• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Dr. Goy MCL
 

 

Statistics

Views

Total Views
2,320
Views on SlideShare
1,482
Embed Views
838

Actions

Likes
2
Downloads
30
Comments
0

6 Embeds 838

http://www.jtcancercenter.org 674
http://humccancer.org 147
http://localhost 10
http://184.106.177.112 3
http://jtcancercenter.org 2
http://www.zoominfo.com 2

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • CR, complete response; CRu, unconfirmed complete response; ORR, overall response rate; PR, partial response.   For more information, go online to: http://clinicaloptions.com/Oncology/Journal%20Options/Articles/Fisher-JCO-2006/Capsule.aspx
  • CR, complete response; CRu, unconfirmed complete response; ORR, overall response rate; PR, partial response.   For more information, go online to: http://clinicaloptions.com/Oncology/Journal%20Options/Articles/Fisher-JCO-2006/Capsule.aspx
  • Abstract 1661Poster Board I-687Introduction: One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL.Methods: Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m 2 days 1 and 4, rituximab 375 mg/m 2 IV day 1, cyclophosphamide 300 mg/m 2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m 2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy.Results: Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths.Conclusion: The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS.
  • Abstract 1661Poster Board I-687Introduction: One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL.Methods: Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m 2 days 1 and 4, rituximab 375 mg/m 2 IV day 1, cyclophosphamide 300 mg/m 2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m 2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy.Results: Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths.Conclusion: The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS.
  • Abstract 1661Poster Board I-687Introduction: One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL.Methods: Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m 2 days 1 and 4, rituximab 375 mg/m 2 IV day 1, cyclophosphamide 300 mg/m 2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m 2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy.Results: Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths.Conclusion: The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS.
  • Institute of Cancer, Centre for Medical Oncology, Barts and The London School of Medicine, University of London, London, United Kingdom.Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation. These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches. Figure 1. Actions of Immunomodulatory Drugs in Multiple Myeloma. Immunomodulatory drugs arrest growth and induce apoptosis in myeloma cells and inhibit adhesion to bone marrow stroma. Stromal elaboration of and cellular response to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor are reduced by immunomodulatory drugs, a process that results in decreased angiogenesis. Generation of the paracrine myeloma growth factor, interleukin-6, and tumor necrosis factor {alpha} (TNF-{alpha}) by stromal cells is reduced, which, in turn, inhibits myeloma-cell growth. The immunomodulatory drugs costimulate T lymphocytes to promote secretion of interleukin-2 and interferon-{gamma} (INF-{gamma}), which cooperate to activate natural killer cells and myeloma-specific immune response. Data are adapted from Teo.6 VCAM denotes vascular-cell adhesion molecule, and Th1 type 1 helper T.
  • CR, complete response; CRu, unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; FL, follicular lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; NR, not reached; PD, partial disease; POD, progression of disease; PR, partial response; Rx, treatment; SD, stable disease; TSF, transformed lymphoma.     For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Hematology%202008/Tracks/Lymphomas/Capsules/262.aspx
  • MCL OR rates in MCL range from 36-53% Heavily pretreated patient population with a median # of 4 prior therapies Responses seen in Velcade failures
  • Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-celllymphoma that if not cured with aggressive chemoimmunotherapyand stem cell transplant is usually fatal. The intravenous proteasomeinhibitor bortezomib produces an overall response rate (ORR)of 33% in patients with relapsed MCL (J ClinOncol 2006;24(30):4867–74 [Abstract/Free Full Text]).Unfortunately, most patients eventually relapse and new agentsare needed for this disease. Two recently conducted phase IItrials (NHL-002 and NHL-003) tested single-agent lenalidomidefor patients with relapsed MCL. Fifty-four patients with MCLwere enrolled into the two studies; 26% (14/54) had receivedprior bortezomib and they are the subject of this report.Methods: Patients with relapsed or refractory MCL and measurabledisease 2 cm after at least one prior treatment regimen includingprior bortezomib were eligible. Patients received 25 mg of lenalidomideorally once daily on days 1–21 of every 28-day cycle.Therapy was continued as tolerated or until disease progression.The 1999 IWLRC methodology was used to assess response and progression.Results: The 14 patients in this study were heavily pretreatedwith a median of 4 (2–6) prior treatments (including bortezomib)and 50% were bortezomib-refractory. Median age was 66 (45–84)years and 6 (43%) patients were female. Median time from diagnosisto lenalidomide treatment was 3.3 (0.7–7.6) years. TheORR with lenalidomide was 57% (8/14), including 21% (3/14) completeresponse (CR)/unconfirmed CR and 36% (5/14) partial responses.One (7%) patient had stable disease. The most common grade 3or 4 adverse events were neutropenia (50%), thrombocytopenia(43%), anemia (21%), fatigue (21%), and leukopenia (21%). Neutropenicfever occurred in 7% of patients.Conclusion: These results demonstrate that lenalidomide oralmonotherapy is very effective with manageable side effects inpatients with relapsed or refractory MCL who had received priortreatment with bortezomib. [788] Response Adapted Assignment of the Number of Chemotherapy Cycles for the Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Is Not Justified: Results of the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Session Type: Oral Session 

 Joerg Schubert, MaritaZiepert, Eva Lengfelder, Martin Mohren, Norma Peter, Marcel Reiser, Michael Clemens, Christina Nickenig, MaikedeWit, Anthony Ho, HartmutEimermacher, Lorenz Truemper, Martin Hoffmann, Roland Mertelsmann, Bernd Metzner, Hans-Guenther Mergenthaler, RuedigerLiersch, Ulrich Duehrsen, Leopold Balleisen, Frank Hartmann, Viola Poeschel, Norbert Schmitz, Markus Loeffler, Michael Pfreundschuh German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL), Saarland University Medical School, Homburg/Saar, Germany 

