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New Drug Trials in Pediatric Oncology:
Challenges and Opportunities
Brenda J. Weigel, M.Sc., M.D.
Associate Professor
Pediatric Hematology/Oncology
Department of Pediatrics and
University of Minnesota Masonic Cancer Center
Outline
• Overview of pediatric oncology phase I trials: rationale for
need
• Overview of drug development
• Examples of new drug integration in pediatric oncology
• Pediatric phase I study design and overview of general
outcomes
Why do we need new agents in
Pediatric Oncology?
Overall Survival in Pediatric Oncology
Has Been Steadily Improving
Overall Survival in Pediatric Oncology
Has Been Steadily Improving
Event-Free Survival in Metastatic Rhadomyosarcoma
Pediatric Patients Only 24% at 2 years
J. Clin. Oncol. 19: 213-19, 2001
Rhabdomyosarcoma Treatment: Worst Degree of
Toxicity for Intermediate Stage Disease
700
(n=1062)
600
500
400
300
200
100
0
Mild
Moderate
Severe
Life
Threatening
Fatal
Adapted from Crist et al. J. Clin Oncol. June 2001
Doxorubicin Cardiotoxicity
Doxorubicin Cardiotoxicity
Why do we need new agents in
Pediatric Oncology?
• Improve cure rates
• Decrease acute toxicity
• Minimize risks for late effects
What Is Needed to Get a Drug
Approved?
Summary of Drug Development
• Drug development is an orderly process designed to
minimize risk and determine benefit
• Clinical studies are required to produce the evidence
to determine risk and benefit
• Clinical drug development is most effective with
understanding and communication between all
involved: scientists and clinical doctors
Select a Drug for Development
•
Available drug/product either from
pharmaceutical company or custom made
•
Biological plausibility: basic biology and
science
•
Pre-clinical information in relevant models of
cancer
•
Pre-clinical and clinical information for dosing,
safety and drug stability
Drug Development in Oncology
• Phase I
Dose Finding and side effects
• Phase II Defining activity by disease: does the
drug work in some patients
• Phase III Prospective randomized trial(s)
defining role of therapy for a given disease:
randomized studies comparing new approach to
standard of care
• Phase IV After market studies: looking for new
diseases for a drug
Example: Gleevac for GIST
• 1985: Dr. Druker starts lab work at DFCI,
Boston evaluating targets for cancer therapy
• 1990: He and others linked the basic science
work to changes in a form of leukemia
• 1990-1993: development of pre-clinical cancer
model systems evaluating the target
• 1993: Dr. Druker relocated to the University of Oregan
and connects with Ciba-Geigy (now Novartis) who had
potential drugs to “hit” the target
• 1998: first studies to find the same targets in GIST and in
some forms of leukemia
• 1999: first human trial of the drug Gleevac in patients with
leukemia
• 2000: pediatric phase I study in Ph+ leukemia
• 2001: FDA gave accelerated approval for Gleevac in
relapsed CML - 53% of patients responded
• 2002: FDA granted full approval for newly diagnosed
CML
• 2002: First trial of Gleevac in GIST
• 2003: FDA expanded approval for other forms of CML and
leukemia
• 2008: FDA grants full approval for GIST as 52% of
patients responded to Gleevac
GIST approval 23 yrs after initial
basic studies on the pathway were
started
Overview of Therapeutic Development
Screening,
animal
studies,
chemistry,
batching
Initial
dose
finding
and safety
studies
Pre-IND. IND Filing
Pre1
clinical
Initial
activity
and
further
safety
studies
2
Comparative
efficacy
studies,
chemistry
scale up,
prepare NDA
3
Post
marketing
safety
review, other
commitments
NDA Filing
4
Pre-IND
Meeting
30 day
multidisciplinary
safety review
Consultation
End of
Phase 2
Meeting
Comprehensive
Premultidisciplinary
NDA
review often
Meeting with Advisory
Monitor safety, review new
protocols, annual reports, approve
exceptions
Committee
discussion
Safety and
Phase 4
monitoring
Overview
• Build the scientific basis and pre-clinical platform to
take a drug to clinical trial
– Approximately 5-10 yrs
• Have sponsorship for trial, averages approximately 1
million dollars for a phase I trial
• Only 1 in 10 drugs make it to phase III testing
– Approximately 5-10 yrs from phase I to phase III approval
• Multiple regulatory steps to drug approval
Prioritization of Novel Targeted
Agents in Pediatric Oncology
Many Challenges
• Many agents potentially available
• Small patient numbers
• Heterogenous diseases
• What are the targets?
• What is the optimal amount of pre-clinical data
to justify a clinical trial?
