risk disease who have failed approved agents and have rapidly progressive disease with cytopenias continues to be challenging. While palliative care is an option, many patients hope to qualify for a clinical trial option. Here we report results of a 28-day metronomic therapy (METRO-28) consisting of continuous administration of very low doses of classical chemotherapeutic agents. Sixteen-day cycles of metronomic therapy were previously shown to have a favorable response with acceptable toxicity profiles in MM patients (Papanikolaou et al. Haematologica 2013). Aim: To investigate the efficacy and toxicity in patients with high-risk relapsed refractory MM (RRMM) ineligible for clinical trial options receiving 1 cycle of METRO-28. Method: We retrospectively analyzed the clinical outcomes of 106 RRMM, treated with 1 cycle of 28-day metronomic chemotherapy at the Tisch Cancer Institute - The Mount Sinai Hospital. METRO-28 consists of 6 agents: dexamethasone 8 mg on days 1 through 4, 7 through 10, 13 through 16, 19 through 22 and 25 through 28; bortezomib 1 mg/m2 on days 1, 4, 7, 10, 13, 16, 19, 22, 25, 28; cisplatin 1 mg/m2 daily; doxorubicin 1 mg/m2 daily; thalidomide 100 mg daily; and vincristine flat dose 0.06 mg daily. METRO-28 was administered through a central line in either the inpatient or outpatient setting. Result: Our cohort of 106 RRMM patients has a median age of 65 years (range: 35-85) and at a median of 59 months from time of diagnosis; 42% were females. They had a median of 7 prior lines of therapy (range: 1 - 25); with 73% triple- and 58% penta-refractory cases. Prior autologous transplantation was utilized in 69% of patients including tandem transplants in 30%. Moreover, 78% of patients carried high-risk cytogenetic features, including 1q21 duplication/amplification (89%), 17p deletion (49%), t(4;14) (17%), t(14;16) (17%) or t(14;20) (3%). At the time of METRO-28 initiation, patients were cytopenic with grade 3 and 4 anemia (21%), neutropenia (8%) and thrombocytopenia (23%). Profound cytopenias in some patients led to early discontinuation of treatment; forty-three patients (41%) received the full 28-day course of METRO-28, while 11%, 17%, 20% and 11% were treated for <1 week, <2 weeks, <3 weeks or <4 weeks, respectively. Grade 3-4 cytopenia increased: anemia 66%, leucopenia 61%, neutropenia 55% and thrombocytopenia 76%. On an intent to treat basis (106 patients), the deepest response included 2% stringent complete response (sCR), 7% near complete response (nCR), 7% very good partial response (VGPR), 28% partial response (PR), 11% minimal response (MR) and 12% stable disease (SD). Only 43 patients (41%) completed all 4 weeks of METRO-28 and had a 72% overall response rate (ORR) and 88% clinical benefit rate (CBR). Seventy-four percent of these patients were able to move on to new therapies, including novel agents and clinical trials. Their overall survival (OS) was 11.8 months (range: 6.1-NE) as opposed to an OS of 4.2 months (range: 3.4-7.2) for patients with <4 weeks of METRO-28. Sixty-three patients had their treatment interrupted: 34 due to disease progression or absence of response, 18 due to bacterial or viral infections and 11 due to hematologic toxicity. Conclusion: Giving 1 cycle of METRO-28 is better tolerated in patients with good hematologic reserve and offers an opportunity for a clinical benefit and a bridge to a subsequent treatment option for these advanced refractory myeloma patients. Disclosures Richter: Takeda: Consultancy; Janssen: Speakers Bureau; Sanofi: Consultancy; AstraZeneca: Consultancy; X4 Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy, Speakers Bureau; Oncopeptides: Consultancy; Secura Bio: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Speakers Bureau. Parekh:Foundation Medicine: Consultancy; Celgene: Research Funding; Karyopharm: Research Funding. Chari:Adaptive Biotechnology: Honoraria; The Binding Site: Honoraria; Array BioPharma: Honoraria; Novartis: Honoraria; Secura Bio: Consultancy; Glaxo Smith Kline: Consultancy; Antengene: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy; Seattle Genetics: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jagannath:Legend Biotech: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Madduri:Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Kinevant: Consultancy; Foundation Medicine: Consultancy.