Background: While the CHOP regimen is widely accepted standard chemotherapy regimen of care for aggressive lymphomas, the optimal number of chemotherapy cycles for the treatment of aggressive lymphomas has not been determined. Since RICOVER-60 is the first randomized comparison between 6 and 8 cycles of chemotherapy, it allowed to analyze whether 8 cycles are better than 6 in patients with poor prognosis and/or those achieving less than a complete response after 4 cycles of chemotherapy. Methods: In the RICOVER-60 trial, 1222 elderly patients (61-80 years, stages I-IV) were randomized to receive 6 or 8 cycles of CHOP-14 with or without rituximab given on days 1, 15, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. Results: In a multivariate analysis adjusted for prognostic factors using 6xCHOP-14 without rituximab as the reference, all intensified regimens improved event-free survival. Compared to 6xCHOP-14, progression-free survival (PFS) improved after 6xR-CHOP-14 and 8xR-CHOP, while overall survival (OS) improved only after 6xR-CHOP-14 ( Pfreundschuh et al., 2006, Blood 108: 64a, Abstract #205) . Since 8 cycles of chemotherapy were not better than 6 in the overall RICOVER-60 population, we searched for subgroups who might have a benefit from the two additional cycles of chemotherapy. The outcome after 6 cycles was at least as good as 8 cycles, in any risk group according to IPI. Compared to patients in CR after 4 cycles (n=261), patients in PR after 4 cycles (n=459) had a significantly worse 3-year PFS (63% vs. 75%; p=.001) and OS (69% vs. 84%; p=0.001), while for patients in CRu (n=276) this applied to PFS (68% vs. 76%; p=0.043), but not to OS (78% vs. 84%; p=0.125). Among patients with mid-therapy CRu, the 3-year progression free rates receiving 6 cycles (6x-CHOP-14: 65%, 6xR-CHOP-14: 72%) and those receiving 8 cycles (8xCHOP-14: 63%; 8xR-CHOP-14: 71%) were not different (p=0.601 and p=0.815 without and with rituximab, respectively). The same was true with respect to overall survival (6xCHOP-14: 82%; 8xCHOP-14: 70%; 6xR-CHOP-14: 80%; 8xR-CHOP-14: 80%; p=0.422 and p=0.759 without and with rituximab, respectively). Conclusion: Patients in CR after 4 cycles of therapy have a better outcome than those in CRu and PR at mid-therapy, with no difference between patients who received 6 and 8 cycles of (R-)CHOP-14. Response-adapted assignment of 8 cycles instead of 6 does not compensate for the worse prognosis of patients achieving less than a CR after 4 cycles. Response-adapted assignment of the number of chemotherapy cycles - either with or without rituximab - is not supported by our data. Supported by Deutsche Krebshilfe. 
Abstract #788 appears in Blood, Volume 110, issue 11, November 16, 2007
 Keywords: Non-Hodgkin Lymphoma|PhaseIII|ClinicalTrial
 Disclosure: Consultancy: M. Pfreundschuh- Roche, Genentech.

Tuesday, December 11, 2007 7:45 AM

 Session Info:   Simultaneous Session: Immuno-Chemotherapy for Diffuse Large B Cell and Follicular Lymphoma (7:30 a.m.-9:00 a.m.)   Close Window
  • Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-celllymphoma that if not cured with aggressive chemoimmunotherapyand stem cell transplant is usually fatal. The intravenous proteasomeinhibitor bortezomib produces an overall response rate (ORR)of 33% in patients with relapsed MCL (J ClinOncol 2006;24(30):4867–74 [Abstract/Free Full Text]).Unfortunately, most patients eventually relapse and new agentsare needed for this disease. Two recently conducted phase IItrials (NHL-002 and NHL-003) tested single-agent lenalidomidefor patients with relapsed MCL. Fifty-four patients with MCLwere enrolled into the two studies; 26% (14/54) had receivedprior bortezomib and they are the subject of this report.Methods: Patients with relapsed or refractory MCL and measurabledisease 2 cm after at least one prior treatment regimen includingprior bortezomib were eligible. Patients received 25 mg of lenalidomideorally once daily on days 1–21 of every 28-day cycle.Therapy was continued as tolerated or until disease progression.The 1999 IWLRC methodology was used to assess response and progression.Results: The 14 patients in this study were heavily pretreatedwith a median of 4 (2–6) prior treatments (including bortezomib)and 50% were bortezomib-refractory. Median age was 66 (45–84)years and 6 (43%) patients were female. Median time from diagnosisto lenalidomide treatment was 3.3 (0.7–7.6) years. TheORR with lenalidomide was 57% (8/14), including 21% (3/14) completeresponse (CR)/unconfirmed CR and 36% (5/14) partial responses.One (7%) patient had stable disease. The most common grade 3or 4 adverse events were neutropenia (50%), thrombocytopenia(43%), anemia (21%), fatigue (21%), and leukopenia (21%). Neutropenicfever occurred in 7% of patients.Conclusion: These results demonstrate that lenalidomide oralmonotherapy is very effective with manageable side effects inpatients with relapsed or refractory MCL who had received priortreatment with bortezomib. [788] Response Adapted Assignment of the Number of Chemotherapy Cycles for the Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Is Not Justified: Results of the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Session Type: Oral Session 

 Joerg Schubert, MaritaZiepert, Eva Lengfelder, Martin Mohren, Norma Peter, Marcel Reiser, Michael Clemens, Christina Nickenig, MaikedeWit, Anthony Ho, HartmutEimermacher, Lorenz Truemper, Martin Hoffmann, Roland Mertelsmann, Bernd Metzner, Hans-Guenther Mergenthaler, RuedigerLiersch, Ulrich Duehrsen, Leopold Balleisen, Frank Hartmann, Viola Poeschel, Norbert Schmitz, Markus Loeffler, Michael Pfreundschuh German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL), Saarland University Medical School, Homburg/Saar, Germany 

