Second Interim Analysis Of A Phase Iii Study Of Idelalisib -Books Download

Second Interim Analysis of a Phase III Study of Idelalisib

2020 | 12 views | 16 Pages | 1.84 MB

Study of Idelalisib and Rituximab for Patients with Relapsed CLL with 17p Deletion and Other Adverse Cytogenetics ... management of chronic lymphocytic leukemia ...



CME Information
OVERVIEW OF ACTIVITY
Each year thousands of clinicians basic scientists and other industry professionals sojourn to major international oncology conferences
like the American Society of Hematology ASH annual meeting to hone their skills network with colleagues and learn about recent
advances altering state of the art management in hematologic oncology As such these events have become global stages where exciting
science cutting edge concepts and practice changing data emerge on a truly grand scale This massive outpouring of information has
enormous benefits for the hematologic oncology community but the truth is it also creates a major challenge for practicing oncologists
and hematologists
Although original data are consistently being presented and published the flood of information unveiled during a major academic
conference is unprecedented and leaves in its wake an enormous volume of new knowledge that practicing oncologists must try to
sift through evaluate and consider applying Unfortunately and quite commonly time constraints and an inability to access these
data sets leave many oncologists struggling to ensure that they re aware of crucial practice altering findings This creates an almost
insurmountable obstacle for clinicians in community practice because they are not only confronted almost overnight with thousands
of new presentations and data sets to consider but they are also severely restricted in their ability to review and interrogate the raw
To bridge the gap between research and patient care this CME activity will deliver a serial review of the most important emerging data
sets on the management of chronic lymphocytic leukemia CLL from the latest ASH meeting including expert perspectives on how
these new evidence based concepts may be applied to routine clinical care This activity will assist medical oncologists hematologists
hematology oncology fellows and other healthcare professionals in the formulation of optimal clinical management strategies and the
timely application of new research findings to best practice patient care
LEARNING OBJECTIVES
Develop an understanding of emerging efficacy and side effect data with novel agents and combination regimens including next
generation anti CD20 antibodies and PI3 kinase BTK and Bcl 2 inhibitors under evaluation for previously untreated and relapsed
refractory CLL and where appropriate facilitate patient access to ongoing trials of these agents
Appreciate the recent FDA approvals of novel targeted agents indicated for the treatment of newly diagnosed and relapsed refractory
CLL and discern how these treatments can be appropriately integrated into clinical practice
Compare and contrast the benefits and risks of chemoimmunotherapy with fludarabine cyclophosphamide rituximab versus
bendamustine rituximab as first line therapy for fit patients with CLL
Apply recent clinical research findings with the newly FDA approved combination of obinutuzumab and chlorambucil to the care of
patients with previously untreated CLL
Recall the activity of salvage therapy with obinutuzumab and chlorambucil after treatment failure of chlorambucil alone in patients
with CLL and comorbidities
ACCREDITATION STATEMENT
Research To Practice is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education
for physicians
CREDIT DESIGNATION STATEMENT
Research To Practice designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits Physicians should claim only
the credit commensurate with the extent of their participation in the activity
HOW TO USE THIS CME ACTIVITY
This CME activity contains slides and edited commentary To receive credit the participant should review the slide presentations read
the commentary complete the Post test with a score of 75 or better and fill out the Educational Assessment and Credit Form located at
ResearchToPractice com 5MJCASH2015 3 CME
CONTENT VALIDATION AND DISCLOSURES
Research To Practice RTP is committed to providing its participants with high quality unbiased and state of the art education We
assess potential conflicts of interest with faculty planners and managers of CME activities Real or apparent conflicts of interest are
identified and resolved through a conflict of interest resolution process In addition all activity content is reviewed by both a member of
the RTP scientific staff and an external independent physician reviewer for fair balance scientific objectivity of studies referenced and
patient care recommendations
FACULTY The following faculty and their spouses partners Tennessee Oncology
reported real or apparent conflicts of interest which have been Nashville Tennessee
