Audio and slides for this presentation are available on YouTube: http://youtu.be/Q_wdfcJO3XE
Ann LaCasce, MD, MMSc, of Dana-Farber/Brigham and Women's Cancer Center Adult Lymphoma Program, talks about new clinical trials and treatments available for lymphoma patients. This presentation was originally given at the Lymphoma Research Foundation North American Forum on Sept. 28, 2013. http://www.dana-farber.org | http://www.lymphoma.org
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Clinical Trials, Emerging New Drugs and Future Concepts in the Treatment of Lymphoma
1. Clinical Trials, Emerging New
Drugs and Future Concepts in
the Treatment of Lymphoma
Ann S. LaCasce, MD, MMSc
Medical Oncologist, Dana-Farber/Brigham and Women’s Cancer
Center Adult Lymphoma Program
Assistant Professor, Harvard Medical School
Director, Dana-Farber/Partners CancerCare Hematology-Medical
Oncology Fellowship Program
2. What is a clinical trial?
• Test the safety and how well a new drug
works in a particular disease
• Test the safety and how well an established
drug works in a new disease
• Compare a new medication to standard
treatment
• Goal for FDA approval of a drug for a
particular use
3. History of clinical trials
Established rules for clinical trial –
• drug must be used on simple, not
composite disease
• quality of drug must correspond
with strength of disease
• must be tested on two contrary
diseases
• time action must be observed
• must be performed on humans
Avicenna, Persian physician and philosopher (1025)
6. NIH – types of trials
Prevention
Prevention
Screening
Screening
Diagnostic
Diagnostic
Treatment
Treatment
Quality
Quality
of Life
of Life
Compassionate
Compassionate
use
use
8. New drug clinical trials
Phase 1
Phase 1
Safety
Safety
20-100 pts
1st in humans
dose, schedule
9. New drug clinical trials
Phase 1
Phase 1
Safety
Safety
20-100 pts
1st in humans
dose, schedule
Phase 2
Phase 2
Efficacy
Efficacy
100-500 pts
How well does
it work?
10. New drug clinical trials
Phase 1
Phase 1
Safety
Safety
20-100 pts
1st in humans
dose, schedule
Phase 2
Phase 2
Efficacy
Efficacy
100-500 pts
How well does
it work?
Phase 3
Phase 3
Confirm
Confirm
>1,000 pts
Compare with
standard of care &
study safety
11. New drug clinical trials
Phase 1
Phase 1
Safety
Safety
20-100 pts
1st in humans
dose, schedule
Phase 2
Phase 2
Efficacy
Efficacy
100-500 pts
How well does
it work?
Phase 3
Phase 3
Confirm
Confirm
>1,000 pts
Compare with
standard of care &
study safety
FDA review
FDA review
Phase 4
Phase 4
Safety in typical
patients
12. Phase I
• In non-cancer studies performed in healthy
volunteers
• In drugs directed against cancer, typically given to
patients with different types of cancer
• Establish safe dose and schedule
• Evaluate side effects
• Give preliminary information regarding if the drug
works
13. Phase I clinical trial of anti-CD20 monoclonal
antibody in recurrent B-cell lymphoma
3 pts
3 pts
10 mg/m2
10 mg/m2
3 pts
3 pts
50 mg/m2
50 mg/m2
3 pts
3 pts
100 mg/m2
100 mg/m2
3 pts
3 pts
250 mg/m2
250 mg/m2
3 pts
3 pts
500 mg/m2
500 mg/m2
Side effects: fever (5); nausea (2), chills(2), low
blood pressure (2), wheezing (1), low platelets (1)
Lymphoma responded in more than half of patients
14. Phase II
The drug or treatment is given to a larger group of people
to see if it is effective and to further evaluate its safety
15. Rituximab therapy for relapsed indolent
lymphoma
• 166 patients
• IDEC-C2B8 375 mg/m2 intravenously weekly for
four doses
• Fever and chills were the most common events
• Low incidence of serious side effects
• Approximately half of patients responded
• FDA approves the drug
16. Phase III clinical trial
In cancer studies, typically no
placebo except in certain
circumstances
17. CHOP plus rituximab versus CHOP in older patients
with diffuse large-B-cell lymphoma
399 pts
Age 60-80
18. CHOP plus rituximab versus CHOP in older patients
with diffuse large-B-cell lymphoma
RCHOP
399 pts
Age 60-80
19. CHOP plus rituximab versus CHOP in older patients
with diffuse large-B-cell lymphoma
RCHOP
399 pts
Age 60-80
CHOP
RCHOP superior and becomes standard treatment
20. Phase IV
After drug approved by FDA
Collect additional information on side effects
Identify any rare or long term toxicity
21. Oversight
• Studies may be conducted by pharmaceutical