Background: While the CHOP regimen is widely accepted standard chemotherapy regimen of care for aggressive lymphomas, the optimal number of chemotherapy cycles for the treatment of aggressive lymphomas has not been determined. Since RICOVER-60 is the first randomized comparison between 6 and 8 cycles of chemotherapy, it allowed to analyze whether 8 cycles are better than 6 in patients with poor prognosis and/or those achieving less than a complete response after 4 cycles of chemotherapy. Methods: In the RICOVER-60 trial, 1222 elderly patients (61-80 years, stages I-IV) were randomized to receive 6 or 8 cycles of CHOP-14 with or without rituximab given on days 1, 15, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. Results: In a multivariate analysis adjusted for prognostic factors using 6xCHOP-14 without rituximab as the reference, all intensified regimens improved event-free survival. Compared to 6xCHOP-14, progression-free survival (PFS) improved after 6xR-CHOP-14 and 8xR-CHOP, while overall survival (OS) improved only after 6xR-CHOP-14 ( Pfreundschuh et al., 2006, Blood 108: 64a, Abstract #205) . Since 8 cycles of chemotherapy were not better than 6 in the overall RICOVER-60 population, we searched for subgroups who might have a benefit from the two additional cycles of chemotherapy. The outcome after 6 cycles was at least as good as 8 cycles, in any risk group according to IPI. Compared to patients in CR after 4 cycles (n=261), patients in PR after 4 cycles (n=459) had a significantly worse 3-year PFS (63% vs. 75%; p=.001) and OS (69% vs. 84%; p=0.001), while for patients in CRu (n=276) this applied to PFS (68% vs. 76%; p=0.043), but not to OS (78% vs. 84%; p=0.125). Among patients with mid-therapy CRu, the 3-year progression free rates receiving 6 cycles (6x-CHOP-14: 65%, 6xR-CHOP-14: 72%) and those receiving 8 cycles (8xCHOP-14: 63%; 8xR-CHOP-14: 71%) were not different (p=0.601 and p=0.815 without and with rituximab, respectively). The same was true with respect to overall survival (6xCHOP-14: 82%; 8xCHOP-14: 70%; 6xR-CHOP-14: 80%; 8xR-CHOP-14: 80%; p=0.422 and p=0.759 without and with rituximab, respectively). Conclusion: Patients in CR after 4 cycles of therapy have a better outcome than those in CRu and PR at mid-therapy, with no difference between patients who received 6 and 8 cycles of (R-)CHOP-14. Response-adapted assignment of 8 cycles instead of 6 does not compensate for the worse prognosis of patients achieving less than a CR after 4 cycles. Response-adapted assignment of the number of chemotherapy cycles - either with or without rituximab - is not supported by our data. Supported by Deutsche Krebshilfe. 
Abstract #788 appears in Blood, Volume 110, issue 11, November 16, 2007
 Keywords: Non-Hodgkin Lymphoma|PhaseIII|ClinicalTrial
 Disclosure: Consultancy: M. Pfreundschuh- Roche, Genentech.

Tuesday, December 11, 2007 7:45 AM

 Session Info:   Simultaneous Session: Immuno-Chemotherapy for Diffuse Large B Cell and Follicular Lymphoma (7:30 a.m.-9:00 a.m.)   Close Window
  • Nov 30, 2011 www.calistogapharma.com CORPORATE OVERVIEW
  • Nov 30, 2011 www.calistogapharma.com CORPORATE OVERVIEW
  • Nov 30, 2011 www.calistogapharma.com CORPORATE OVERVIEW
  • median follow-up time of 10 years
  • CR, complete response; HL, Hodgkin lymphoma; Inv., investigator; IRF, independent review facility; ORR, overall response rate; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease.