A Multicenter, Single-Arm, Open-Label Study To Evaluate the Efficacy and Safety of Single-Agent Lenalidomide in Patients with Relapsed and Refractory Multiple Myeloma; Prelininary Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1565-1565 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Stable Disease ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Multicenter Phase ◽  
Best Response

Abstract INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory MM determined that the maximum tolerated dose (MTD) of lenalidomide was 25 mg/day, based upon myelosuppression encountered beyond 28 days, which was manageable with growth factor support and dose reduction. In a multicenter phase 2 study to determine optimal dose and schedule, 102 pts with relapsed or refractory MM were randomized to receive lenalidomide at either 15 mg bid (n=34) or 30 mg qd (n=68), for 21 days every 4 wks. Both treatment arms showed significant activity with manageable toxicity. An increased incidence of cytopenia was noted in the 15-mg bid group and thus the 30 mg qd schedule was taken forward. METHODS: The objective of this multicenter, phase 2, open-label study (CC-5013-MM-014) was to further evaluate the effectiveness and safety of single-agent lenalidomide administered at a dose of 30 mg qd for 21 days every 28 days (28-day cycle) in pts with relapsed and refractory MM. Eligible patients included those who had received prior thalidomide, bortezomib, or SCT. RESULTS: 222 pts were enrolled into the study. All patients had received at least 2 prior anti-myeloma treatments, including bortezomib (41%), thalidomide (80%), and SCT (44%). Table 1 shows Best Response data, excluding patients in whom responses were not evaluable (n=10). Partial response or better occurred in 25% of patients and SD or better in 71%. Time to Progression was a median of 22.4 wks (range 1.8– 66 wks). The median survival has not been reached (the lower bound of the 95% CI exceeds 15 months). The most common treatment-related AEs (those reported in ≥10% of patients overall) included upper respiratory tract infection, neutropenia and thrombocytopenia. AEs that most frequently led to dose reduction or interruption by percentage of cases were neutropenia (40%), thrombocytopenia (23%), fatigue (5%), and anemia (5%). CONCLUSION: Oral lenalidomide in relapsed and refractory MM patients achieved PR+CR in 25%, stable disease or better in 71%, a median TTP of approximately 6 months and a median survival that has not been reached. Toxicity has been manageable with a very low incidence of DVT and minimal treatment-emergent neuropathy. Table 1. Best Response Best Response* n (%) *Excluding patients not evaluable (n=10); CR=complete response and PR=partial response (EBMT criteria) ≥PR (CR + PR) 53 (25) Stable disease 152 (71)

First Interim Results of a Phase I/II Study of Lenalidomide in Combination with Anti-PD-1 Monoclonal Antibody MDV9300 (CT-011) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1838-1838 ◽  
Author(s):  
Yvonne A. Efebera ◽  
Ashley E Rosko ◽  
Craig Hofmeister ◽  
Joe Benner ◽  
Courtney Bakan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
T Cell ◽  
Partial Response ◽  
Phase I ◽  
Nk Cells ◽  
Disease Progression ◽  
Stable Disease ◽  
Nk Cell ◽  
Grade 3

