Download Developing Molecularly Targeted Therapies in Combination

Developing Molecularly Targeted
Therapies in Combination With Radiation:
Challenges and Opportunities
Dr Glen Clack
Senior Medical Director
Oncology Translational Medicine Unit
AstraZeneca
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Set area descriptor | Sub level 1
Barriers Perceived by Pharma
• Preclinical Testing and Model Systems
• Funding Sources and Selection of Candidate Agents of Interest
• Determining the Sequence of Combining Radiation
• Phase I Clinical Safety
• Path to Registration
• Commercial
Workshop for development of radiosensitisers, NCI,
August 8–9, 2012: key recommendations
Prioritizing agent development
• Biomarker-based patient selection available (If not concurrent development of predictive biomarkers
during the preclinical and early clinical phases of testing followed by subsequent clinical validation)
• Mandate pretreatment tumour biopsy and/or serum collection; ideally serially during early therapy and at
the time of recurrence.
• Understanding proper sequencing of combining targeted agents with radiation therapy
Safety
• Phase I studies critical to determine the safety combinatio with radiation/chemoradiation; only a sitespecific and not disease-specific requirement
• Minimal 30-day observational period after completion of radiotherapy should be used to gauge the acute
toxicities of a novel treatment
Clinical trial designs
• Innovative phase I designs (eg, time-to-event continuous reassessment method); improve study efficiency
and cumulative safety analysis.
• Modular clinical trial platform, in which several agents/combinations are individually tested in parallel
noncomparative arms
Regulatory
• Better engagement with Regulators and pharma
• The FDA should issue an advisory clarifying requirements for approval of an agent in combination with
radiotherapy
• The development of novel radiation sensitizers should be financially supported consistent with other
priorities in cancer research
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AZ Clinical Radiation combinations: DDR agents
Drug
Study
Combination partners
Disease
AZD (DNAPK)
Strong interest
Plus RT
NSCLC, SCLC
AZD0156 (ATM)
Strong interest
Plus RT
Not defined
AZD6738 (ATR)
PATRIOT/CRUK
Plus RT
Dose escalation; then parallel
tracks above/below diaphragm
AZD1775 (WEE1)
PN018
Plus gemcitabine/RT
Pancreas
PN013/CTEP
Plus temozolamide/RT
Newly diagnosed GBM
PN016/CTEP
Plus RT
Childhood pontine GBM
PN015/CTEP
Plus cisplatin/RT
Cervix
Study 25
Plus RT
Inoperable metastatic breast
Study 41
Plus RT +/- cisplatin
NSCLC
Study 61
Plus RT
Relapsed GBM
Study 31
Combo with C225 and RT
HNSCC
Study 42/COOLART
Plus RT
Laryngeal and oropharyngeal
carcinoma
Study 28
Combo with cis, pac and beva
Ovary newly diagnosed
Study 19
Plus RT
Oesophageal
Olaparib (PARP)
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PATRIOT Study DESIGN
PI: Kevin Harrington
Part A
‘All comers’
phase I population
Monotherapy
MTD, PoM,
PK, PDc
Safety, Tolerability
Part B
ATM-deficient
phase I population
Monotherapy ‘fast tracked’
dose escalation
Monotherapy cohort
expansion(s)
Monotherapy ‘end stage
‘disease and ‘maintenance’
opportunities
12 (up to 36) patients
12-36 patients
Three sites recruiting –
RMH, Guy’s, UCHL
Monotherapy
PoP, Efficacy
PK, PDc, Safety
Tolerability
Radiation combination dose
escalation
(2 parallel groups: tumours
above or below diaphragm)
Up to 36 patients
Part C
All comers
Palliative radiotherapy population
Currently • Dose escalation, part A
• Cohort 3, 80 mg BD continuous dosing
Radiation
combination cohort
expansion
(2 parallel groups:
tumours above or
below diaphragm)
Radiation
potentiation
opportunities
12 patients
Combination therapy
PoP, Efficacy, PK, PDc
Safety, Tolerability
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Author | 00 Month Year
Set area descriptor | Sub level 1
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Author | 00 Month Year
Set area descriptor | Sub level 1
Barriers Perceived by Pharma
• Preclinical Testing and Model Systems
- Lack of ability to translate pre-clinical work to clinic
• Funding Sources and Selection of Candidate Agents of Interest
- Lack of portfolio driven strategy
- Lack of support from individual project teams
• Determining the Sequence of Combining Radiation
- Determining interactions between targeted agent, radiation and/or
chemotherapy
• Phase I Clinical Safety
- Length of observational period
• Path to Registration
- End points
- Lengthy development timelines
• Commercial
- Return on investment
Output: 1st annual workshop for preclinical and clinical
development of radiosensitisers, NCI, August 8–9, 2012
Summary of workshop recommendations for the accelerated development of novel targeted radiation enhancers
Determination of agent activity
1.1
Agents of interest should enhance radiation effects through either synergistic or additive mechanisms but, if not,
should at least have single-agent or combination activity with chemotherapy.