Dr. Goy MCL Dr. Goy MCL Presentation Transcript

  • Andre Goy, MD Chairman and Director John Theurer Cancer Center Lymphoma Program Head Professor of Medicine UMDNJ Mantle Cell Lymph oma “ Novel Therapies” 1 st International Educational Symposium on Mantle Cell Lymphoma
  • Disclosure Celgene, Millennium, Pharmacyclics: Research support (clinical trials).
  • 11/11/11 On 11.11.11, the time and date will be a perfect same-numbered palindrome - reading the same backwards as forwards - an event which can only happen on one day every 100 years….
  • 11/11/11 Doomsday...? More weddings... New spiritual Era ? Good luck??
  • Special Dates in the Maya Calendar …. "They were actually preparing for this catastrophe by buying real estate on high places and by stocking up on whatever the 16th-century equivalent of duct tape and bottled water was," John Hoopes, Maya History Scholar….
  • Our sponsors and organizing committee All my co-investigators and colleagues All patients and families All staff nurses and beyond…
  • The entire TEAM without whom we COULD NOT do what we DO!!!
    • MCL responds to initial therapy but a large proportion of patients relapse
    • Dose-intensive therapies / high dose therapies have improved PFS in excess of 5 years
    • MCL develops commonly over time chemoresistance
    Mantle Cell Lymphoma
    • Challenging nature of disease has pushed clinical research
    • Continue effort in clinical TRIALS ++++
    • Considerable progress in biology of MCL  new targets
    Mantle Cell Lymphoma as a GREAT TEACHER
  • MCL median OS has improved (from 2.5y to > 5y) over last 2 decades
    • Better induction therapy
    • Deeper quality of 1 st response (molecular CR)
    • Maintenance strategies ?
    • BETTER salvage therapies / options +++
    MCL – Improved Outcome!!!
  • MCL Remains a Challenge in the Relapse Setting FFS Poor outcome with conventional cytotoxics Med duration of response ≈ 6ms with “regular” chemo regimens 29 pts Classic R-HyperCVAD Wang, Cancer Nov 2008
  • Tam, Blood April 2009 MCL Remains a Challenge in the Relapse Setting HDT- ASCT much << in relapse setting Addition of rituximab beneficial only frontline setting
  • New Cytotoxics
  • New Cytotoxics: Bendamustine Leoni, Sem Hematol, April 2011 Strong alkylating agent Developed in Germany in the mid-twentieth century
  • New Cytotoxics: Bendamustine Ohamchi, Cancer Science Sept 2010 69 pts (11 MCL) Japan MCL: ORR 100% / 73% CR-CRu Bendamustine (120 mg/m(2) ) days 1-2 of a 21-day cycle x 6 cycles At a median follow up of 12.6 months, median PFS not reached
  • New Cytotoxics: Bendamustine Robinson, JCO Sept 2008 B + R in relapsed indolent B-cell NHL and MCL Rituximab: day 1: 375mg/m 2 + Bendamustine (90 mg/m(2) ) days 2&3 28-day cycle x 6 cycles Subtype No. of Patients ORR (%) CR (%) CRu (%) PR* (%) SD (%) PD (%) Total 66 92 41 14 38 8 0 Pathologic subtype      Indolent NHL 54 93 41 13 39 7 0     MCL 12 92 42 17 33 8 0 Rituximab exposure      Prior rituximab 37 87 35 14 38 14 0      No prior rituximab 29 100 48 14 38 0 0
  • STiL: First-line Bendamustine + Rituximab in Pts With FL, MCL, MZL Rummel MJ, et al. ASH 2009. Abstract 405. 90 MCL pts subset Bendamustine-Rituximab (n = 260) B 90 mg/m 2 day 1 and 2 R 375 mg/m 2 day 1 Max 6 cycles, q 4 weeks R-CHOP (n = 253) Max 6 cycles, q 3 weeks Stage III or IV CD20+ NHL (N = 549)
  • STiL Trial: PFS (Primary Endpoint)
    • B-R superior to R-CHOP for PFS in overall (54.9 vs 34.8 mos, P = .00012)
    • In sub-analysis, B-R superior to R-CHOP in MCL ( P = .0146)
    Rummel MJ, et al. ASH 2009. Abstract 405. 0.0 0.2 0.4 0.6 0.8 1.0 0 72 48 35 24 12 60 0.1 0.3 0.5 0.7 0.9 B-R R-CHOP MCL P = .0146 Also favorable toxicity profile Parameter B-R R-CHOP p v alue CR, % 39.6 30.3 .026 TTNT, mos NR 37.5 .001
  • New Biologicals (also called targeted agents)
  • Targeting the Proteasome Ruschak A M et al. JNCI J Natl Cancer Inst 2011;103:1007-1017
  • Yewdell, Nat Immunl. Rev 3, 952-961 The Ubiquitin–proteasome Pathway Aaron Ciechanover Avram Hershko Irwin Rose Nobel Prize in Chemistry 2004
  • Through this pathway, the cell gets rid of excess / redundant proteins and misfolded / abnormal proteins and regulates biological processes (homeostasis).
  • The Ubiquitin–proteasome Pathway
    • 30000 proteasomes per cell
    • MAIN way to degrade / recycle intra cellular proteins
    • 1/3 proteins have ½ life 10mn !!
    5% our entire cellular proteins renewed each day! Yewdell, Nat Immunl. Rev 3, 952-961
    • Initially studied to understand protein degradation process
    • Wide range of natural products can inhibit proteasome
    • Several PI have been developed  peptidomimetic that can compete with enzymatic sites
    • Bind (reversibly or not) catalytic sites (“jammed proteasome”)
    Proteasome Inhibitors
  • Sites of action of proteasome inhibitors Ruschak A M et al. JNCI J Natl Cancer Inst 2011;103:1007-1017
