December 12, 2011

Emerging Lymphoma And Myeloma Treatments Focus On Improving Individual Patient Response

Lymphoma and myeloma are both malignant diseases that arise from lymphocytes, a subset of blood cells, and commonly involve lymph nodes and the bone marrow. Although considerable progress has been made in the treatment of these diseases, they remain a significant challenge for patients and their hematologists. New research introducing unique treatment approaches and targets for lymphoma and myeloma will be presented today at the 53rd Annual Meeting of the American Society of Hematology.

“New insights into the biology of the hematologic malignancies, especially lymphoma and multiple myeloma, are facilitating the design of novel treatment strategies,” said Jane N. Winter, MD, moderator of the press conference and Professor of Medicine in the Division of Hematology-Oncology at Northwestern University Feinberg School of Medicine in Chicago. “With new therapies that reflect our improved understanding of the molecular basis of these diseases, we are seeing valuable improvements in outcomes for patients.”

This press conference will take place on Sunday, December 11, at 8:00 a.m. PST.

Cereblon Expression is Required for the Anti-Myeloma Activity of Lenalidomide and Pomalidomide [Abstract 127]

A new study uncovers the genetic mechanisms that regulate whether commonly used immune-modulating drugs for multiple myeloma, known as IMiDs, will work in certain patients who may be less responsive to therapy.

Thalidomide became well-known in the early 1960s for its link to severe birth defects when administered to pregnant mothers to treat morning sickness; however, in 1999, investigators discovered that the drug worked well in about one-third of patients with multiple myeloma (MM). Since this discovery, thalidomide and other drugs like it (such as lenalidomide and pomalidomide, together known as IMiDs) have proven to be highly effective in the treatment of blood cancers like MM.

The exact mechanisms and targets through which these therapies work to enhance immune response or kill cancer cells has been largely unknown; therefore, it has been challenging to understand which patients to treat and to distinguish the positive properties of these drugs from the side effects. After recent research identified a specific protein known as cereblon as a primary mediator of the birth defects caused by thalidomide, a hypothesis emerged that cereblon may also be responsible for the anti-tumor properties of IMiDs.

To test whether the presence of cereblon in myeloma cells might be partly responsible for resistance or response to MM treatment, and thus may potentially serve as a target for therapeutic intervention, researchers examined MM cell lines resistant to IMiDs and found that expression of the cereblon gene was either low or entirely absent, suggesting a possible link between resistance to IMiDs and presence of the protein.

The team then lowered the level of cereblon expression in five human-derived MM cell lines, which caused the cell lines to become almost completely resistant to lenalidomide (compared with control cell lines) yet remain sensitive to other myeloma therapies such as melphalan, dexamethasone, and bortezomib. The investigators then examined the DNA of 10 MM patients who were resistant to IMiD therapy and found low levels of cereblon expression in eight of those 10 patients, further emphasizing that cereblon expression appears necessary for IMiDs to work properly. Interestingly, some resistant patients had normal cereblon levels, suggesting that while cereblon may be an absolute requirement for response, there are likely other mechanisms present that play a role in drug resistance.

“These findings help us understand which patients may be more or less likely to respond to therapy and will allow us to focus on other ways we can target cereblon as a possible biomarker to improve treatment and patient outcomes in multiple myeloma,” said senior author Keith Stewart, MD, Professor of Medicine in the Division of Hematology-Oncology at Mayo Clinic in Scottsdale, Ariz. “This work also suggests that we can begin to isolate the cause of birth defects from the anti-cancer properties in order to develop safer drugs in the future.”

Yuan Xiao Zhu, PhD, will present this study in an oral presentation on Sunday, December 11, at 4:30 p.m. PST at the San Diego Convention Center in Room 6DE.

Final Analysis of a Randomized Comparison of ABVD Chemotherapy with a Strategy that Includes Radiation Therapy (RT) in Patients with Limited-Stage Hodgkin Lymphoma (HL): NCIC CTG/ECOG HD.6 [Abstract 590]

New research concludes that patients with limited-stage Hodgkin lymphoma treated with a standard chemotherapy regimen have better overall survival rates compared with those receiving a radiation-based treatment.

