Developing Molecularly Targeted Therapies in Combination Wi - PowerPoint Presentation

Slide1

Developing Molecularly Targeted Therapies in Combination With Radiation:

Dr Glen ClackSenior Medical DirectorOncology Translational Medicine UnitAstraZeneca

Challenges and OpportunitiesSlide2

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Author | 00 Month YearSet area descriptor | Sub level 1Slide3

Barriers Perceived by Pharma

Preclinical Testing and Model SystemsFunding Sources and Selection of Candidate Agents of Interest

Determining the Sequence of Combining RadiationPhase I Clinical Safety

Path to Registration

CommercialSlide4

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 therapySafety Phase I studies critical to determine the safety combinatio with radiation/chemoradiation; only a site-specific 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 treatmentClinical 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 armsRegulatory 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

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Author | 00 Month Year

Set area descriptor | Sub level 1

Drug

Study

Combination partners

Disease

AZD (DNAPK)

Strong interest

Plus RT

NSCLC, SCLCAZD0156 (ATM)Strong interestPlus RTNot definedAZD6738 (ATR)PATRIOT/CRUKPlus RTDose escalation; then parallel tracks above/below diaphragmAZD1775 (WEE1)PN018Plus gemcitabine/RTPancreasPN013/CTEPPlus temozolamide/RTNewly diagnosed GBMPN016/CTEPPlus RTChildhood pontine GBMPN015/CTEPPlus cisplatin/RTCervixOlaparib (PARP)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

OesophagealSlide6

PATRIOT

Study DESIGN

Monotherapy

‘fast tracked’ dose escalation

Part A

‘All comers’

phase I population

Monotherapy

cohort expansion(s)

Part B

ATM-deficient

phase I populationRadiation combination dose escalation(2 parallel groups: tumours above or below diaphragm)Part CAll comersPalliative radiotherapy populationMonotherapy MTD, PoM, PK, PDcSafety, TolerabilityMonotherapy PoP, EfficacyPK, PDc, SafetyTolerabilityCombination therapy

PoP, Efficacy, PK, PDcSafety, Tolerability

Radiation combination cohort expansion

(2 parallel groups: tumours above or below diaphragm)

12-36 patients

12 (up to 36) patients

Up to 36 patients

12 patients

Monotherapy

‘end stage ‘disease and ‘maintenance’ opportunities

Radiation

potentiation

opportunities

Currently -

Dose escalation, part A

Cohort 3, 80 mg BD continuous dosing

Three sites recruiting –

RMH, Guy’s, UCHL

PI: Kevin HarringtonSlide7

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Author | 00 Month YearSet area descriptor | Sub level 1Slide9

Barriers Perceived by Pharma

Preclinical Testing and Model SystemsLack of ability to translate pre-clinical work to clinicFunding 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 investmentSlide10

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.2.2Agents 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.2.3Concurrent 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.2.4Understanding the proper sequencing of combining targeted agents with radiation therapy will be important before carrying out large clinical trials.10Slide11

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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.

3.3Late toxicity should be monitored in early-phase clinical trials even when acute toxicity is used as a primary safety endpoint.Clinical trial designs4.1Alternative innovative phase I designs (eg, time-to-event continuous reassessment method) should be considered to improve study efficiency and cumulative safety analysis.4.2An 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.4.3The economic benefits and a platform-based clinical trial design should be recognized and prioritized.Regulatory5.1Both 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.5.2The 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.5.3The development of novel radiation sensitizers should be financially supported consistent with other priorities in cancer research.