Strategies to Prioritize
• Biology: Target identification
• Tumor type
• Drug availability and formulation
• Pre-clinical data
• Clinical data
Biology
• Identify the target
• Neuroblastoma and anaplastic large cell
lymphoma
• Alk-1
• Is having the target enough?
• Sarcomas
• IGF pathway
• Different tumors, different receptor/ligand
dependence
• Resistence mechanisms/accessory pathways?
ALK-1 Genetic Alterations in Cancer
ALK aberrations
Mutations Amplification
Translocations
Neuroblastoma
ALCL
IMT
NSCLC
Somatic
Somatic unique shared unique
unique
Germline
No activity Ligand
dependent
No activity
Constitutive
Constitutive
Clin Cancer Res 2009;15:5609-14
IGF Pathway
Oncologist 2009
Different Tumors: Different Dependence
IGF Pathway
Tumor
Cytogenetics
Fusion
Gene
Ligan
d
Receptor Relevance
Alveolar RMS
t(2:13),t(1:13)
PAX3-FKHR IGF-II
PAX7-FKHR
IGF-IR
Autocrine
growth factor
Embryonal
RMS
complex
-
IGF-II
IGF-IR
Autocrine
growth factor
Synovial
Sarcoma
t(X:18)
SS18-SSX1
SS18-SSX2
IGF-II
IGF-IR
SS18-SSX
induced
transformation
Ewing’s
Sarcoma
t(11:22)
EWS-FLI1
IGF-I
IGF-IR
Required for
EWS-FLI
transformation
Osteosarcoma
complex
-
IGF-I
IGF-II
IGF-IR
IGF-IR
activation
stimulates
growth
J Pathol 2009;217:469-482
Tumor Type
• Target agent development based on tumor type
• Antibody therapy
• Neuroblastoma, CH14.18
• CNS tumors
• Issues of blood brain barrier
Drug Availability and
Formulation
• Oral vs IV
• Suspension
• Deluent: DMSO etc
• Industry or CTEP
Pre-clinical Data
• Cell lines
• Readily available for most cancers
• Can investigate and understand targets
• No understanding of host factors
• Animal Models
• Issues of immunodeficient mice if using
xenografts
• Orthotopic vs alternative site
• Dose/schedule/toxicity
Pediatric Preclinical Testing
Program (PPTP)
(http://pptp.stjude.org/)
Examples of In Vivo Growth
Curves
NB-SD
Rh10
Combination Treatment with Rapamycin & Cyclophosphamide
Rh18
KT-14
IMC-A12
in Vivo
Growth
Curves
Rhabdomy
o-sarcoma
Therapy with Rapamycin + IGF-1R Antibody
Osteosarcoma (OS9)
Ewing Sarcoma (EW5)
Kurmasheva et al.
AACR 2008
Clinical Data
• Do studies in adults predict success in
pediatrics?
• Generally very different tumor types except
maybe sarcomas
• Do phase I responses predict phase II
success then phase III improvement in
outcome???
• Not so far for rhabdomyosarcoma
What is the Main Aim of Every
Pediatric Oncology Phase I Study?
• Evaluation of toxicity in a pediatric
population
– What are the dose limiting toxicities (DLTs)?
– Define the maximally tolerated dose (MTD)
Secondary Aims in Pediatric
Oncology Phase I Studies
• Define the pharmacokinetics of a drug in a
pediatric population
• Evaluate relevant biological end-points in a
pediatric population
Example
Camptothecin’s in
Rhabdomyosarcoma
New Drug Development in RMS
Xenograft to Phase III Clinical Trials
Xenograft model
Phase II Window
Definitive
Phase III Study
Melphalan
+ vincristine
Active
Too toxic
Ifosfamide
+ etoposide
Active
IRS IV
+ doxorubicin
Active
Single agent
(IRS V)
Active
No activity in relapse
+ cyclophos
(D9501)
Active
Intermediate-Risk
(D9803)
Topotecan
Irinotecan RMS Studies
• Xenograft model predicted substantial
clinical activity
• Responses noted in SJCRH phase I trial
• High response rate in MSKCC patients
Camptothecin Derivatives in
resistant xenografts
Tumor
Rh 12/VCR
Rh 18/VCR
Rh 18/TOPO
Rh 28/LPAM
VRC5/TOPO
Camptothecin
Irinotecan Topotecan
++++
+++
++++++
+++++
++++++
+
+++++
+
+++
+
Window timeline and accrual*
1988
1991
1995
ID
IE v VM
96
93
Topo
39
353
*Contemporary high risk patients
1996
1999
2001
TC
CPT
CPT/V
57
20
48
Irinotecan Window Study
• CPT-11 is active against high-risk
metastatic rhabdomyosarcoma but as single
agent has high PD rate
Irinotecan + Vincristine are Synergistic
Control
CPT + Vcr
Weeks
Weeks
Tumor Volume
Weeks
Tumor Volume
CPT 0.4 mg/kg
(dx5)2 x 3
Tumor Volume
Tumor Volume