Abstract Introduction: Multiple myeloma (MM) is associated with profound and widespread disarray of both the adaptive and innate arms of the immune system including loss of effector T cell function, humoral immune deficiency, and natural killer (NK) cell immunity. This immunosuppressive milieu is crucial to promoting disease progression. Standard treatment options (immunomodulators (IMIDs) and proteosome inhibitors, radiation, and high-dose corticosteroids) offer modest benefit, but also contribute to further immune suppression. Little is known regarding the mechanisms by which immune dysfunction and immunoevasion occur. Our group has characterized an important role for the programmed death receptor-1 (PD-1) / PD-L1 signaling axis in these processes. MDV9300 (formerly CT-011 / Pidilizumab) is a novel IgG1 humanized monoclonal antibody (mAb) that modulates the immune response through interaction with PD-1. Lenalidomide (Len) an IMID exerts efficacy in MM in part through enhancement of NK cell versus MM effect - an effect likely mediated through T cell production of interleukin (IL)-2. In our in-vitro study, pretreatment of NK cells with MDV9300 with or without Len enhanced immune complex formation between NK cells and MM tumor targets and also augmented NK cell activation and cytotoxicity against MM. We sought to determine the safety, tolerability and any early signs of efficacy in relapsed or refractory MM patients using MDV9300 in combination with Len. Methods: In the phase I portion, the primary endpoint is to determine the maximum tolerated dose (MTD) of the combination. Key eligibility criteria are relapsed or refractory disease but not progressed on Len 25 mg; ≥2 prior lines of therapy, absolute neutrophil count ≥ 1000/µL; Platelets ≥60,000/µL; and creatinine clearance of ≥ 40ml/min. Patients are treated with escalating doses of MDV9300 and Len utilizing a 3x3 escalation design (Table 1). If stable disease is the best response after 4 cycles, patients have the option of adding dexamethasone (20-40mg weekly). Len dose may be modified independently of MDV9300. Patients can receive a maximum of 12 cycles of therapy. Results: Twelve patients are evaluable to date. The median age was 68.5 (range 49-82) and the median time from diagnosis 4.98 years (range 1.54-12.62). At study entry, 67% had high risk cytogenetics (del 17p, complex karyotype, gain 1q) and the median number of prior treatment lines was 2 (range 2-11). 100% of patients had received prior Len, bortezomib and Dex, 50% alkylating agents (cyclophosphamide, oral melphalan, bendamustine), 75% autologous stem cell transplant, 25% pomalidomide and 33% carfilzomib. MDV9300 infusion has been well tolerated with only one grade 2 infusion related toxicity with sore throat. The patient received hydrocortisone with no further reaction observed. Grade 3/4 Anemia, neutropenia, and thrombocytopenia attributable to therapy have been seen in 25%, 23%, and 34% of patients, respectively. Other common grade 2-3 therapy related adverse events are fatigue (50%), anorexia (17%), and hypophosphatemia (17%). There has been no grade 3 or higher infection and no worsening of neuropathy from baseline. Len dose was reduced in 3 patients (25%) and increased in one. There has been no dose reduction in MDV9300. Dex 20 mg or less was added in 2 patients for muscle cramps and < PR after 3 cycles. To date 7 patients are off therapy; 1 due to grade 3 fatigue and 6 due to disease progression. Five patients continue on therapy at respective 12, 11, 9, 5 and 3 months. Responses to date have been 3 Very good partial response,1 partial response, 2 minimal response and 2 stable disease. Conclusion: The combination of steroid sparing MDV9300 and Len regimen has demonstrated an acceptable toxicity profile to date with evidence of anti-myeloma activity. This is the first reported combination anti-PD-1 based immune therapy for MM. Updated results will be presented at the meeting including the MTD dose for phase II. Table 1. MDV9300- mg/kg Intravenously given on day 3 every 28 days Lenalidomide- mg orally days 1-21 every 28 days DLT Evaluable DLTs Cohort 1 1.5 15 6 Grade 3 fatigue. Cohort extended to 6 Cohort 2 3 15 3 none Cohort 3 3 25 3 none Cohort 4 6 25 0 Acknowledgments: Drug has been provided by Medivation; The study is sponsored by the American Cancer Society Disclosures No relevant conflicts of interest to declare.

Preliminary Safety and Efficacy Results from an International Phase 3b Study for Expanded Access to Bortezomib in 624 Patients with Relapsed and/or Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3530-3530 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Andrew Belch ◽  
Miles Prince ◽  
Maria Nambo Lucio ◽  
Angelo Maiolino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Median Time ◽  
Stable Disease ◽  
Progressive Disease ◽  
Karnofsky Performance Status ◽  
M Protein ◽  
Significant Activity ◽  
Expanded Access ◽  
Grade 3