Patients with limited-stage Hodgkin lymphoma (HL) are often treated with combination therapy containing chemotherapy plus radiation (RT). While this therapy is successful in controlling HL, these patients remain challenged by potential long-term complications of radiation exposure such as heart conditions or subsequent cancers.

To determine if HL patients treated with standard chemotherapy (ABVD) have better long-term survival than those treated with radiation-based therapy, researchers from Canada's NCIC Clinical Trials Group (NCIC CTG) designed a trial comparing the 12-year overall survival (OS) between the two groups. The Eastern Cooperative Oncology Group (ECOG) also participated in the trial. Along with overall survival, the trial also examined secondary survival factors, including freedom from disease progression (FFDP) and event-free survival (EFS).

Approximately 400 patients with non-bulky (small tumor size) clinical stage I-IIA HL were stratified into low- and high-risk groups and randomized into two treatment arms: those who received ABVD and those who received extended-field RT (with or without ABVD). By comparing survival rates of the two treatment arms, researchers found that at 12 years, participants treated with ABVD had better OS (94%) than those treated with radiation-based therapy (87%). However, patients treated with RT had better FFDP than those who were randomized to ABVD alone, a finding that was aligned with previous results of short-term success rates using RT. Researchers did not find a significant difference in EFS between the groups.

When analyzing results specifically for high-risk patients, who may carry a poorer prognosis, the findings were generally similar to the primary analysis, with higher OS rates observed in the ABVD treatment arm group (92%) when compared to the ABVD plus RT group (81%). Late effects of treatment, such as heart conditions or secondary cancers, were also less frequent in patients treated with ABVD alone.

“The results of our study suggest that in the long-term patients with limited-stage HL may be better served by a treatment approach that uses chemotherapy without radiation, as this method seems to be associated with fewer deaths from other causes,” said lead author Ralph M. Meyer, MD, Director of the NCIC CTG. “After 12 years of follow-up, we have gained valuable and reliable insights about the long-term value of specific therapeutic interventions to help clinicians make more informed treatment decisions and better manage the possible risks for their patients.”

Data from this study are updated from a five-year outcomes study published in 2005. The study was made possible through NCIC CTG´s grant funding from the Canadian Cancer Society Research Institute. The NCIC CTG and ECOG each receive grant funding support from the U.S. National Cancer Institute.

Dr. Meyer will present this study in an oral presentation on Monday, December 12, at 3:00 p.m. PST at the San Diego Convention Center in Ballroom 20A.

Randomized Phase II Trial Comparing GA101 (Obinutuzumab) with Rituximab in Patients with Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Preliminary Analysis of the GAUSS Study [Abstract 269]

The first clinical trial to directly compare rituximab with the new anti-CD20 monoclonal antibody obinutuzumab for the treatment of relapsed non-Hodgkin lymphoma (NHL) has shown higher response rates for patients treated with the novel therapy.

NHL survival rates have increased dramatically in the last several decades because of such proven and effective targeted therapies as rituximab that aim directly at the key molecular features of the disease. Despite advances in NHL treatment, hematologists continue to be challenged by drug resistance and disease relapses among their patients. Obinutuzumab, also known as GA101, is a new investigational therapy and the first type II bio-engineered monoclonal antibody specifically targeting CD20 (a prominent lymphoma biomarker) to be studied for use in NHL. Early research with GA101 has shown potential anti-lymphoma activity, but no studies have compared the results against current clinical options directly.

To compare the efficacy and safety of GA101 versus rituximab in patients with relapsed NHL, an international Phase II clinical trial was undertaken measuring overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety outcomes among patients on both treatments. A total of 175 patients were randomized to receive four weekly injections of either GA101 or rituximab with response to treatment assessed between 28 and 42 days after the last dose. Those patients who responded to treatment received ongoing doses of GA101 or rituximab every two months for up to two years.

After a complete assessment by both investigators and an independent radiology review, trial data revealed that treatment with GA101 resulted in higher response rates in patients compared to treatment with rituximab. The ORR for GA101 was 44.6 percent versus 33.3 percent for rituximab, and the complete remission (or unconfirmed complete remission) rate in the GA101 arm was 12.2 percent compared to 5.3 percent for rituximab.