Vcr 1 mg/kg
q7d x 9
Weeks
The challenge of high-risk RMS
– IE
– ID
– VAC (IRS III)
1.0
IRS/COG RMS Window Trials
Failure Free Survival
0.9
Failure-Free Survival
• Window trials identify new
agents and combinations
• But – without improvement
in outcome
• Combinations with most
activity
0.8
p=0.016
0.7
0.6
IRS-III
0.5
0.4
0.3
0.2
0.1
Topo
TC
CPT-11
IE, ID, VM
0.0
0
1
2
3
4
5
Time
trialgp
IRS3
alkylator
topo/cpt11
CNSR
29
39
16
FAIL
86
150
100
TOTAL
115
189
116
MEDIAN
1.48
1.19
1
Window Responses in Rhabdomyosarcoma
Window
Ifosphamide/doxorubicin
CR PR Response
11% 41%
52%
Vincristine/melphalan
4%
51%
55%
Ifosphamide/etoposide
5%
36%
41%
Topotecan
3%
46%
49%
Topotecan/cyclophosphamide
4%
46%
50%
Irinotecan
0%
45%
45%
Irinotecan/vincristine
2%
73%
75%
ARST0431 schema
Study Conduct
• Opened for patient enrollment: July 17, 2006
• Closed to patient enrollment: June 13, 2008
• Study amended 03/07 based on data from ARST0121
showing similar toxicity and efficacy of irinotecan
given daily x 5 x 2 or daily x 5 x 1
• 109 patients enrolled
– 20 received irinotecan on daily x 5 x 2 schedule
– 89 received irinotecan on daily x 5 x 1 schedule
Response, Early Event-Free Survival
• 6-week response data
• CR: 7%; PR : 57% (CR+PR=64%); PD: 5%
• Early response data similar to that seen in previous
studies of patients with metastatic disease
• The early response rate was also similar by histology
(RR for embyronal RMS: 58%; alveolar RMS: 66%)
• 18 month event-free survival estimated to be 66%
(95% confidence interval: 55%, 75%)
• 18 month overall survival estimated to be 80%
IGF Targeting,
Rhabdomyosarcoma and
Developmental Therapeutics
COG ADVL0712 – Study Design
• Standard Pediatric Phase I Eligibility Criteria
• Part A: Dose-finding Phase in refractory solid
tumors
• excluding CNS tumors and lymphomas
• Part B: Expanded Cohort for Ewing
sarcoma/PNET
• Treatment:
• IMC-A12 IV over 1 hour once weekly in 28 day
cycles
• 2 dose levels (6 mg/kg and 9 mg/kg)
Patient Characteristics
Total Number Patients
24
Evaluable toxicity/response
22 / 22
Median age, years (range)
15 (7 – 21)
Male/female
11 / 13
Diagnoses Part A - Dose Finding Cohort
Osteosarcoma
3
Rhabdomyosarcoma
2
Non-rhabdo STS
5
Wilms tumor
2
Diagnoses Part B – Expansion Cohort
Ewing sarcoma (6 mg/kg)
12
Dose-limiting Toxicities
Part A: Dose Finding
Dose
# Entered
# Eval
# DLT
DLT Detail
6
6
6
1
Grade 4 Thrombocytopenia
9
6
6
0
-
(mg/kg)
Part B: Ewing Sarcoma/PNET
Dose
(mg/kg)
6
# Entered
# Eval
# DLT
DLT Detail
12
10
0
-
Response Summary
(RECIST)
Part A: Dose Finding
Dose
# Eval
Objectives Responses
CR
PR
SD*
Diagnoses
6 mg/kg
6
1
Alveolar Soft-Part Sarcoma
9 mg/kg
6
1
Fibrosarcoma
Part B: Ewing Sarcoma/PNET Cohort
Dose
6 mg/kg
# Eval
10
Objectives Responses
CR
PR
SD*
1
4
Diagnoses
Ewing Sarcoma
* Stable disease ≥ 3 cycles (Median 7,
Range 3-11)
06/13/08
07/01/08
Response by FDG PET
06/13/08
07/01/08
Current Status of IMC-A12 Studies in COG
• ADVL0712, single agent phase I completed
• ADVL0821, single agent phase 2 ongoing
• ADVL0813, phase I in combination with
temsirolimus ongoing
• ADVL0822, phase 2 combination with
temsirolimus, pending
• ARST08P1, pilot with ARST0431
chemotherapy in HR RMS
Review of Pediatric Oncology
Phase I Experience
Lee et al. J Clin Oncol Nov. 2005
Review of 15 Year Experience
• 69 studies published 1990-2004
– 55 single-agent
– 14 multi-agent
• 46 different anti-cancer agents
• Populations
– 9 studies in leukemia only
– 14 studies in either solid tumors or leukemia
• 1973 patients enrolled
– 1779 patients (90.2%) fully evaluable for toxicity
– 1809 patients (91.7%) evaluable for response
– Median age 10.9 yrs
Diagnoses Enrolled on Phase I Studies
Traditional Pediatric Oncology
Phase I Study Design
• Starting dose: approx 80% of adult MTD
• Escalation Schema
– 0/3 pts with DLT – escalate to next level
– 1/3 pts with DLT – expand to 6 pts