Abstract Background: Bortezomib (VELCADE®) is a first-in-class, reversible proteasome inhibitor with activity in multiple myeloma (MM) and other malignancies. Bortezomib showed significant activity in previous phase 2 and 3 studies in patients (pts) with previously treated MM. This international multicenter open-label phase 3b study allowed expanded access to bortezomib therapy in pts with relapsed/refractory MM treated with ≥ 2 previous lines of therapy. Methods: Pts with MM were eligible if they had received ≥ 2 prior lines of therapy and required treatment due to relapsed or progressive disease. Pts with grade ≥ 2 peripheral neuropathy (PN) were excluded. Pts received 1.3 mg/m2 IV bolus bortezomib on days 1, 4, 8, and 11 of each 3-week cycle for up to 8 cycles; dexamethasone (20 mg/d PO on the day of and day after bortezomib dose) could be added after cycle 2 for progressive disease or after cycle 4 for stable disease. Adverse events (AEs) were assessed beginning at the start of treatment and continuing until 30–42 days after treatment and were graded based on NCI-CTC version 2.0. Efficacy assessment was performed based on changes in disease burden as measured by monoclonal (M)-protein concentration in serum and urine every 2 cycles (6 weeks). Response was assessed using modified SWOG criteria: complete response (CR) was a 100% reduction in M-protein; very good partial response (VGPR), 75–99% reduction; partial response (PR), 50–74% reduction; minimal response (MR), 25–49% reduction; and stable disease, < 25% reduction. Increasing M-protein levels indicated progressive disease. Results: 624 pts in 93 centers from 21 countries received at least 1 dose of treatment and were evaluable for safety (55.3% male; median age 62.7 years). 68% of pts received 3–11 lines of previous therapy. Karnofsky performance status was ≤70 in 25.6% of pts; 141 pts (22.6%) were ≥ 70 years of age. Pts completed a median of 5 cycles of therapy (range 0–13); 39.3% of pts completed all 8 planned cycles. Grade 3/4 treatment-emergent (related and unrelated) AEs were reported in 430 pts (68.9%), with thrombocytopenia (29.2%), neutropenia (13.3%), and anemia (11.7%) the most common hematologic AEs. Grade 3/4 PN was reported in 8.2% of pts. Overall, 165 pts (26.4%) discontinued therapy due to treatment-related AEs. Best responses among evaluable pts (n = 593) included 12.0% CR, 23.1% VGPR, 19.1% PR, and 16.5% MR, for an overall response rate of 70.7%. Median time to first response was 42 days (range 7–125), and median time to best response was 63 days (range 7–235). Conclusions: Bortezomib 1.3 mg/m2 administered biweekly q3 weeks was well tolerated with manageable toxicities in pts with relapsed and/or refractory MM. Response rates with bortezomib were high, even in heavily pretreated pts, inducing > 25% CR/VGPR. This study confirms results from initial clinical trials in a broader population.

Efficacy and Safety of Salvage Therapy Using Carfilzomib for Relapsed or Refractory Multiple Myeloma Patients: A Multicentre Retrospective Observational Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5371-5371
Author(s):  
Eli Muchtar ◽  
Moshe Gatt ◽  
Ory Rouvio ◽  
Chezi Ganzel ◽  
Evgeni Chubar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Partial Response ◽  
Drug Combination ◽  
Salvage Therapy ◽  
Odds Ratio ◽  
Single Agent ◽  
Dose Schedule ◽  
Advisory Board ◽  
Refractory Multiple Myeloma

Abstract Introduction: Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. Methods: All consecutive patients with RR-MM who received carfilzomib-containing salvage therapy outside of a clinical trial between March 2013 and April 2015 were included in this study. For the response and survival analyses, patients were included only if they received at least one full cycle of carfilzomib and response evaluation was available. Carfilzomib was used either as a single agent or in combinations with other drugs, according to the treating physician's choice. Per manufacturer's recommendations, carfilzomib was given by intravenous infusion over 10-30 minutes on days 1, 2,8,9,15,16 of 28-days cycle. The recommended dose of carfilzomib was 20 mg/m2 on days 1 and 2 in cycle 1, which was increased on subsequent administrations to 27 mg/m2 (the 20/27 mg/m2 schedule), provided that the previous dose was well tolerated. Doses, however, were modified according to the treating physician's discretion. Results: One-hundred and thirty-five patients were included. The median age at carfilzomib initiation was 67.9 years (range, 41-88). Male and female patients were equally balanced. Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 was evident in 14.8% of patients. All patients were previously exposed to bortezomib and 93% to lenalidomide as well. The median time from last treatment to carfilzomib was 5.5 months (range, 0.3-43). Patients had received a median of 3 lines of therapy prior to carfilzomib (range, 1-7). The median number of administrated cycles of carfilzomib was 4 (range, 0.3-22). The majority of patients (79.3%) received carfilzomib according to the 20/27 mg/m2 dose schedule. The remaining patients received carfilzomib either at a dose that did not exceed 20 mg/m2 (11.8%) or at maximal dose higher than 27 mg/m2 (8.9%, mostly as a 20/27/56 mg/m2 dose schedule). Carfilzomib was administrated as a single agent in 5.1% of patients or combined with a second agent in 43% of them. Additionally, 46.7% of patients received carfilzomib as part of a three-drug combination and 5.2% of patients as part of four-drug combination or more. In comparison to patients who received two-drug combination (or carfilzomib alone), patients who received three-drug (or more) combination were younger, with less prior treatment lines and higher baseline haemoglobin, albumin and eGFR (Table I). There was also pre-selection by lower frequency of ImIds resistance in the three-drug combination sub-group, but bortezomib resistance was similar between sub-groups. One hundred and twenty three patients (91.1% of patients) were evaluable for response and survival analysis. The overall response rate was 48.8%, with one patient (0.8%) achieving complete response (CR), 30 patients (24.4%) attaining very good partial response (VGPR) and 29 patients (23.6%) with partial response (PR). Additionally, 15 patients (12.2%) achieved minimal response (MR), reaching a clinical benefit response (CBR) rate of 61%. A multivariate analysis revealed three parameters negatively impact the likelihood of achieving response: bortezomib resistance (odds ratio 0.33, 95% CI 0.12-0.94, p=0.03); lenalidomide resistance (odds ratio 0.31, 95% CI 0.11-0.91, p=0.03), and albumin <3.5 g/dL (odds ratio 0.32, 95% CI 0.14-0.71 p=0.005). The median duration of response was 8.3 months, significantly higher in patients receiving three-drug combination and in patients presenting without extramedullary disease. The median progression free survival (PFS) and overall survival for the entire cohort were 4.9 months (95% CI 3.9-6.9) and 19.3 months (95% CI 9.4-not yet reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. Conclusion: In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields an effective results with a manageable toxicity. Drug resistance is an important factor in determining response quality to carfilzomib. Disclosures Raanani: Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board; BMS: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding.