Overall, GA101 was well tolerated by most study participants. Although patients on GA101 treatment had a higher rate of infusion reactions, which are a common complication of treatment with monoclonal antibodies, they were generally considered mild and did not result in significant differences in treatment discontinuation. A greater number of patients in the rituximab arm experienced severe adverse events during the four-week induction period (nine patients vs. five GA101 patients). Severe adverse events in GA101 patients included infusion reactions, neutropenia with fever, pleural effusion (a build-up of fluid in the lung tissue), and kidney stones. Finally, more rituximab-treated patients than GA101-treated patients discontinued therapy during the induction period.

“This is the first head-to-head trial of a novel anti-CD20 monoclonal antibody, GA101, against rituximab and we are encouraged to see a trend toward higher response rates without appreciable differences in safety,” said lead author Laurie H. Sehn, MD, MPH, Clinical Associate Professor in the Division of Medical Oncology at the University of British Columbia and the British Columbia Cancer Agency, Center for Lymphoid Cancer in Vancouver, Canada. “Given the promising efficacy of this drug, definitive Phase III studies evaluating its benefit are warranted and are currently underway.”

Dr. Sehn will present this study in an oral presentation on Monday, December 12, at 8:00 a.m. PST at the San Diego Conventino Center in Ballroom 20A. 

The Bruton´s Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study [Abstract 983]

A recent update of a multicenter Phase Ib/II clinical trial concludes that the novel Bruton´s Tyrosine Kinase (BTK) inhibitor PCI-32765 may be an important new targeted treatment approach for patients with chronic lymphocytic leukemia (CLL).

Tyrosine kinase enzymes are important targets for cancer research because they function as “on/off switches” in many cell functions and can signal cells to either maintain normal functioning or to grow uncontrollably, leading to cancer. BTK in particular is largely responsible for the signaling that drives normal B-cell development, making it a primary target for research on B-cell malignancies such as non-Hodgkin lymphoma (NHL).

PCI-32765 is an orally-administered BTK inhibitor that induces apoptosis, or programmed cell suicide, and inhibits function of malignant B-cells. Earlier promising studies of PCI-32765 have shown that the compound may be highly active and tolerable in patients with CLL.

The current analysis summarizes results of an ongoing study using PCI-32756 as a treatment for patients with relapsed CLL. Two cohorts of CLL patients were treated with PCI-32765 at doses of either 420 mg (n=27) or 840 mg (n=34) daily for 28-day cycles until they showed signs of disease progression. Nearly three-fourths (72%) of participating patients had at least one high-risk feature, indicating that they may not respond well to treatment.

After a review of the current analysis, researchers concluded that PCI-32765 was associated with high rates of six-month progression-free survival in patients with relapsed CLL. At 10 months follow-up, 70 percent of patients in the 420 mg treatment group achieved an objective response to therapy (previously reported as 48%), and 44 percent of the patients in the 840 mg cohort achieved an objective response at six months follow-up. An additional 19 percent of the 420 mg cohort and 35 percent of the 840 mg cohort had a nodal partial response, meaning their disease responded to therapy as represented by a 50 percent or greater reduction in lymph node size, but some lymph nodules persisted. Importantly, 82 percent of patients remain on treatment, and only 8 percent have experienced progressive disease.

Two patients discontinued the trial because of adverse events, and six patients required a dose reduction. The most frequently reported adverse events included diarrhea, fatigue, nausea, and ecchymosis (apparent skin bruising). Serious adverse events (SAEs, which are considered relatively common among this immune-compromised patient population) occurred in 38 percent of patients, with 10 percent considered potentially related to treatment. Grade 3 severe AEs considered potentially related to treatment occurred in 21 percent of patients. In addition, the majority of patients experienced high lymphocyte count, an event well-documented with this type of treatment, during the first two months of treatment that resolved over time.

“Our results suggest that PC-32765 has the potential to be highly effective and tolerable, and, more importantly, appears to be working well in patients with poor prognoses,” said lead author Susan O´Brien, MD, Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “As we become better equipped to target specific cellular functions, it is our hope that therapies like PCI-32765 will become effective interventions to manage disease in patients with CLL.”

Dr. O´Brien will present this study in an oral presentation on Tuesday, December 13, at 8:30 a.m. PST at the San Diego Convention Center in Ballroom 20A. 