  • Proteasome Inhibitors Chemical structure Name Type Developer Route of administration Devlpt. status Bortezomib Reversible Millennium: The Takeda Oncology Company IV FDA approved CEP-18770 Reversible Cephalon IV, oral Phase I MLN-9708 Reversible Millennium: The Takeda Oncology Company IV, oral Phase I Carfilzomib Irreversible Onyx IV Phase Ib ONX 0912 Irreversible Onyx Oral Phase I NPI-0052 Irreversible Nereus IV Phase I
  • Ruschak A M et al. JNCI J Natl Cancer Inst 2011;103:1007-1017 Effects of Proteasome Inhibition on Tumor and Stromal Targets Microenvironment ↓ NF-  B, ↓ cytokines, ↓ cell adhesion molecules, ↓ VEGF, ↓ TNF- α Apoptosis ↑ p53, ↑ p21, ↑ Bax, ↑ tBID, ↑ Bcl-2, ↓ MAPK, ↓ survivin, ↓ XIAP, ↓ cIAP ↑ Caspases Cell Cycle Arrest ↑ p53, ↑ p21, ↑ p27, ↓ NF-  B, ↓ MAPK, ↑ cyclins A/B/D/E, ↑ c-fos/c-jun, ↑ Myc, ↑ beta catenin Stress Response ↓ DNA repair, ↓ Pgp, ↑ TopII, ↑ TopI, ↓ NF-  B, ↓ MAPK, chemo- and radiosensitization Accumulation of abnormal mutated /or misfolded proteins
    • Blockade of degradation of
    • normal (short lived proteins) and
    • abnormal proteins (more common in cancer cells)
    •  cell death
  • Bortezomib: 1 st in class approved in NHL – 1 st activity shown in mantle cell lymphoma
  • 1. O’Connor OA, et al. Br J Haematol. 2009;145:34-39. 2. Goy A, et al. J Clin Oncol. 2005;23:667-675. 3. Strauss SJ, et al. J Clin Oncol. 2006;13:2105-2112. 4. Belch A, et al. Ann Oncol. 2007;18:116-121. 5. Fisher RI, et al. J Clin Oncol. 2006;24:4867 -48 74. Similar ORR across studies and for untreated / relapsed 1.5 mg/m 2 1.3 mg/m 2 Bortezomib: Summary of Efficacy in Mantle Cell Lymphoma Study N CR PR ORR, % O’Connor [1] 40 5 (13) 14 (35) 47 Goy [2] 29 6 (20.5) 6 (20.5) 41 Strauss [3] 24 1 (4) 6 (25) 29 Belch, n [4] 13 untreated/ 15 relapsed 0 1 6 6 46 47 PINNACLE, n (%) [5] 141 11 (8) 36 (26) 47 (33) Total 262 24 (9) 74 (28) 98 (37)
  • Response / Subset Analysis Median DOR in pts with CR/CRu not reached at 26.5 mos Goy A, et al. Ann Oncol. 2009;20:520-525. Fisher RI, et al. J Clin Oncol. 2006;24:4867-4874. Bortezomib: PINNACLE Trial Update Parameter Response Evaluable (n = 141) Refractory MCL* (n = 58) Prior High- Intensity Therapy † (n = 58) ORR, % 32 29 25 CR/CRu, % 8 6 10 Median DOR, mos 9.2 5.9 Not reached
  • Most common adverse events (AEs, N=155) Fisher RI et al. J Clin Oncol . 2006;24:4867-4874 Gerecitano J et al. Br J Haematol . 2006;134(4):391-398 Frequent Supportive care Do not stop RX Predictive response? ORR 73% vs 33% w/o rash Toxicity Any grade n (%) Grade ≥ 3 n (%) Fatigue 95 (61) 19 (12) Peripheral neuropathies NEC 85 (55) 20 (13) Constipation 77 (50) 4 (3) Diarrhea NOS 73 (47) 11 (7) Nausea 68 (44) 4 (3) Rash NOS 43 (28) 4 (3) Vomiting NOS 42 (27) 4 (3) Anorexia 36 (23) 5 (3) Dizziness (excluding vertigo) 36 (23) 5 (3) Dyspnea NOS 35 (23) 7 (5) Insomnia 33 (21) 1 (< 1) Thrombocytopenia 33 (21) 17 (11)
  • MCL - Combination with chemo regimens Furman et al, Cancer July 2010 Ruan et al, JCO Feb 2011 Phase I R-CHOP
    • Cornell – R-CHOP + BTZ days 1 & 4 / dose escalation 0.7, 1 and 1.3)
    • 6 cycles / 20 pts 16 DLBCL – 4MCL
    • Well tolerated / neuropathy (only 1gr 3)  days 1 and 4 only ≠ GELA
    • DLT not reached – dose established for phase II 1.3mg/m 2
  • MCL - Combination with chemo regimens Furman et al, Cancer July 2010 Ruan et al, JCO Feb 2011 Med follow-up 30ms Med PFS 21ms Phase II BTZ + R-CHOP in MCL Phase I BTZ + R-CHOP
    • Cornell – R-CHOP + BTZ days 1 & 4 / dose escalation 0.7, 1 and 1.3)
    • 6 cycles / 20 pts 16 DLBCL – 4MCL
    • Well tolerated / neuropathy (only 1gr 3)  days 1 and 4 only ≠ GELA
    • DLT not reached – dose established for phase II 1.3mg/m 2
    Parameter Results Nb pts 36 Med age 66y (45–80) Stage 34 stage III-IV MIPI 39% high MIPI ORR 82% CR-CRu 64%
  • Chang et al, BJH Aug 2011 CR, CRu, PR Rituximab 375 mg/m 2 d1 Cyclophosphamide 300 mg/m 2 q12h / d1-3 Doxorubicin 50 mg/m 2 48 h CI d1-2 Vincristine 2 mg d3 Dexamethasone 40 mg d1-4 6 cycles Rituximab 375 mg/m 2 qw × 4 q6mo × 4 Untreated MCL (N= 30) + Bortezomib 1.5mg / m 2 d 1 and 4 ONLY q 21d excessive neuropathy  changed to 1.3mg/m 2 and vincristine to 1mg Phase II study University of Wisconsin & Wisconsin Oncology Network – 30 pts ORR 90% CR rate 77% 3-year PFS 63% and OS 86% Modified R-HyperCVAD + Bortezomib
    • 76 pts eligible btw 5/07 - 10/08
    • Med age 62 (40-76)
    • 91% stage III/IV
    • 64 pts (84%) completed VcR-CVAD
    B. S. Kahl et al, Blood, 2009 114: Abstract 1661 *6 PR no BM redone... CR post modified R-HyperCVAD alone 64% Longer follow-up needed for PFS Modified R-HyperCVAD + Bortezomib ECOG 1405 Response Value ORR 96% CR 75% PR* 21% MIPI 39% high MIPI
  • Romaguera et al, Br Jnl Hematol Oct 2010
    • Dosing:
      • cycles A days 1 and 4 @1.3mg/m 2
      • Cycles B: esc doses 0.7, 1, 1.3