1.2
Preclinical testing is crucial to provide evidence that the agent of interest has radiation enhancement effect; At least
two cell lines from the same disease site should be required, whereas in vivo animal testing should be used to
further demonstrate radiation enhancement effect whenever a suitable animal model for the cancer type exists.
1.3
When generation of in vitro or in vivo preclinical data is not feasible, strong justification must be provided for the
inability to perform these studies before proposing a clinical study.
Prioritizing agent development
2.1
The development of radiation-enhancing agents should be prioritized when biomarker-based patient selection is
available.
2.2
Agents without validated predictive biomarkers available for clinical testing could be brought into clinical testing but
with the mandate that there are clear plans for concurrent preclinical research and clinical development of predictive
biomarkers from pretreatment tissue specimens.
2.3
Concurrent development of predictive biomarkers should be a priority during the preclinical and early clinical phases
of testing followed by subsequent clinical validation. Clinical studies must mandate pretreatment tumor biopsy
and/or serum collection, with strong consideration given to acquisition of serial tissue collection during early therapy
and at the time of recurrence.
2.4
Understanding the proper sequencing of combining targeted agents with radiation therapy will be important before
carrying out large clinical trials.
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Summary of workshop recommendations for the accelerated development of novel targeted radiation enhancers
Safety
3.1
Phase I studies are critical to determine the safety of combining a new agent with radiation (or chemoradiation), but
this should only be a site-specific and not a disease-specific requirement. For instance, clinical testing of a novel
agent with radiation for rectal cancer need not be repeated for prostate cancer, cervical cancer, or other pelvic
tumors.
3.2
A minimal 30-day observational period after completion of radiotherapy should be used to gauge the acute toxicities
of a novel treatment.
3.3
Late toxicity should be monitored in early-phase clinical trials even when acute toxicity is used as a primary safety
endpoint.
Clinical trial designs
4.1
Alternative innovative phase I designs (eg, time-to-event continuous reassessment method) should be considered
to improve study efficiency and cumulative safety analysis.
4.2
An efficient way to rapidly test novel agents in combination with radiation is through a modular clinical trial platform,
in which several agents/combinations are individually tested in parallel noncomparative arms.
4.3
The economic benefits and a platform-based clinical trial design should be recognized and prioritized.
Regulatory
5.1
Both the US Food and Drug Administration (FDA) and the pharmaceutical industry should acknowledge that
combination trials with radiation can help to dramatically improve cure rates of nonmetastatic patients, representing
a new pathway for expediting the drug approval process. The FDA should issue an advisory clarifying requirements
for approval of an agent in combination with radiotherapy or with a previously established chemotherapy and
radiation therapy combination.
5.2
The Cancer Therapy Evaluation Program (CTEP) should consistently issue mass solicitations for drug combination
trials that have specific calls for proposals in combination with radiation and simultaneously facilitate development of
compounds as radiosensitizers within the CTEP portfolio.
5.3
The development of novel radiation sensitizers should be financially supported consistent with other priorities in
cancer research.
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