American Society of Hematology 53rd Annual Meeting

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on new treatment techniques for patients with bleeding and clotting disorders, improving recovery and outcomes in transplantation, targeted therapies for acute and chronic leukemia, and assessing therapeutic strategies for sickle cell disease. For the complete annual meeting program and abstracts, visit Get up-to-date information about the annual meeting by following ASH on Twitter @ASH_hematology.

The American Society of Hematology is the world´s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology. The official journal of ASH is Blood, the most cited peer-reviewed publication in the field, which is available weekly in print and online.

[127] Cereblon Expression Is Required for the Anti-Myeloma Activity of Lenalidomide and Pomalidomide

Yuan Xiao Zhu, PhD1*, Esteban Braggio, PhD1, Chang-Xin Shi, PhD1*, Jessica Schmidt1*, Laura Bruins1*, Steven R. Schuster, MD1*, Rafael Fonseca, MD1, P. Leif Bergsagel, MD1, Chad C. Bjorklund, Ph.D.2, Robert Z. Orlowski, MD, PhD2and A. Keith Stewart, MD1

1Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ
2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX

The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. A landmark paper has recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. We hypothesized that this protein would also be required for myeloma (MM) cytotoxicity. To examine this issue we first tested 12 MM cell lines: 4 of which (OCIMY5, OPM1, SKMM2 and KMS12 PE) were very resistant to treatment with both lenalidomide and pomalidomide. Of these, OCIMY5 and OPM1 showed CRBN gene expression levels at the bottom 10% across the human MM cell lines. We next used CRBN shRNA lentiviral expression constructs to knock down CRBN in 5 human-derived myeloma cell lines (HMCLs) (KMS18, MM1.S, H929, OPM2 and JJN3). HMCLs infected with CRBN shRNAs have a significant reduction of CRBN expression and subsequent diminished cell viability (reduced 65-78%). Surviving MM cells with CRBN knock down demonstrate an acquired (essentially complete) resistance to lenalidomide when compared with controls but retained sensitivity to melphalan, dexamethasone and bortezomib. Gene expression changes induced by lenalidomide were dramatically suppressed in those CRBN depleted cells, e.g., OPM2 cells only showed 30 down regulated (3% of control) and 150 up-regulated genes (24% of control) after lenalidomide treatment, further emphasizing that CRBN is required for lenalidomide activity. We next compared by array comparative genomic hybridization the differences between MM1.S (lenalidomide sensitive) and its isogenic lenalidomide resistant line (MM1.S res), generated by culturing MM1.S in gradually increasing concentrations of lenalidomide. Only three structural abnormalities were noted differentiating the two lines one of which was deletion of CRBN. In fact the baseline MM1.S cell line has a minor population of 9% of cells with CRBN depletion which becomes dominant after lenalidomide treatment. However, further scrutiny of CRBN status in additional HMCLs and MM patients (irrespective of therapy and stage) suggested that copy-number abnormalities affecting this gene are uncommon events in MM, with 12% of HMCLs (7 out of 60) and only 1.2% of MM patients (3 out of 238) showing CRBN monoallelic deletion. Next, we examined by quantitative polymerase chain reaction (Q-PCR) ten MM patients who had become resistant to lenalidomide therapy. CRBN expression level by Q-PCR in 8 of 10 patient samples had a significant reduction (20% to 90% reduction compared to baseline) at time of drug resistance, suggesting CRBN expression as a potential biomarker to predict IMiD response. Notably however some clearly resistant patients have normal CRBN, demonstrating that while CRBN is absolutely required for response, multiple resistance mechanisms are likely present. By gene and protein expression downstream targets of CRBN were examined and included interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. In summary, we demonstrate here that CRBN is essential for IMiD activity and preliminary data support that low levels of CRBN predict for poor drug response. In addition, our data suggest that CRBN is a critical molecule but not the unique source of IMiD resistance. We suggest that the “IMiDs” be renamed Cereblon binding small molecules to more accurately reflect their mechanism of action.

Disclosures: Orlowski: Celgene: Honoraria, Membership on an entity´s Board of Directors or advisory committees, Research Funding.

