Goals. Aims and design of Phase I trials. Challenges in the new era of oncology. Complex and multidisciplinary Phase I.

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2 Goals Aims and design of Phase I trials Challenges in the new era of oncology Complex and multidisciplinary Phase I Perspectives

3 Drug Development Preclinical Phase I Phase II Phase III Phase IV

4 Phase I Trials Objectives: Define the appropriate dose for Phase II Provide data on pharmacokinetics and pharmacodynamic Concepts: DLT (dose limiting toxicity) MTD (Maximum tolerated dose) Structure: Pretreated patients Single institution

5 Phase I: Design Citotoxic drug: Starts from 1/10 of the letal dose to animals Progressive dose escalation Classical modified Fibonacci schedule

6 Se toxicidade <= 33% Incluir mais 3 pacientes Se toxicidade # 0 Nível 1 (3-6 pacientes) Se toxicidade 0 100% dose Nível 2 (3-6 pacientes) Se toxicidade 0 67% dose Se toxicidade >= 33% Interromper estudo Interromper estudo 50% dose 40% dose 33% dose Retornar à coorte anterior e incluir mais 6 pacientes. Se toxicidade 0, essa será a DMT. Dose para fase II. DTL

7 Phase I Designs: Limitations Many patients get subclinical doses Long studies Limited information on inter-patient variability and cumulative dose Not suitable to non citotoxic drugs

8 Future perspectives 29/09/2017 Male, 52 y, PS=1, NSCLC IV Altered pathways : Therapeutic options: VEGF EGFR Bcl-2 rhu-vegf; SU6668 ± CT c225; ZD1839; OSI774 ± CT Antisense oligonucleotide ± CT Expected overall survival: months

9 Reality of current treatment 29/09/2007 Male, 52 y, PS=1, NSCLC IV Treatment: Paliative chemotherapy based on cytoxic drugs Response rates: 30% Median survival: 9 months

10 Classical cytotoxic chemotherapy Theory: Tumor exponential growth Differences in proliferation rates between malignant and benign cells Reality: Conceptually wrong Non specific Toxic Low efficacy

11 Cancer molecular biology Understanding cancer from molecular biology: 1st phase: Gene unravelling 2nd phase: Molecular characterization 3rd phase: Functional characterization Impact: Diagnosis Prognosis Treatment

12 Signal transduction, carcinogenesis and targeted drugs Activation of oncogenes Disruption of DNA repair PTEN PI3-K AKT R K py py K STAT R py RAS RAF SOS GRB2 MEK MAPK Inactivation of tumor supressor genes DNA P Gene transcription Cell cycle progression PP Myc Cyclin D1 Jun Fos Myc Cyclin D1 Proliferation/ differentiation Viability/ apoptosis Angiogenesis Metastasis

13 Phase I: Differences Between Cytotoxic and Targeted Agents New agents have a different spectrum of toxicity or even a lack of toxicity Targeted biological effect may be the major goal

14 Phase I for Targeted Agents: Conceptual Questions Should toxicity be the primary endpoint? Should the recommended dose for Phase II be the highest tolerable based on toxicity?

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16 Phase I for Targeted Agents: Ideal Endpoints Pharmacokinetic measures AUC Peak levels Pharmacodynamic measures Target inhibition in tumor or normal tissue Dynamic imaging

17 Baselga,JCO, 2002

18 Phase I for Targeted Agents: Real World Survey of 60 Phase I with targeted agents 36 halted dose escalation based on toxicity Phase II dose was definition 35 was based on toxicity 9 was based on PK Tumor PD in 5 studies Normal tissue PD in 15 studies Imaging in 6 studies Parulekar, JNCI 2004

19 Phase I for Targeted Agents: Conceptual Questions MTD and PK remain reasonable endpoints Molecular proof of principle must be pursued whenever possible (biopsies, imaging) Lack of validated biomarkers and bioassays

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22 INCA Experience in the Development of Targeted Drugs Phase I of Erlotinib + chemoradiation in cervical cancer Phase I of Erlotinib + chemoradiation in head and neck cancer Phase I of Cetuximab + chemoradiation in anal carcinoma

23 INCA Experience in the Development of Targeted Drugs Phase I of Erlotinib + chemoradiation in cervical cancer Phase I of Erlotinib + chemoradiation in head and neck cancer Phase I of Cetuximab + chemoradiation in anal carcinoma

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25 Rationale High incidence Limited results with classical chemoradiation in advanced stages Biology not explored

26 Rationale EGFR pathway R R PTEN DNA PI3-K AKT K py py STAT RAS RAF K SOS py GRB2 MEK MAPK P Gene transcription Cell cycle progression PP Myc Cyclin D1 Jun Fos Myc Cyclin D1 Proliferação/ maturação Viabilidade/ apoptose Angiogênese Metástases

27 Rationale Erlotinib

28 Patients and Methods 9 patients Cohort I 50mg Cohort II 100mg Cohort III 150mg

29 Design Erlotinib Radiation Brachytherapy C C C C C Entry S0 S1 S2 S3 S4 S5 S6 S7 S8 S16 Pharmacogenomics Pharmacogenomics FDG-PET Toxicity FDG-PET

30 Results Phase I 15 patients: 50mg 3 100mg 4 150mg 8 (1 DLT)

31 Results Grade 3 toxicity in 3 patients - Rash (3) - Diarrhea (2) - Leucopenia (1)

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33 Conclusions Recommended Phase II dose of 150mg The first report on TKI combined to pelvic radiation Phase I (innovative) are feasible in Brazil

34 Perspectives Phase II ongoing Imaging FDG-PET Pharmacogenomic studies New studies using the same model

35 Acknowledgments Clinical Oncology (Dr Cláudio Calazan) Ginecology (Drs. Giulliana Morales e Patrícia Patury) Radiology HC2 (Dra. Cláudia Camisão) Rxt (Drs. Célia Viegas e Felipe Erlich) Nuclear medicine (Drs. Sérgio Altino e Marcelo Mamede) Clinical Research (Roberta, Renata, Iraci e Fabrício) Roche

36 Issues for Phase I Lack of validated bioassays Increasing cost and complexity Long timelines (corrections during the process) Low efficiency (rates of drug approval)

37 Role of Phase 0 Trials in Oncology Kummar, Nature 2007

38 Differences between Phase 0 and Phase I Trials in Oncology

39 Drug Development 2007 and Beyond Preclinical Phase 0 Phase I Phase II Phase III Phase IV

40 Perspectives and Conclusions New era in oncology New era in drug development Innovation Preclinical models and tumor banking are mandatory