Results of PX-171-003-A1, An Open-Label, Single-Arm, Phase 2 (Ph 2) Study of Carfilzomib (CFZ) In Patients (pts) with Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 985-985 ◽  
Author(s):  
David Samuel diCapua Siegel ◽  
Thomas Martin ◽  
Michael Wang ◽  
Ravi Vij ◽  
Andrzej J Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Single Agent ◽  
Study Entry ◽  
Open Label ◽  
Advisory Committees ◽  
Ortho Biotech

Abstract Abstract 985 Introduction: CFZ is a novel and highly selective epoxyketone proteasome inhibitor currently in clinical development for the treatment of multiple myeloma (MM). Ph 1 and 2 studies with CFZ have demonstrated durable single-agent antitumor activity in pts with relapsed or refractory (R/R) MM. The present study, PX-171-003-A1, was an open-label, single-arm Ph 2b trial and enrolled patients with multiply relapsed MM whose disease was refractory (defined as <25% response on, or progression during or <60 days after completion of, therapy) to their last treatment regimen. Patients must have received ≥2 prior therapies including: 1) bortezomib (BTZ) and either thalidomide (THAL) or lenalidomide (LEN), and 2) an alkylating agent. Materials and Methods: Pts received CFZ at 20 mg/m2 on a QDx2 schedule (Days 1, 2, 8, 9, 15, and 16 every 28 days) in cycle (C) 1 and were dose escalated to 27 mg/m2 on the same schedule thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study (PX-171-010). The primary endpoint was overall response rate (ORR) (≥ partial response [PR]). Secondary endpoints included: clinical benefit response (CBR) (ORR + Minimal response [MR]), duration of response for ≥PR (DOR), overall survival (OS), time to progression (TTP), progression free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed and confirmed by an Independent Response Committee (IRC). Results: 266 pts were enrolled with a median duration of MM of 5.4 years including 83% whose disease had progressed on or within 60 d of last therapy and 17% whose disease had achieved <25 % response to the regimen immediately preceding study entry. Of the 266 pts enrolled pts, 257 were evaluable for response; 9 patients were considered not evaluable based on missing baseline or lacking at least one post-baseline M-protein. An ORR (≥PR) of 24% with a median DOR of 7.4 mo (range 6.2–10.3) was determined. Responses are detailed in the table. The CBR (ORR + MR) was 36%. Median DOR of pts with MRs was 6.3 months, indicating that long-term MRs were observed. An additional 32% (83 pts) achieved SD for at least 6 wks. To date, 79 pts (30%) completed ≥6 C and >11% of pts have completed all 12 C of protocol specified therapy and most have entered the extension protocol; 15 pts remain on study (all >10 C). OS and TTP data for the overall population will also be reported. The enrolled pts in this study were heavily pretreated having received a median of 5 prior lines of therapy (range 1–20, median of 13 anti-myeloma agents). 85% of pts had received at least 2 and 37% had received at least 3 drugs in the regimen just prior to entering the study. Prior anti-myeloma agents included 99.6% (265/266 pts) BTZ (median 2 prior regimens containing BTZ), 99.6% either THAL (74%) or LEN (94%), 98% corticosteroids, 91% alkylating agents, and 74% stem cell transplant; 65% of pts were refractory to BTZ at any point in time prior to study entry. The most common treatment-emergent adverse events ≥ Grade (G) 3 regardless of relationship to study drug were predominantly hematologic and included thrombocytopenia (22%), anemia (20%), lymphopenia (10%), pneumonia (8%), neutropenia (8%), fatigue (7%), hyponatremia (5%), and hypercalcemia (5%). Although 206 pts (77%) had G1/2 peripheral neuropathy (PN) at baseline, new onset PN was infrequent and G ≥3 PN occurred in <1%. Interestingly, in this subset of patients, efficacy response was nearly identical to that seen in the full study population with an ORR (≥PR) of 24%. Conclusions: Single-agent CFZ achieved durable responses in pts with R/R MM whose disease had relapsed after all available therapies including BTZ and immunomodulatory agents. The CBR and median DOR achieved with this steroid-sparing regimen establish that CFZ has the potential to offer substantial clinical benefit to patients with relapsed or refractory disease. CFZ was well-tolerated and side effects were clinically manageable with no new or unexpected toxicities observed. Importantly, exacerbation of pre-existing PN was uncommon. Cumulative side effects were not observed, allowing prolonged single-agent dosing for chronic disease control. Disclosures: Siegel: Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Stewart:Millennium: Consultancy; Celgene: Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx : Research Funding.