[590] Final Analysis of a Randomized Comparison of ABVD Chemotherapy with a Strategy That Includes Radiation Therapy (RT) in Patients with Limited-Stage Hodgkin Lymphoma (HL): NCIC CTG/ECOG HD.6

Ralph M. Meyer, MD1, Mary Gospodarowicz, MD2*, Joseph M. Connors, MD3, Robert G Pearcey, MD4*, Woodrow A Wells, MD2*, Jane N. Winter, MD5, Sandra J. Horning, MD6, A. Rashid Dar, MD7*, Chaim Shustik, MD8, Douglas A. Stewart, MD9, Michael Crump, MD, FRCPC10, Marina S Djurfeldt, MSc11*, Bingshu E Chen, PhD12* and Lois E Shepherd, M.D.13

1Oncology, NCIC Clinical Trials Group - Queen's University, Kingston, ON, Canada
2Radiation Oncology, UHN-Princess Margaret Hospital, Toronto, ON, Canada
3British Columbia Cancer Agency, Vancouver, BC, Canada
4Radiation Oncology, Cross Cancer Institute , Edmonton, AB, Canada
5Lymphoma Committee, ECOG, Chicago, IL
6Senior VP Global Head, Clinical Dev. (Hem./Onc.), Genentech, Inc., South San Francisco, CA
7Oncology, London Health Sciences, London, ON, Canada
8Division of Haematology, McGill University Health Center, Montreal, QC, Canada
9Department of Medicine/Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
10Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
11NCIC Clinical Trials Group - Queen's University, Kingston, ON, Canada
12Community Health and Epidemiology, NCIC Clinical Trials Group - Queen's University, Kingston, ON, Canada
13Pathology and Molecular Medicine, NCIC Clinical Trials Group - Queen's University, Kingston, ON, Canada

Background: The NCIC CTG / ECOG HD.6 trial is based on the hypothesis that for patients with limited-stage HL, treatment with single-modality ABVD provides comparable disease control, is associated with a reduced incidence of deaths due to late treatment effects and thus might improve long-term survival in comparison with treatment that includes extended-field RT. In this randomized controlled phase III trial, our primary objective was to compare the 12-yr overall survivals (OS) of limited-stage HL patients treated with ABVD alone with those receiving therapy that includes RT. Secondary outcomes include freedom from disease progression (FFDP), in which those dying prior to disease progression are censored, and event-free survival (EFS), in which the first of disease progression or death is considered an event.  In 2005, we published 5-yr outcomes (median follow-up 4.2 yrs [Meyer, J Clin Oncol]). We now report results of the final analysis.

Methods: Eligible patients had non-bulky clinical stage I-IIA HL; patients with subdiaphragmatic disease were eligible if disease was confined to the iliac, inguinal and/or femoral regions. Prior to randomization, patients were stratified into low and high-risk categories; low-risk patients had all of lymphocyte predominant or nodular sclerosis histology, age < 40 yrs, ESR < 50, and involvement of 3 or fewer disease-site regions; all others were high-risk. Patients randomized to therapy that includes RT received single-modality subtotal nodal irradiation (STNI) if low-risk and combined-modality ABVD (2 cycles) plus STNI if high-risk. All patients randomized to the experimental arm received single-modality ABVD (4 cycles); those not demonstrating a complete remission with restaging after 2 cycles received 6 cycles. Between March 1994 and April 2002, 405 patients were entered; 399 were eligible and included in the primary analysis (modified intent—to-treat [ITT]). The clinical cut-off date for follow-up was 2010/DEC/31 and the database was locked on 2011/JUL/15. All P-values are 2-sided.