    • No unexpected toxicity / one grade 3 sensory neuropathy
    • No pulmonary toxicity
    • 19/20 CR (1 pt only  ASCT)
    Phase II ongoing (Classic) R-HyperCVAD + Bortezomib MDACC and John Theurer Cancer Center
  • MCL – Other Bortezomib Combinations Combination Design Results / comments SWOG S0601 R-CHOP-Bz induction + 8 cycles maintenance Bz Phase II completed NCT 00376961 R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing NCT00722137
  • MCL – Other Bortezomib Combinations Combination Design Results / comments SWOG S0601 R-CHOP-Bz induction + 8 cycles maintenance Bz Phase II completed NCT 00376961 R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing NCT00722137 CALGB C50403 HDT/ASCT  Maintenance Bz vs Consolidaton Bz Randomized phase II maint vs consolidation
  • MCL – Other Bortezomib Combinations Combination Design Results / comments SWOG S0601 R-CHOP-Bz induction + 8 cycles maintenance Bz Phase II completed NCT 00376961 R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing NCT00722137 CALGB C50403 HDT/ASCT  Maintenance Bz vs Consolidaton Bz Randomized phase II maint vs consolidation NCI/Wilson Bz  R-EPOCH-Bz  Maintenance randomization Window of opportunity markers / circulating MCL cells
  • MCL – Other Bortezomib Combinations Combination Design Results / comments SWOG S0601 R-CHOP-Bz induction + 8 cycles maintenance Bz Phase II completed NCT 00376961 R-CHOP vs R-CHBzP Replacing vincristine with Bz Phase III ongoing NCT00722137 CALGB C50403 HDT/ASCT  Maintenance Bz vs Consolidaton Bz Randomized phase II maint vs consolidation NCI/Wilson (Grant ASCO 2011 #8022) Bz  R-EPOCH-Bz  Maintenance randomization Window of opportunity markers / circulating MCL cells Bendamustine + R + BTZ (Friedberg/ Blood March 2011) Relapsed / ref indolent NHL BR (benda 90mg.m 2 ) BTZ 1.3 days 1,4,8,11 29 pts 16FL, 7 MCL ORR 93% / 71% in MCL 2y PFS 47% CALGB BTZ + Len >10/19 pts resp / ongoing
  • O ’Connor. Clin Lymphoma Myeloma . 2005;6:191; Leonard. Int J Cancer . 2006;119:971; Demo. Cancer Res . 2007;67:6383; Ahn. Blood . 2007 Stewart. ASCO 2007 (abstr 8003); Chauhan. Br J Cance r. 2006;95:961. Other Proteasome Inhibitors Marizomib (NPI-0052) Phase I Bortezomib Approved for MCL Carfilzomib (PR-171) Phase II-III MM Highly selective for chymotrypsin-like Inhibits both chymotrypsin-like and caspase-like Binds all 3 enzymatic sites Reversible Irreversible Irreversible
  • O’Connor Clin Cancer Res Nov 2009 Stewart ASCO 2007 ORR 54% in BTZ-naive patients and 26% in pts w/ prior exposure to bortezomib Activity in WM / NHL phase II P / Tox: hematological, NO or minimal neuropathy Carfilzomib 0 % proteasome inhibition D2 D8 D9 D1 0 Time (weeks) D15 D16 D1 D5 1 2 3 4 D14 D28 80 80 1 2 PX-171-001 QDx5; 9 day rest 2 week cycle Continuous suppression of proteasome activity PX-171-002 QDx2 weekly for 3 wks; 12 day rest 4 week cycle Prevent full recovery of proteasome between doses
  • Annual “Celebrating Life and Liberty” Cancer Survivors Event JTCC - Sept 2011
  • Lenalidomide mechanisms of action remains poorly understood / pleiotropic effects Antiangiogenic, microenvt, direct antiproliferative, NK, and T-regs List A. N Engl J Med. 2007;357:2183-2186. Ramsay AG, et al. J Clin Invest. 2008;118: 2427-2437. Lenalidomide / IMiDs Lenalidomide repairs suppressed T-cell immunological synapse formation in CLL and follicular lymphoma
    • N = 203; MCL pts, n = 53
    • Median number prior Rx: 3 (1-8)
    • DOR: NR (13.7 mos in prior NHL-002 trial)
    Zinzani PL, et al. ASH 2008. Abstract 262. Reeder CB, et al. ASH 2008. Abstract 1560. Czuczman MS, et al. ASH 2008. Abstract 268. Habermann TM, et al. Br J Haematol. 2009;145:344-349. Lenalidomide in MCL – Trial 003 Results % Response ORR 41
    • 14 pts prior bortezomib
    57 CR/CRu 13 PR 28 SD 26 PD 33 Toxicity (myelotoxocity)* Dose reductions 38
  • NHL-003: MCL subset 54 pts Zinzani et al. ASH # 262 Reeder ASCO 2009, abst # 8569 Patients (%) PFS (days) Kaplan-Meier Estimates (n=54) Response Duration (days) Kaplan-Meier Estimates (n=23) Median Response Duration has not been reached Responders (%) Lenalidomide in MCL – Trial 003 100 80 40 20 0 60 0 100 200 300 400 100 80 40 20 0 60 0 100 200 300 400
  • Zaja Ash 2010, abst # 966 Ahmadi ASH 2010, abst # 3962 Lenalidomide in MCL – Next Step Study Results/Comments MCL-001 “EMERGE” Rel / ref MCL: single agent 25 mg/pivotal trial 117 / 135 pts enrolled MCL-002 “SPRINT” Randomized rel / ref MCL: lenalidomide vs invest’s choice
  • Wang ICML 2011 Morrison, ASCO 2010 abst # 8106 Lenalidomide in MCL – Next Step Study Results/Comments Len + Rituximab Len 20mg 21/28 days + R 375 mg /m 2 x 4 46 pts (1-4 prior RX) / ORR 57% 33% CR Median duration of response 18.9 ms Gr 3-4 toxicities: neutropenia (17%), lymphopenia (7.2%), and thrombocytopenia (4.5%) Len + Bortezomib CALGB / ongoing / target 54 pts Len + Bortezomib + Rituximab Sarah Cannon / ongoing