resolved through a conflict of interest resolution process Contracted Research AstraZeneca Pharmaceuticals LP
Stephen M Ansell MD PhD Celgene Corporation Cephalon Inc Genentech BioOncology
Professor of Medicine GlaxoSmithKline Novartis Pharmaceuticals Corporation Roche
Division of Hematology Laboratories Inc Takeda Oncology
Mayo Clinic Jonathan W Friedberg MD MMSc
Rochester Minnesota Samuel Durand Professor of Medicine
Research Funding Bristol Myers Squibb Company Celldex Director Wilmot Cancer Center
Therapeutics University of Rochester
Ian W Flinn MD PhD Rochester New York
Director of Blood Cancer Research Advisory Committee and Other Uncompensated Activities
Sarah Cannon Research Institute Genentech BioOncology
Mitchell R Smith MD PhD RESEARCH TO PRACTICE STAFF AND EXTERNAL REVIEWERS
Director of Lymphoid Malignancies Program at Taussig Cancer The scientific staff and reviewers for Research To Practice have
Institute no real or apparent conflicts of interest to disclose
Cleveland Clinic This educational activity contains discussion of published and
Cleveland Ohio or investigational uses of agents that are not indicated by
Consulting Agreements Celgene Corporation Spectrum the Food and Drug Administration Research To Practice does
Pharmaceuticals Inc Takeda Oncology Contracted Research not recommend the use of any agent outside of the labeled
Abbott Laboratories indications Please refer to the official prescribing information
EDITOR Dr Love is president and CEO of Research To Practice for each product for discussion of approved indications
which receives funds in the form of educational grants to develop contraindications and warnings The opinions expressed are those
CME activities from the following commercial interests AbbVie of the presenters and are not to be construed as those of the
Inc Amgen Inc Astellas Scientific and Medical Affairs Inc publisher or grantors
AstraZeneca Pharmaceuticals LP Aveo Pharmaceuticals Bayer This activity is supported by educational grants from
HealthCare Pharmaceuticals Biodesix Inc Boehringer Ingelheim Bristol Myers Squibb Company Celgene Corporation
Pharmaceuticals Inc Boston Biomedical Pharma Inc Bristol Incyte Corporation Onyx Pharmaceuticals an Amgen subsidiary
Myers Squibb Company Celgene Corporation Clovis Oncology Seattle Genetics and Takeda Oncology
Daiichi Sankyo Inc Dendreon Corporation Eisai Inc Exelixis Hardware Software Requirements
Inc Foundation Medicine Genentech BioOncology Genomic A high speed Internet connection
Health Inc Gilead Sciences Inc Incyte Corporation Janssen A monitor set to 1280 x 1024 pixels or more
Biotech Inc Jazz Pharmaceuticals Inc Lilly Medivation Inc Internet Explorer 7 or later Firefox 3 0 or later Chrome
Merck Myriad Genetic Laboratories Inc Novartis Pharmaceuticals Safari 3 0 or later
Corporation Novocure Onyx Pharmaceuticals an Amgen Adobe Flash Player 10 2 plug in or later
subsidiary Pharmacyclics Inc Prometheus Laboratories Adobe Acrobat Reader
Inc Regeneron Pharmaceuticals Sanofi Seattle Genetics Optional Sound card and speakers for audio
Sigma Tau Pharmaceuticals Inc Sirtex Medical Ltd Spectrum
Pharmaceuticals Inc Taiho Oncology Inc Takeda Oncology Teva Last review date April 2015
Oncology Tokai Pharmaceuticals Inc and VisionGate Inc Expiration date April 2016
POST ASH Issue 3 2015
To go directly to slides and commentary for this issue click here
When the German CLL Study Group one of the most prolific clinical trial organizations
in the world launched the landmark Phase III CLL10 trial in 2008 few if any
expected that the central question the study sought to answer would in essence
be outdated by the time the results became available CLL10 focused on a classic
oncology research issue the comparative clinical benefits of 2 chemobiologic
regimens fludarabine cyclophosphamide rituximab FCR and bendamustine rituximab
BR and although the results as summarized below have important practical clinical
implications today it is increasingly evident that the overall treatment strategy in this
disease is undergoing a massive reconfiguration For that reason this issue of 5 Minute
Journal Club evaluates not only the seminal CLL10 trial findings but also a sample of
2014 ASH data sets on several new agents regimens and strategies that have burst
onto the scene in the past couple of years and have many investigators thinking that
chronic lymphocytic leukemia CLL may soon fall into the basic clinical paradigm of
chronic myelogenous leukemia CML namely a chronic disease requiring long term
outpatient management that may be associated with prolonged survival
Here s a summary of what happened in San Francisco related to CLL
CLL10 FCR versus BR patients without del 17p
The updated data from CLL10 continue to support what clinical experience had already
strongly suggested namely that FCR yields clear cut improvements in disease related
outcomes including a statistically and clinically significant increase in median progression
free survival PFS 55 2 versus 41 7 months and rates of bone marrow minimal residual