Results: The median duration of follow-up is 11.3 yrs. The OS was superior in patients randomized to ABVD (P=.04; HR=0.5; 12-yr estimates 94% vs. 87%). In comparison with patients randomized to therapy that includes RT, FFDP trended to being inferior in patients randomized to ABVD (P=.07; HR=1.82; 12-yr estimates 88% vs. 92%); no differences in EFS were detected (P=.5; HR=0.87; 12-yr estimates 86% vs. 80%). Sensitivity analyses included a true ITT evaluating all randomized patients and adding data obtained between the clinical cut-off and data-lock dates; results were robust and yielded similar findings.  Causes of death in ABVD vs. RT-arm patients (N = 12 vs. 24) included HL or early treatment complication (6 vs. 4), second cancers (4 vs. 9), and other (2 vs. 11).  Analysis of high-risk patients allocated to ABVD (N=137) vs. ABVD+STNI (N=139) showed similar respective results to the primary analysis: in comparison with those randomized to RT, OS was superior in the ABVD arm (12-yr estimates 92% vs. 81%; HR=.47; P=.04), FFDP was inferior (12-yr estimates 87% vs. 94%; HR=3.03; P=.01) and no differences in EFS were detected (12-yr estimates 84% vs. 78%; HR=.87; P=.6). Late-effects trended to being less frequent in ABVD patients, including second cancers (6.1% vs. 10.8%) and cardiac events (9.7% vs. 14.8%).

Conclusions: We conclude that in patients with limited-stage HL, ABVD improves OS as compared with treatment that includes STNI, including combined modality therapy, because it is associated with fewer deaths from causes other than HL. The HD.6 trial hypothesis was thus confirmed. With respect to modern RT approaches, the implications of our results are: i) at 12 years, 88% of patients are disease-free and more than 90% are alive when initially treated with ABVD alone; ii) limitations exist in using FFDP as a proxy measure for OS when late treatment effects may occur; and, iii) when treatment strategies have competing risks, long-term follow-up provides crucial insights into the interpretations of best therapy.

Disclosures: Connors: Seattle Genetics: Consultancy, Research Funding; F Hoffmann-La Roche: Research Funding.Horning: Genentech: Employment, Equity Ownership. Crump: Millennium Pharmaceuticals: Consultancy, Membership on an entity´s Board of Directors or advisory committees; Ortho Johnson & Johnson: Consultancy, Membership on an entity´s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity´s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity´s Board of Directors or advisory committees.

[269] Randomized Phase II Trial Comparing GA101 (Obinutuzumab) with Rituximab in Patients with Relapsed CD20+ Indolent B-Cell Non“‘Hodgkin Lymphoma: Preliminary Analysis of the GAUSS Study

Laurie H. Sehn, MD, MPH1, Andre Goy, MD2, Fritz C. Offner, MD, PhD 3, Giovanni Martinelli, MD4, Jonathan Friedberg, MD5, Susan F. Lasserre, MSc6*, Gregg Fine, MD7* and Oliver W. Press, MD, PhD8

1Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
2The John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
3Dienst Hematologie, University Hospital Ghent, Ghent, Belgium
4European Institute of Oncology, Milan, Italy
5James P. Wilmot Cancer Center, University of Rochester, Rochester, NY
6Hoffman-La Roche Ltd., Basel, Switzerland
7Genentech, Inc., South San Francisco, CA
8Fred Hutchinson Cancer Research Center, Seattle, WA

Background: GA101 is the first type II glycoengineered CD20 monoclonal antibody in phase II/III clinical trials for CLL and NHL. In pre-clinical models GA101 mediated enhanced direct cell death and increased ADCC compared to other anti-CD20 antibodies. GA101 single-arm clinical studies have demonstrated responses in patients (pts) with relapsed/refractory NHL and CLL, but to date there have been no direct comparisons with rituximab. The aim of this randomized phase II trial was to compare efficacy and safety of monotherapy with GA101 versus rituximab in pts with relapsed indolent NHL.

Study Design and Patients: Pts with relapsed indolent NHL requiring therapy who had demonstrated a prior response (CR/CRu or PR) to a rituximab-containing regimen lasting 6 months were eligible. A total of 175 pts (149 follicular (FL) and 26 non-follicular indolent NHL) stratified by histology were randomized 1:1 to receive 4 weekly infusions (Days 1, 8, 15, 22) of either GA101 (1000 mg, n=87) or rituximab (375 mg/m2, n=88). End of treatment response was assessed 28-42 days after the last induction dose. Pts without evidence of progression following induction therapy received ongoing treatment with GA101 or rituximab every 2 months for up to 2 years at the same dose. The primary endpoint was overall response rate (ORR) in the FL population. Secondary endpoints included PFS, OS, and safety. Treatment arms were well balanced for standard prognostic features (age, ECOG PS, Ann Arbor stage, FLIPI risk score at initial diagnosis, LDH) and prior treatment characteristics. Pts in both arms had received a median of 2 prior lines of therapy (range: 1—7 GA101 arm; 1—6 rituximab arm) and 99% had received prior rituximab. At baseline, pts in the GA101 cohort had a larger volume of disease based on the median sum of product diameters; SPD GA101 cohort 2397 mm2 (range 192—29326 mm2) v  SPD rituximab cohort 1934 mm2 (range 252—11255 mm2).