  • Targeting PI3K/mTOR Pathway PI3K/mTOR pathway functions like an “integrator” of cell stimuli from the environment (cell surface through number of receptor kinases) and available “nutrients” to allow cell survival / proliferation PI3K and mTOR signaling critically regulates metabolism, growth or survival Witzig T et al, Current Treat Oncol, July 2006
  • Targeting PI3K/mTOR Pathway Rapamycin extracted / Rapa Nui 70’s Witzig T et al, J Clin Oncol 2005;23:5347-5356 Ansell S et al, Cancer 2008;113(3):508-14
    • OR R 41% (11/27) 1 CR
    • Median of 4 prior RX
    • Better toxicity profile
    25mg weekly 
    • Med TTP 6.5 months
    • Med DOR 6.9 months
    Similar ORR, DOR and TTP @ both 250 mg and 25 mg flat weekly dose
    • 38% ORR (13/34) - 1 CR
    • Grade 3 or 4 toxicity 91% pts
      • - Heme: thrombocytopenia (100%) anemia (66%) neutropenia (77%)
      • - GI, mucositis, fatigue, hyperglycemia, neuropathy
    250mg weekly Temsirolimus (CCI-779)
  • Temsirolimus – Phase III MCL Multicenter, open-label, phase III trial, International study 54 patients per arm; 2 -7 previous therapies Temsirolimus treatment to continue until progression or unacceptable toxicity Hess, JCO, Aug 2009 Temsirolimus 175 mg qw x 3 then 25 mg qw R A N D O M I Z E Relapsed/refractory MCL Required rituximab anthracycline alkylating agent (N = 162) Investigators’ choice single agent Temsirolimus 175 mg qw x 3 then 75 mg qw
  • Temsirolimus – Phase III MCL Multicenter, open-label, phase III trial Hess, JCO, Aug 2009 Most common grade 3 or 4 AEs in the temsirolimus groups were thrombocytopenia, anemia, neutropenia and asthenia Approved in EU
  • Witzig T et al, J Clin Oncol 2005;23:5347-5356 Rizzieri DA et al, Clin Can Res 2008;14:2756-2762 Yee KW et al, Clin Cancer Res 2006;12:5165-5173 Reeder CB et al, ASH 2007, abstr 121 Hesse G et al, ASCO 2008, abstr 8513 mTOR Inhibitors – Next Step Drugior BTZ) Design Results/Comments Temsirolimus (CCI-779) Temsirolimus + rituximab Relapsed MCL / > CR Rituximab, Cladribine, and Temsirolimus Other comb w/ R-CHOP/ BBR etc..
  • Witzig T et al, J Clin Oncol 2005;23:5347-5356 Rizzieri DA et al, Clin Can Res 2008;14:2756-2762 Yee KW et al, Clin Cancer Res 2006;12:5165-5173 Reeder CB et al, ASH 2007, abstr 121 Hesse G et al, ASCO 2008, abstr 8513 mTOR Inhibitors – Next Step Drugior BTZ) Design Results/Comments Temsirolimus (CCI-779) Temsirolimus + rituximab Relapsed MCL / > CR Rituximab, Cladribine, and Temsirolimus Other comb w/ R-CHOP/ BBR etc.. Everolimus (RAD001) Oral 10 mg QD until PD or toxicity MCL 19 cases ORR: 32%; 11% CR, DOR 5.5 ms Well tolerated: Gr 3-4 neutropenia 17% thrombocytopenia 35% Same design for phase II pivotal trial (PILLAR-1) (prior BTZ) International study completed
  • Witzig T et al, J Clin Oncol 2005;23:5347-5356 Rizzieri DA et al, Clin Can Res 2008;14:2756-2762 Yee KW et al, Clin Cancer Res 2006;12:5165-5173 Reeder CB et al, ASH 2007, abstr 121 Hesse G et al, ASCO 2008, abstr 8513 mTOR Inhibitors – Next Step Drugior BTZ) Design Results/Comments Temsirolimus (CCI-779) Temsirolimus + rituximab Relapsed MCL / > CR Rituximab, Cladribine, and Temsirolimus Other comb w/ R-CHOP/ BBR etc.. Everolimus (RAD001) Oral 10 mg QD until PD or toxicity MCL 19 cases ORR: 32%; 11% CR, DOR 5.5 ms Well tolerated: Gr 3-4 neutropenia 17% thrombocytopenia 35% Same design for phase II pivotal trial (PILLAR-1) (prior BTZ) International study completed Next generation mTORi CC223 OSI-027 ( TORC1 and TORC2 inhibition) / ongoing
  • CXCR5 BAFFR Stromal cell IL-6R CXCL13 BAFF IL-6 PI3K Inhibitors PI3K Delta Pathway Drives Proliferation Cell survival Trafficking BCR PI3K Delta CD40 STAT T308 S473 AKT JAK TRAF6 NF-  B pathway JAK mTOR BTK PLC  2 PKC GSK-3 LYN SYK    LYN/SYK T-cell Signaling stimulus gp130 gp130 STAT BTK PLC  2 p70s6k elf4E Malignant B-cell membrane
  • CAL-101 Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions No off-target activity against Class II or III PI3K, mTOR, or DNA-PK No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™) Reference: Lannutti, Blood 2010 CAL-101 is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta Class I PI3K Isoform Cell-Based Activity PDGF-induced pAKT LPA-induced pAKT fMLP-induced CD63+ Fc  R1-induced CD63+ EC 50 (nM) >20,000 1,900 3,000 8 Alpha Beta Gamma Delta
  • Single-Agent CAL-101 in NHL and CLL NHL (N=51) Characteristic MCL (N=21) iNHL (N=30) CLL (N=54) Age, median [range], years 71 [52-82] 61.5 [32-85] 62.5 [37-82] Bulky disease, % 57 50 81 Adverse genetics (del 17p), % -- -- 36 Prior therapies, median [range], n 5 [1-12] 4 [1-10] 5 [2-15] Prior therapy type, % Rituximab 100 100 98 Alkylating agent 100 87 87 Anthracycline/anthracenedione 95 50 -- Purine analog -- 30 100 Bortezomib (MCL)/Alemtuzumab (CLL) 76 -- 31
    • ORR: indolent NHL: 15/24 (62%) / MCL: 10/16 (62%) (mostly PR) and 0/9 (0%) for DLBCL