disease MRD negativity at final restaging 26 6 versus 11 1 However with less than
3 years of follow up no overall survival benefit has been seen Just as predictably the
data reveal that FCR produced considerably more toxicity particularly in older individuals
65 years in whom the rate of infection was 47 7 compared to 20 6 with BR The
bottom line is that most investigators believe that both regimens have a role and the risk
for toxicity must be carefully considered during patient selection
Impact of MRD status
The intriguing concept of defining undetectable levels of disease after treatment to
better understand potential prognosis has been explored in various forms across many
hematologic cancers In this regard at ASH we saw a report from the German group
evaluating pooled data from the CLL8 FC versus FCR and CLL10 trials examining the
value of peripheral blood MRD negative status at response evaluation What was seen
was a strong correlation between MRD status and outcome that seemed at least as
predictive of PFS as clinical response and of particular interest patients considered to
have a partial response clinically had a much better prognosis if their bone marrow was
MRD negative 61 7 versus 28 1 months Discussions are now ongoing about how to
integrate MRD status into prospective trial design and potentially clinical decision making
Obinutuzumab Ob
Since the FDA approval of Ob in combination with chlorambucil a drug that many had
not been regularly using for CLL there has been constant questioning about whether
this novel Type II anti CD20 antibody could be employed with other chemotherapeutic
regimens Not surprisingly a number of studies are ongoing that examine this issue
including the Phase III GREEN trial which is targeting 800 patients with both previously
treated and untreated CLL and evaluates Ob alone or with one of several types of
chemotherapy This effort is also interesting in that it examines a modified dosing
scheme of 25 mg on day 1 and 975 mg on day 2 in an attempt to address the high
rates of infusion related reactions that have previously been reported with Ob At ASH
we saw early safety data from the previously untreated cohort in the study which
showed a 13 3 rate of Grade 3 or higher infusion related reactions with 2 5 of
patients discontinuing treatment due to this side effect As greater experience is gained
with this interesting agent it has become clear that these infusion reactions occur
mainly during the first cycle and may be related to cell death and or cytokine release
Efficacy findings from this study are not yet available and until then clinicians will
need to consider whether they want to dust off chlorambucil and give it a go with Ob
Interestingly during a recent interview for our audio series with investigator Dr Jeffrey
Sharman I was surprised to learn that he avoids this issue altogether and unabashedly
uses Ob alone as up front therapy in select patients
Clearly the German CLL group was busy at ASH as they also treated us to more from
the pivotal CLL11 trial which was first presented at ASCO 2013 and paved the way
for the approval of Ob From that and related presentations we learned among other
things that Ob chlorambucil is superior to rituximab chlorambucil in a number of ways
including rates of MRD negativity in blood 38 versus 3 Additional data unveiled at
ASH evaluated patients in the trial who were initially randomly assigned to chlorambucil
alone but upon relapse generally due to lack of response to chlorambucil were
crossed over to Ob chlorambucil Of great interest 26 of 30 patients 87 experienced
objective responses further suggesting that Ob itself might have significant and
perhaps underappreciated intrinsic anti CLL activity that is greater than that previously
observed with rituximab monotherapy an important and useful therapeutic tool in
follicular lymphoma
Anti CD20 maintenance in CLL
Although maintenance rituximab has been commonly used in many patients receiving
R chemotherapy for follicular and mantle cell lymphoma our survey and polling data
have clearly illustrated that hematologic investigators do not endorse this approach
in CLL However provocative results from 2 interesting trials unveiled at ASH have
some beginning to reevaluate this stance
First the AGMT CLL8 a trial randomly assigned 263 patients who completed first
or second line chemotherapy rituximab to 24 months of rituximab maintenance or
observation and demonstrated an approximately 50 reduction in the rate of disease
progression with maintenance No survival benefit was seen although crossover in
the control group was allowed The other related and cleverly named Phase III effort
the PROLONG trial evaluated ofatumumab maintenance after second or third line
treatment with chemotherapy anti CD20 and again there was an approximate 50
reduction in risk of disease progression Although more data on this important question
would be ideal some investigators feel that these results are enough to compel
