Developing Molecularly Targeted Therapies in Combination With Radiation

Developing Molecularly Targeted Therapies in Combination With Radiation: Challenges and Opportunities Dr Glen Clack Senior Medical Director Oncology Translational Medicine Unit Astra. Zeneca

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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 4

AZ Clinical Radiation combinations: DDR agents Drug Study Combination partners Disease AZD (DNAPK) Strong interest Plus RT NSCLC, SCLC AZD 0156 (ATM) Strong interest Plus RT Not defined AZD 6738 (ATR) PATRIOT/CRUK Plus RT Dose escalation; then parallel tracks above/below diaphragm AZD 1775 (WEE 1) PN 018 Plus gemcitabine/RT Pancreas PN 013/CTEP Plus temozolamide/RT Newly diagnosed GBM PN 016/CTEP Plus RT Childhood pontine GBM PN 015/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 C 225 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) 5 Set area descriptor | Sub level 1

PATRIOT Study DESIGN PI: Kevin Harrington Part A ‘All comers’ phase I population Monotherapy MTD, Po. M, 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 Po. P, 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 Po. P, Efficacy, PK, PDc Safety, Tolerability

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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: 1 st 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. 10

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. 11