    • Heavily pretreated: nb of prior therapies was 5 (1-12)
    • Median [range] duration of response in MCL: 3 months (1- 8)
    • Well tolerated / transient increase of LFTs
    • Increase / mobilization circulating B-cells / tumor cells
    Single-Agent CAL-101 in NHL and CLL
  • MCL (n=21) iNHL (n=30) CLL (n=54) Variety of dosings from 50 BID to 350 BID Kahl, ASH 2010, abst # 17777 O’Brien, Pan Pacific NHL Conf, Aug 2011 Single-Agent CAL-101 in NHL and CLL
    • BCR-crosslinking  activation series downstream tyrosine kinases
    • BCR is critical for normal B-cell maturation and survival:
      • transgenic mice / disruption of BCRs  apoptosis mature B-cells
    • In NHL BCR signal “chronically on” (w/o ligand)  “tonic signaling “ (prognostic value in DLBCL)
    Chen, Blood 2008 From: Nat Rev Immunol 2:945 Rationale for Targeting the BCR Pathway in Lymphoma
  • Chen, Blood 2008 Irish J M et al. PNAS 2010;107:12747-12754 Targeting the BCR Pathway in Lymphoma
    • BCR-associated kinases are targets of new drugs in preclinical and clinical development
    • Syk (spleen tyrosine kinase) inhibitors: R406, Portola’s Syk inhibitors 1
    • Btk (Bruton’s tyrosine kinase) inhibitors: PCI-32765 from Pharmacyclics, Avila’s compounds ( AVL-292)
    1 Quiroga MP, et al. Blood 114(5):1029-37, 07/2009 2 Niedermeier M, et al. Blood 113(22):5549-57, 5/2009 From: Nat Rev Immunol 2:945 Targeting the BCR Pathway in Lymphoma
    • Bruton ’s Tyrosine Kinase (Btk) is also an essential element of BCR signaling pathway / downstream of Syk
    • Expressed in B-cells, mast cells and monocytes
    • Mutations in Btk prevent B-cell maturation (400 mutations reported)  clinically X-linked agammaglobulinemia
    Bruton ’s Tyrosine Kinase (Btk) A Critical B-Cell Signaling Kinase
  • PCI-32765
    • Forms a specific and irreversible bond with cysteine-481 in Btk
    • Potent Btk inhibition at IC 50 = 0.5 nM
    • Orally bioavailable with daily dosing resulting in 24-hr target inhibition  qd
    • Preclinically in CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF- κ B DNA binding, cell proliferation AND cell migration and adhesion
    Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075 , 2010 Herman SEM et al: : Blood. 2011 Mar 21. Ponader, et al., Proc ASH, 2010 PCI-32765: Novel Small Molecule Inhibitor of BTK N N N N N H 2 O N O
  • Fowler, Blood ASH 2010; 116 : 964. Advani,ICML, Lugano 2011 Phase I NHL / CLL – Enrollment (56 pts) Median age, years (range) M/ F, n (%) 65 (41-82) 38 (68) / 18 (32) Histology, n (%) FL 16 (29) CLL/SLL 16 (29) MCL 9 (16) DLBCL 7 (16) MZL / MALT 4 (7) WM 4 (7) Median prior therapies, number (range) 3 (1-10)
  • 1 AEs >14% * Ecchymosis and pneumonia are combination of several preferred terms Grade 3/4 Hematology 2 Most Common Adverse Events 1 2 Based on clinical review of AE and Lab data Fowler, Blood ASH 2010; 116 : 964. Advani, ICML, Lugano 2011 Phase I NHL / CLL - Adverse Events
  • Pre-treatment 2 months on treatment Absolute Lymphocyte Count O’Brien, Pan Pacific NHL Conf, Aug 2011 Burger, O‘Brien, ASH 2010, Blood 116: abst # 57 Pattern of Response: Blood Lymphocytes vs Lymph Nodes
  • 2 Based on clinical review of AE and Lab data * 1 CLL pt had nodal response with lymphocytosis; ** Based on IgM Fowler, Blood ASH 2010; 116 : 964. Advani,ICML, Lugano 2011 Phase I – PCI-32765 – Best Response N CR PR SD PD NE ORR% ITT (n=56) ORR% Eval (n=50) CLL/SLL 16 1 10 3 * 2 69% 79% MCL 9 3 4 1 1 78% 78% WM 4 3 ** 1 75% 75% FL 16 3 3 3 4 3 38% 46% MZL/MALT 4 1 1 1 1 25% 33% DLBCL 7 2 1 4 29% 29% TOTAL 56 7 24 9 10 6 55% 62%
  • % Change of Tumor Burden 41/48 (85%) Fowler, Blood ASH 2010; 116 : 964. Advani,ICML, Lugano 2011 PCI-32765 Max % Change in Tumor Burden CLL/SLL MCL DLBCL FL Other Indolent NHL
    • Well tolerated with a modest toxicity profile
    • Majority of adverse events were Grade 1 or 2 in severity and easily managed/reversible
    • No cumulative toxicity with treatment duration > 6 months
    • Continuous occupancy of Btk at doses ≥ 2.5 mg/kg
    • Significant activity with durable responses observed in multiple histologic subtypes / MCL +++
    • Phase II trials ongoing and combinations
    Conclusions Oral BTK inhibitor PCI-32765 in NHL
  • Other Targets in MCL Parek, Semin Cancer Biol. 2011
    • MULTIPLE new targets
    • (Non-cross) resistant with chemotherapy
    • CLINICAL TRIALS +++ / new combinations
    • BIOMARKERS? / to decide among novel therapies???
    MCL - Novel Therapies - Conclusions
  • Induction Consolidation Maintenance Relapse MCL: Considerable Progress! CHOP/ CVP/ MCP / Fludarabine BEFORE ASCT Debated?? No maintenance IFN ? HDT / ASCT Dose-intensive Therapies HD AraC and Rituximab NOW HDT / ASCT Rituximab Bortezomib? BTZ, CFZ New Mab Lenalidomide mTORi BTKi PI3Ki Other: Bcl-2, HADCi
  • Thank You! [email_address] Thank You! jtcancercenter.org