Phase II Study of the c-Met Inhibitor ARQ 197 (Tivantinib) in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2976-2976 ◽  
Author(s):  
Stephan Joseph Dorkhom ◽  
Shadia Zaman ◽  
Sheeba K. Thomas ◽  
Raymond Alexanian ◽  
Jatin J. Shah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Phase Ii ◽  
Stable Disease ◽  
Plasma Cells ◽  
Phase Ii Study ◽  
Single Agent ◽  
Arq 197 ◽  
Met Inhibitor ◽  
Grade 3

Abstract Abstract 2976 Background: c-Met receptor tyrosine kinase (RTK) activity has been implicated in establishing the oncogenic phenotype across several human cancers with high levels of the activating c-Met ligand, hepatocyte growth factor (HGF). Malignant plasma cells secrete HGF-activator (HGFA), which converts HGF to its active form, and high HGF levels are correlated with a poor prognosis in multiple myeloma (MM). Syndecan 1 (CD138) on malignant plasma cells binds HGF and potentiates interleukin-6-induced growth and migration. HGF stimulation of myeloma cells also activates autophosphorylation of c-Met and other critical downstream signaling pathways promoting oncogenesis. Finally, pre-clinical studies have shown that suppression of c-Met signaling with a number of small molecules, including ARQ 197, induced myeloma cell apoptosis. Tevantinib-mediated cytotoxic response was observed at concentrations of less than 5 μM, which are achievable in the clinic. These findings supported the hypothesis that suppression of the HGF/c-Met signaling axis could be a rational strategy against relapsed multiple myeloma. Methods: In this phase II study, the efficacy and safety of ARQ 197, a non-competitive and highly selective inhibitor of the c-Met RTK, is being studied in patients with relapsed multiple myeloma. Primary objectives were to determine the overall response rate (ORR) to single-agent tivantinib in patients with relapsed multiple myeloma who had received one to four prior lines of therapy, and to define the toxicities in this population. ARQ 197 was administered at a starting oral dose of 360 mg twice daily with meals for each day of every 4-week treatment cycle. This dose was selected from prior phase I investigations in solid tumors, and at this dose level, steady-state plasma level sof ARQ-197 were 7 μM. Treatment could continue providing that patients did not experience undue toxicities, or disease progression. Tivantinib is provided through the Cancer Therapy Evaluation Program (CTEP), and this study is supported by CTEP, as well as the M. D. Anderson Cancer Center SPORE in Multiple Myeloma. Results: A total of 10 patients have been enrolled and treated to date, all of whom were evaluable for toxicity, with 8 evaluable for response based on having completed two treatment cycles. Patients had received from 1–3 prior lines of therapy for their disease, and 7/10 (70%) had presented with International Staging System stage I disease at diagnosis. All patients on study had an ECOG performance status of 1 or better, and received a median of 3.5 cycles of tivantinib (range 1–7). The most common adverse events (AEs) of any grade seen in at least 30% of patients included diarrhea (30%), dizziness (30%), dry eyes (30%), shortness of breath (30%), memory change (30%), myalgias (40%), fatigue (60%), and neutropenia (60%). Serious AEs (SAEs) occurred in 2 patients, including one patient with grade 3 syncope, and another with grade 4 neutropenia and a grade 3 anal fissure. Stable disease (SD) has been seen as the best response in 5/7 (71%) evaluable patients, which was maintained for up to 7 cycles, while the remaining patients showed evidence of disease progression. Conclusion: Enrollment is continuing to this first study of any c-Met inhibitor in patients with relapsed multiple myeloma to better define the role of single-agent tivantinib in this setting. To date, tivantinib has been tolerated well, and some evidence of activity has been seen, with stable disease in 63% of patients, all of whom were progressing at the time of enrollment. Updated toxicity and efficacy data will be presented at the time of the Annual Meeting. Correlative studies are also underway with the goal of identifying potential predictive biomarkers. Disclosures: Off Label Use: Tivantinib is being evaluated for patients with relapsed myeloma, but is not yet approved in this setting.

Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination with Bortezomib in Patients with Advanced Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1172-1172 ◽  
Author(s):  
Donna M. Weber ◽  
Sundar Jagannath ◽  
Amitabha Mazumder ◽  
Ronald Sobecks ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Phase I ◽  
Stable Disease ◽  
Phase I Trial ◽  
Performance Status ◽  
Single Agent ◽  
Primary Objective ◽  
Combination Regimen ◽  
Ecog Performance Status

Abstract Background: Vorinostat is a histone deacetylase inhibitor that has demonstrated antiproliferative and proapoptotic activity alone and in combination with the proteasome inhibitor bortezomib in preclinical multiple myeloma (MM) models. In a Phase I study, vorinostat also demonstrated modest single agent activity in patients (pts) with relapsed or refractory MM. Patients and Methods: We conducted a Phase I trial of oral vorinostat (200 mg bid or 400 mg daily × 14 days (d1–14) in combination with bortezomib 0.7 or 0.9 mg/m2 i.v. on d 4, 8, 11 and 15 or 0.9, 1.1, or 1.3 mg/m2 i.v. on d 1, 4, 8 and 11. Cycles were repeated every 21 d for a maximum of 8 cycles until progressive disease (PD) or intolerable toxicity. Pts with active relapsed or refractory MM who had not received bortezomib in the preceding 3 months and with adequate hematologic, hepatic, and renal function, and ECOG performance status of 0–2 were eligible. The primary objective was to determine the maximum tolerated dose (MTD). Activity (utilizing EBMT criteria) and safety of the combination regimen were also assessed. Results: Twenty pts have been enrolled: median age, 61 years (range 52–76), median number prior systemic therapies, 3 (range 1–14), prior therapy with bortezomib (4 pts). Eighteen pts have received ≥ 1 dose and were evaluable for safety as of 7/1/07. One pt (cohort 3) experienced a dose-limiting toxicity (DLT, Table). The MTD has not been reached. The most common drug-related toxicities of any grade were nausea (56%), thrombocytopenia (50%), diarrhea (39%), vomiting (39%), fatigue (39%), and anemia (22%). Grade ≥ 3 drug-related adverse events were thrombocytopenia (33%, none associated with bleeding), peripheral neuropathy (11%), neutropenia (11%, none associated with fever), diarrhea (6%), diverticulitis (6%), fatigue (6%), increased AST (6%), memory changes (6%), nausea (6%), vomiting (6%), and upper respiratory infection (6%). Eight pts discontinued treatment, 3 due to PD and 5 due to adverse experiences [fatigue (2), nausea (2), diverticulitis (1)]. Of 17 evaluable pts for efficacy, all had measurable response or stable disease; 4 had a partial response, 2 had a minimal response, and 11 stable disease. Among 3 evaluable pts previously treated with bortezomib, 1 achieved a partial response and 1, minimal response. Pts at the highest dose level were not yet evaluable for response. Conclusion: Although accrual continues to determine the MTD, the combination of vorinostat and bortezomib is well tolerated and effective in this group of heavily pretreated pts with refractory/relapsed MM. Table Cohort Vorinostat Dose (mg) Bortezomib Dose (mg/m2) N # of Cycles DLTs Best Response MR = minimal response; NE = not evaluable; PR = partial response; SD = stable disease. *Days 4, 8, 11 and 15. †Days 1, 4, 8 and 11. ‡Treatment cycle in progress. 1 200 0.7* 3 3, 3, 14 - SD (2), PR 2 200 0.9* 3 4, 5, 6 - SD (2), PR 3 400 0.9† 6 2, 3, 5, 6, 6, 6 Transient AST elevation SD (3), MR, PR (2) 4 400 1.1† 5 3, 3, 4, 5, 11 - SD (4), MR 5 400 1.3† 3 1‡, 1‡, 2 - NE (3)