– 2 of 3-6 pts with DLT: MTD exceeded
• MTD: the dose level at which 0 or 1/6 pts
experience DLT with at least 2 of 3-6 pts
encountering DLT at the next higher dose
Safety of Pediatric Oncology
Phase I Studies
• Likelihood of developing a DLT once
enrolled onto a study: 24%
• Toxic death rate: 0.5%
Tumor Response Rates on Pediatric
Phase I Studies
• 40/67 studies has at least one objective response
• 1809 patients evaluable for response
– 50 CRs
– 123 PRs
• Response rate
– Overall 9.6%
– Single-agent 6.8%
– Multi-agent 20.1%
Do Pediatric Pharmacokinetics and
Pharmacodynamics Differ from Adults?
• Phramacokinetics
– Is drug clearance observed in adults predictive
of that observed in children?
• Pharmacodynamics
– Is the adult MTD predictive of the pediatric
MTD?
Plasma Drug Clearance is Correlated
Between Adults and Children
(r=0.98) and Adult Drug Clearance
is Predictive of Pediatric Clearance
1000.00
100.00
10.00
1.00
0.10
0.01
0.00
1000 100
10
1
0.1
0.01 0.001
Drug Clearance in Adults (L/h/m2)
Drug Clearance in Children
(L/h/m2)
Plasma Drug Clearance
Pediatric MTD 0.7-1.6 of Adult MTD for
Cytotoxic Agents
Less Data for Correlation of MTD in
Biologic Agents
Current Challenges
• Many new drugs are biological agents with
minimal toxicity: need to redefine concept of
MTD
• Currently pharmacological and biological studies
are considered optional for enrollment on pediatric
oncology phase I studies
– How do we ultimately determine what drugs to move
forward if minimal biological data relevant to
childhood cancer?
Summary: Potential Risks of
Pediatric Oncology Phase I Studies
• Approximately 25% of patients have DLT
– DLTs are almost always reversible
– Lower risk of severe toxicity compared to upfront
studies
• 0.5% toxic death rate
– Includes possibly, probably or definitely related to drug
– Potentially could be further decreased by capping
escalation at 1.6x adult MTD
• Risk of significant morbidity and mortality on
phase I trials is lower then most front-line and
salvage regimens
Potential Benefits of Pediatric
Oncology Phase I Studies
• 9.6% overall response rate
• Time to progression (SD) likely higher but no
good data
• Most current phase I trials are predominantly
outpatient regimens
• Contribute to improving care for future patients
• Hope
Balancing Risks and Benefits
• Cure is not a realistic goal of phase I therapy
• Set realistic expectations
– Tolerability
– Impact on QOL
– Likelihood of tumor regression/response
• Symptom control and other palliative care
issues are of paramount importance
Principles of Informed Consent
• Present information about the diagnosis
• Discuss standard of care treatment
• Discuss trial design/experimental agent or
question
• NO obligation to enroll
• Give time for all questions to be discussed
Role of Pediatric Oncology
Nurse in Phase Early Phase Trials
• Direct patient care provider
• Patient advocate
– Provide support while families look for miracle cures balancing
palliative care needs/issues
• Educator
– Serve as a resource for new drug therapies, toxicities and
protocols, provide information to families/patients and other
providers/team members
• Researcher
– Follow the protocol, vigilant attention to detail and data
management
– Study requirements much more rigid and detailed than later phase
trials
– Opportunity to participate in national clinical trials
J. Dahl www.aphon.org 24:3: 6-7, 2010
Pediatric Oncology Phase I Studies
• Challenges
– How do we pick the right agents to study in
pediatrics?
– How do we assess new drugs that will never
reach a classic MTD but may have great
biological activity?
– How do we evaluate drugs in combination?
Pediatric Oncology Phase I Studies
• Opportunities
–
–
–
–
Improve therapy for children with cancer
Minimize toxicities of therapy
Minimize late effects
Gain greater understanding of biology of tumors
Thank You
Any Questions or
Comments?