clinicians to discuss and or recommend this approach in select patients at least until
the many new options and treatments are sorted out
You can t attend a conference these days without witnessing a new and relevant data
set with this blockbuster Bruton tyrosine kinase inhibitor and ASH was no exception
as we saw results from the Phase II RESONATETM 17 trial focused on 144 patients with
del 17p CLL who experienced disease progression while receiving between 1 and 4 prior
lines of therapy Perhaps not surprisingly as few of these studies fail to disappoint most
patients had objective responses and about 80 were progression free at 1 year These
relevant findings are central to the current first line approval of the drug in this situation
However it is important to note that although ibrutinib results in similar response rates in
this population these patients have shorter PFS and overall survival
Interestingly there is a belief that del 17p may only be part of the story and for that
reason investigators at MD Anderson evaluated CKT complex metaphase karyotype by
whole genome sequencing defined as 3 or more distinct chromosomal abnormalities
in 100 consecutive cases of CLL treated with ibrutinib What they found is that CKT is
a better predictor of benefit from ibrutinib than del 17p However this clearly needs
additional confirmation before whole genome sequencing makes its way into trials or
clinical practice
Idelalisib
One of the important features of ibrutinib in CLL is the consistency of response in
patients with adverse prognostic factors like 17p deletion but the drug is not alone in
this regard At ASH we saw a subset analysis from the major Phase III trial reported
in the New England Journal demonstrating that idelalisib rituximab is a highly effective
regimen including in patients with del 17p del 11q and unmutated IGHV These findings
suggest that this regimen may have an important early role in patients with these genetic
abnormalities who have previously received or are not candidates for ibrutinib
Venetoclax formerly ABT 199
Despite the new moniker more data presented at ASH reveal that things remain
entirely the same and that this novel Bcl 2 inhibitor antiapoptotic agent is a very active
drug Most notably in a Phase II trial of 49 patients with relapsed or refractory
CLL small lymphocytic lymphoma the combination of venetoclax with rituximab
demonstrated an impressive 88 objective response rate with 31 complete response
CR or CR with incomplete blood count recovery including in 7 of 9 patients with
del 17p MRD negativity in the bone marrow was recorded in 17 patients Significantly
5 dose cohorts were studied and it appears that a schedule was uncovered that seems
to avoid tumor lysis syndrome a complication reported previously with this agent
Although it remains to be seen how these novel and encouraging therapies will be
optimally mixed matched and sequenced in CLL it seems highly likely that the survival
of patients will continue to be extended and perhaps soon mirror the normal life
expectancies of patients under active treatment for CML ASH 2014 will be remembered
as another important step forward in this rewarding march toward a new standard
Next on this series we provide an ASH update on myeloproliferative neoplasms
including more data on the most recently approved treatment in these diseases the
use of ruxolitinib in polycythemia vera
Neil Love MD
Research To Practice
Miami Florida
Research To Practice is accredited by the Accreditation Council for Continuing Medical Education to
provide continuing medical education for physicians
Research To Practice designates this enduring material for a maximum of 2 AMA PRA Category
1 CreditsTM Physicians should claim only the credit commensurate with the extent of their
participation in the activity
This activity is supported by educational grants from Bristol Myers Squibb Company
Celgene Corporation Incyte Corporation Onyx Pharmaceuticals an Amgen subsidiary
Seattle Genetics and Takeda Oncology
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Second Interim Analysis of a Phase III Study of Idelalisib
and Rituximab for Patients with Relapsed CLL with 17p
Deletion and Other Adverse Cytogenetics
Presentation discussed in this issue
Sharman J et al Second interim analysis of a phase 3 study of idelalisib Zydelig
plus rituximab for relapsed chronic lymphocytic leukemia Efficacy analysis in
patient subpopulations with del 17p and other adverse prognostic factors Proc
ASH 2014 Abstract 330
Slides from a presentation at ASH 2014 and transcribed comments
from a recent interview with Jonathan W Friedberg MD MMSc
For more visit ResearchToPractice com 5MJCASH2015
For more visit ResearchToPractice com 5MJCASH2015
For more visit ResearchToPractice com 5MJCASH2015
For more visit ResearchToPractice com 5MJCASH2015
For more visit ResearchToPractice com 5MJCASH2015
For more visit ResearchToPractice com 5MJCASH2015
For more visit ResearchToPractice com 5MJCASH2015


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