Results: The primary efficacy analysis was conducted in the FL population at the end of induction. Based on investigator assessment, ORR for GA101 was 43.2% (32/74) v 38.7% (29/75) for rituximab. The difference in response rates was 4.6% (95% CI [-12.0, 21.1]). The CR/CRu rate in the GA101 arm was 10.8% v 6.7% for rituximab. At the time of analysis 28/149 pts had progressed, 15/74 on GA101 and 13/75 on rituximab. A central blinded radiology review (IRF) was performed to independently assess response. The difference in response rates by the IRF was 15.2% (95% CI [-0.7, 31.2]; ORR, GA101 v rituximab: 43.2% [32/74] v 28.0% [21/75]). In the overall population (FL + non-follicular indolent NHL), the ORR as assessed by investigators was 43.2% (38/88) v 35.6% (31/87) and by the IRF was 42.0% (37/88) v 24.1% (21/87) for GA101 and rituximab, respectively. Safety was analyzed in the overall population. No new safety signals were observed in either arm. One patient in the rituximab arm died from cardio-pulmonary arrest and 1 patient in the GA101 arm died from pulmonary aspergillosis. More pts discontinued therapy during induction in the rituximab arm (7 pts v 4 GA101 pts). Discontinuations with GA101 occurred as a result of infusion related reactions (IRR, 3 pts) and orthostatic hypotension (1 pt). A greater number of pts in the rituximab arm experienced an SAE during the induction period (9 pts v 5 GA101 pts). SAEs in the GA101 arm occurred as a result of IRR (2 pts), febrile neutropenia (1 pt), pleural effusion (1 pt) and nephrolithiasis (1 pt). More pts in the GA101 arm reported IRRs (GA101 v rituximab: any grade, 72% v 49%; grade 3/4, 11% v 5%). IRRs were primarily seen during the first infusion and decreased in both frequency and severity with subsequent infusions. Other AEs (any grade) that occurred at a 5% higher incidence with GA101 included fatigue (23% v 17%), cough (10% v 1%), back pain (7% v2%), decreased appetite (7% v 2%) and insomnia (5% v 0%).

Conclusions: Treatment with GA101 in pts with relapsed NHL resulted in higher response rates compared to rituximab as assessed by both investigators and the IRF at an early time point. GA101 was well tolerated, although a higher rate of IRRs was noted, the majority were grade 1/2 in severity and did not result in significant differences in treatment discontinuation. This is the first head to head trial of GA101 against rituximab and has demonstrated higher response rates without appreciable differences in safety. GA101 is under study in phase III trials in combination with chemotherapy.

Disclosures: Wang: Pharmacyclics: Research Funding. Off Label Use: PCI-32765 in mantle cell lymphoma in a phase 2 clinical trial . Martin: Pharmacyclics: Research Funding.  Blum: Pharmacyclics: Research Funding.  Kahl:Pharmacyclics: Research Funding. Maeda: Pharmacyclics: Research Funding. Advani: Pharmacyclics: Research Funding. Williams: Pharmacyclics: Research Funding. Rule: Pharmacyclics: Research Funding. Rodriguez:Pharmacyclics: Employment, Equity Ownership. Pang: Pharmacyclics: Consultancy. Hedrick: Pharmacyclics: Employment, Equity Ownership. Goy: Pharmacyclics: Research Funding.