companies, single or group of investigators
(including cooperative groups)
• Careful oversight to ensure ethical and safe conduct
• Institutional Review Board (IRB)
– Evaluate protocol
– Review consent form
– Oversee ongoing conduct of trial
25. FDA definitions
Fast Track:
Fast Track:
Frequent meetings with
Frequent meetings with
FDA re drug
FDA re drug
development plan
development plan
Eligible for accelerated
Eligible for accelerated
approval and priority
approval and priority
review, if relevant
review, if relevant
criteria are met
criteria are met
Rolling review
Rolling review
26. FDA definitions
Fast Track:
Fast Track:
Breakthrough Therapy:
Breakthrough Therapy:
Frequent meetings with
Frequent meetings with
FDA re drug
FDA re drug
development plan
development plan
All Fast Track features
All Fast Track features
Eligible for accelerated
Eligible for accelerated
approval and priority
approval and priority
review, if relevant
review, if relevant
criteria are met
criteria are met
Rolling review
Rolling review
Intensive guidance on
Intensive guidance on
drug development
drug development
program, beginning as
program, beginning as
early as Phase 1
early as Phase 1
Organizational
Organizational
commitment involving
commitment involving
senior managers
senior managers
29. SGN-30
CD30
Anti-CD30 antibody
• Phase 2 study in patients with HL or
CD30+ anaplastic large cell lymphoma
• Several patients with T-cell lymphoma
experienced disease improvement
but activity disappointing
• Favorable side effect profile
CD 30 positive lymphoma cell
30. Brentuximab vedotin
Antibody drug conjugate (ADC)
Chemotherapy drug (MMAE)
Antibody
CD-30
ADC binds to CD30
ADC-CD30 complex
taken into cell
MMAE is released
MMAE disrupts
microtubule network
G2/M cell
cycle arrest
Cell dies
31. Brentuximab vedotin FDA approval
Hodgkin lymphoma
Hodgkin lymphoma
Phase 2 study
Phase 2 study
Relapsed disease
Relapsed disease
Anaplastic large cell
Anaplastic large cell
lymphoma
lymphoma
Phase 2 study
Phase 2 study
Relapsed disease
Relapsed disease
Extremely active drug in both diseases
Manageable side effect profile with peripheral
neuropathy as predominant issue
32. Brentuximab vedotin FDA approval
Hodgkin lymphoma
Hodgkin lymphoma
Phase 2 study
Phase 2 study
Relapsed disease
Relapsed disease
Anaplastic large cell
Anaplastic large cell
lymphoma
lymphoma
Phase 2 study
Phase 2 study
Relapsed disease
Relapsed disease
Extremely active drug in both diseases
Manageable side effect profile with peripheral
neuropathy as predominant issue
39. Brentuximab development NHL
Phase 2
Phase 2
relapsed CD30+
relapsed CD30+
NHL
NHL
BV+CHP
BV+CHP
Phase 3
Phase 3
CD30+
CD30+
NHL
NHL
CHOP
CHOP
40. Learning from the past
• Thalidomide with a checkered past
• Introduced in the late 50’s as
a sedative thought to be safe
for pregnant women with morning
sickness
• Tragic toxicity of limb deformities
• 1990’s found to have activity in
leprosy and HIV
• Later found to be active in multiple
myeloma and approved as initial
therapy by FDA in 2006
• Prominent side effects of neuropathy
and fatigue
46. Evolution of front-line therapy in follicular
lymphoma
CHOP or CVP conventional chemotherapy
47. Evolution of front-line therapy in follicular
lymphoma
CHOP or CVP conventional chemotherapy
CHOP or CVP plus rituximab
48. Evolution of front-line therapy in follicular
lymphoma
CHOP or CVP conventional chemotherapy
CHOP or CVP plus rituximab
Bendamustine plus rituximab
49. Evolution of front-line therapy in follicular
lymphoma
CHOP or CVP conventional chemotherapy
CHOP or CVP plus rituximab
Bendamustine plus rituximab
Lenaliomide plus rituximab
50. Evolution of front-line therapy in follicular
lymphoma
CHOP or CVP conventional chemotherapy
CHOP or CVP plus rituximab
Bendamustine plus rituximab
Lenaliomide plus rituximab
Lenaliomide plus rituximab ? + additional novel agent
56. Idelalisib
Submitted to
Submitted to
the FDA
the FDA
in rituximab
in rituximab
refractory
refractory
iNHL
iNHL
On-going
On-going
clinical trials
clinical trials
oral drug
favorable side effect profile
CLL
CLL
MCL
MCL
iNHL
iNHL
57. Personalized medicine in lymphoma
Targeting ABC
Targeting ABC
DLBCL
DLBCL
Ibrutinib
Ibrutinib
Tissue biopsy to
Tissue biopsy to
determine DLBCL
determine DLBCL
subtype
subtype
lenalidomide
lenalidomide