Phase I Study of IMGN901, Used as Monotherapy, in Patients with Heavily Pre-Treated CD56-Positive Multiple Myeloma - A Preliminary Safety and Efficacy Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2883-2883 ◽  
Author(s):  
Asher Chanan-Khan ◽  
Jeffrey Wolf ◽  
Mecide Gharibo ◽  
Sundar Jagannath ◽  
Nikhil C. Munshi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Level ◽  
Single Agent ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 2883 Poster Board II-859 Background: IMGN901 (huN901-DM1/BB-10901) is a novel anticancer agent consisting of a potent cytotoxic maytansinoid, DM1, attached to a CD56-binding monoclonal antibody, huN901, using an engineered linker. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. In preclinical settings, IMGN901 showed significant in vitro and in vivo anti-myeloma activity as a single agent and in combination with approved drugs such as lenalidomide. Objectives: To determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and activity of IMGN901, used as monotherapy, in patients with MM. Methods: Patients with CD56+ relapsed or relapsed/refractory MM receive a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled into each dose level in cohorts of 3, with dose-limiting toxicity (DLT) triggering cohort expansion. The European Bone Marrow Transplant (EBMT) criteria were used for response assessment. Results: Twenty-three CD56+ MM patients have received IMGN901 at doses ranging from 40 to 140 mg/m2/week. Most of these 23 patients had been treated with 6 or more chemotherapy regimens prior to study entry. Two of 6 patients treated at the 140 mg/m2/week dose experienced DLT (grade 3 fatigue and grade 3 acute renal failure) and a lower dose has been defined as the MTD. Commonly reported adverse events that were at least possibly related to IMGN901 were fatigue, increased aspartate aminotransferase, increased uric acid, sensory neuropathy and headache. None of the patients experienced serious hypersensitivity reactions or demonstrated a humoral response against either the antibody or DM1 component of IMGN901. Sustained partial response (PR) was documented in 1 patient treated at 140 mg/m2/week and 3 minor responses (MR) were reported in 1 patient each at doses of 60, 90, and 112 mg/m2/week. Of the 23 patients receiving any dose level of IMGN901, 8 remained on IMGN901 treatment for at least 15 weeks. Five of these 8 patients continued treatment on IMGN901 for at least 24 weeks, and two of these 5 patients remained on IMGN901 for at least 50 weeks. Preliminary PK results indicate an approximately linear relationship between dose and observed maximal serum concentration. Conclusion: This is the first study of IMGN901 in patients with MM. The MTD of this agent in MM patients is now defined. Our experience with IMGN901 in this clinical trial demonstrates an overall favorable safety profile. Although the primary objective of this clinical trial was to determine the MTD of single agent IMGN901, exciting single agent activity was observed in heavily pretreated MM patients. This is particularly encouraging as the duration of treatment with IMGN901 in some patients was longer than duration of treatment with prior regimens of approved agents. Clinical observations noted here (including single agent efficacy and the favorable toxicity profile) as well as findings from preclinical combination studies warrant continued investigation of this novel agent in patients with MM especially in combination with approved anti-myeloma agents/regimens such as lenalidomide and dexamethasone. Disclosures: Chanan-Khan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Miller:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Guild:ImmunoGen, Inc: Employment. Zildjian:ImmunoGen, Inc: Employment. Qin:ImmunoGen, Inc.: Employment. O'Leary:ImmunoGen, Inc.: Employment.

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