[983] The Bruton´s Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study

Susan O'Brien, MD1, Jan A. Burger, MD, PhD2, Kristie A. Blum, MD3, Richard R. Furman, MD4, Steven E. Coutre, MD5, Jeff Sharman, MD6*, Ian W. Flinn, MD, PhD7, Barbara Grant, MD8*, Nyla A. Heerema, PhD9, Amy J. Johnson, PhD3, Tasheda Navarro10*, Eric Holmgren, PhD10*, Eric Hedrick, MD10 and John C. Byrd, MD11

1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3The Ohio State University, Columbus, OH
4Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY
5Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA
6US Oncology, Springfield, OR
7Sarah Cannon Research Institute, Nashville, TN
8Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT
9Pathology, The Ohio State University, Columbus, OH
10Pharmacyclics, Inc, Sunnyvale, CA
11Division of Hematology, The Ohio State University, Columbus, OH

Introduction: BTK is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally-administered irreversible inhibitor of BTK which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. An early analysis of the phase Ib/II study PCYC-1102 showed PCI-32765 to be highly active and tolerable in patients with CLL (Byrd, ASCO 2011). Here we report longer-term follow-up of this multicenter phase Ib/II trial.

Methods and Patients: Two cohorts of CLL patients (previously untreated 65 years old and relapsed/refractory [R/R] disease following at least 2 prior therapies, including fludarabine) were treated with oral PCI-32765 administered daily for 28-day cycles until progression of disease. Doses of 420mg (previously untreated and R/R) and 840mg daily (R/R) were examined. The patients with R/R disease are the subject of this report.

Results: Sixty-one R/R CLL/SLL patients were enrolled (420mg cohort n=27, 840mg cohort n=34). The median follow-up time for the 420mg cohort is 10.2 months and for the 840mg cohort is 6.5 months. The median number of prior treatment regimens for the 420mg cohort was 3 (2-10) and for the 840mg cohort was 5 (1-12). Seventy-two percent of patients had at least one poor-risk molecular feature: del(17p) 31%, del(11q) 33%, IgVH un-mutated 57%. Treatment has been well tolerated. Two patients have discontinued for adverse events (AE); 6 patients have required reduction of PCI-32765 dose (420mg cohort 2/27, 840mg cohort 4/34). Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis have been the most frequently reported AEs. Serious AEs (SAEs) have occurred in 38% of patients; SAEs considered potentially related to PCI-32765 have occurred in 10% of patients. Grade 3 AEs considered potentially related to PCI-32765 occurred in 21% of patients. A characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of Rx, followed by resolution over time, has been observed in the majority of patients. Objective response (ORR; PR + CR) by IWCLL criteria in the 420mg cohort cohort, previously reported as 48% with 6.2 months median follow-up (Byrd, et al ASCO 2011), is now 70% with 10.2 months median follow-up. ORR in the 840mg cohort is 44% at 6.5 months median follow-up. An additional 19%, and 35% of patients in these cohorts, respectively, have a nodal PR (>50% reduction in aggregate lymph node size) with residual lymphocytosis. ORR appears to be independent of molecular risk features. Eighty-two percent of patients (50/61; 420mg cohort 22/27, 840mg cohort 28/34) remain on PCI-32765. Only 8% (5/61) of patients have had progressive disease (PD); 6-month PFS is 92% in the 420mg cohort and 90% in the 840mg cohort. Treatment cessation not related to PD or AE includes: death (n=2) or investigator discretion (n=3).

Conclusions: The potent BTK inhibitor PCI-32765 is well tolerated and is associated with high rates of 6-month PFS in R/R CLL/ SLL. Phase III trials of PCI-32765 in CLL/ SLL are planned.

Disclosures: O'Brien: Pharmacyclics, Inc: Membership on an entity´s Board of Directors or advisory committees, Research Funding. Burger: Pharmacyclics, Inc: Research Funding. Blum: Pharmacyclics: Research Funding. Furman: Pharmacyclics, Inc: Research Funding. Coutre: Pharmacyclics, Inc: Research Funding. Sharman: Pharmacyclics, Inc: Research Funding. Flinn: Pharmacyclics, Inc: Research Funding. Grant: Pharmacyclics, Inc: Research Funding. Heerema: Pharmacyclics, Inc: Research Funding. Johnson: Pharmacyclics, Inc: Research Funding. Navarro: Pharmacyclics, Inc: Employment, Equity Ownership. Holmgren: Pharmacyclics, Inc: Consultancy. Hedrick: Pharmacyclics: Employment, Equity Ownership. Byrd: Pharmacyclics, Inc: Research Funding.


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