Brain tumor clinical trials: a surgeon s perspective

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1 Brain tumor clinical trials: a surgeon s perspective Fred G. Barker II, MD Penn Brain Tumor Academy May 13, 2016 No financial conflicts Non-FDA-approved drug uses will be discussed

2 Brain tumor clinical trials RCTs for malignant glioma began in 1978 with trials evaluating XRT and/or cytotoxic chemotherapy after resection of malignant glioma Since then over 300 RCTs and countless smaller trials on glioblastoma have been reported

3 Cytotoxic chemotherapy era Drug development for cytotoxic agent Phase I (safety; ~20 patients) Phase II (activity; patients) endpoint: imaging response Phase III (efficacy; ~300 patients) ~8% of new drugs eventually approved for use

4 National Clinical Trials Network (NCTN) * ** *=Merger of CALGB, NCCTG, ACOSOG **=Merger of NSABP, RTOG, GOG 21,000 patients accrued and treated per year

5 q 1978 median survival 8 months median survival 18 months

6 Personalization Histology-specific trials for malignant glioma (GBM; 1990 s) Biomarker specific trials (e.g. MGMT, 1p/19q, EGFRvIII vaccine; 2000 s) Individually tailored therapy (2010 s) HSP vaccines (GBM) key single-gene alterations (SEGA)

7 NOA-08 Trial: OS and PFS by MGMT Status and treatment arm: MGMT+: TMZ>XRT MGMT-: TMZ<XRT Wick et al, Lancet Oncol 2012

8 Targeted therapy vemurafenib for advanced melanoma (2008) V600E BRAF inhibitor

9 imatinib for PHL-positive CML (ASCO 2002) selective inhibitor of BCR-ABL fusion tyr kinase

13 TCGA (2013)

16 microsatellite instability and TIL in colon CA Alexander et al. Am J Path 2001

17 Checkpoint inhibitors and mismatch repair

21 SEGA (everolimus) pilocytic astrocytoma PXA chondrosarcoma pilomyxoid tumor DNET choroid plexus papilloma pineal parenchymal tumors neurocytoma acoustic neuroma meningioma hemangioblastoma endolymphatic duct tumor subependymoma craniopharyngioma chordoma esthesioneuroblastoma SNUC

23 *approved for some breast, renal cell, neuroendocrine tumor patients *

25 benign suprasellar tumor, ~300/yr in US 20 yr after diagnosis: 72% major visual field deficits 67% hyperphagia or obesity 48% unable to work at premorbid level 11% completely dependent for ADLs

26 Introduction: classical subtypes Adamantinomatous Papillary Age Group Children/Adults Adults Histology

27 Craniopharyngioma survival by histological subtype SEER Shankar GM, Barker FG unpublished

28 Genomic characterization of craniopharyngiomas (2014)

29 Subtypes are characterized by single driver mutations Adamantinomatous Papillary CTNNB1 62 of 65 (95%) adamantinomatous tumors with CTNNB1 mutations BRAF 37 of 39 (95%) papillary tumors with BRAF V600E mutations Driver mutations were mutually exclusive between the subtypes Brastianos et al. Nature Genet. 2014

30 Craniopharyngiomas have low mutation rates Low Mutation Rate High Mutation Rate Hematologic / Pediatric Carcinogenic

31 Case History: 38 yo with multiply recurrent papillary craniopharyngioma Brastianos et al. JNCI 2015

32 Rapid response to targeted therapy: dabrafenib / trametinib Brastianos et al. JNCI 2015

33 Response of cystic and noncystic components Brastianos et al. JNCI 2015

34 Phase 0 trials Trials that expose <10 patients to new drugs that measure endpoints reflecting drug availability and biological activity May include tissue penetration, biological measures that suggest intended mechanism really works Goal: Optimal biological dose ***Surgeons (tissue) vital to design & conduct of phase 0 trials

35 Treatment effect in resected tumor tissue Ki-67 CD68 (macrophages) CD4/CD8 22% Pretreatment Posttreatment 0.5% Brastianos et al. JNCI 2015

36 BRAF V600E mutation was detected in patient s peripheral blood Postoperative sample Craniopharyngioma Patient Samples Negative Controls Positive Control Brastianos et al. JNCI 2015

37 BRAF V600E was the only recurrent clonal event detected (pre- and post-treatment) Brastianos et al. JNCI 2015

38 Phase II trial of BRAF and MEK inhibitors in papillary craniopharyngiomas Priscilla Brastianos, Fred Barker, Dan Cahill, Sandro Santagata, Helen Shih, Paul Brown, Eva Galanis Alliance concept A CTEP approved

39 Phase II trial of BRAF/MEK inhibitors in papillary craniopharyngiomas Cohort A: Newly diagnosed craniopharyngioma Baseline brain MRI (with volumetrics) Brain MRI q6 weeks for 3 months, then every 8 weeks Measurable disease Biopsy-proven papillary craniopharyngioma BRAF and MEK inhibitor 3 months of therapy Surgery or radiation Cohort B: Recurrent craniopharyngioma Measurable disease Biopsy-papillary recurrent craniopharyngioma Prior history of radiation BRAF and MEK inhibitor 3 months of therapy Surgery or radiation or continuation of BRAF and MEK inhibitor

40 Correlative studies (Santagata/Brastianos/Getz) BRAF testing (integrated biomarker) Rebiopsy at progression and/or posttreatment resection when feasible Circulating tumor markers Pharmacokinetic studies to measure tumordrug levels Pharmacodynamic studies pre- and posttreatment

41 Meningioma genomes are relatively simple Copy number alterations Rearrangements/ translocations Mutations Rates of genetic alterations in meningiomas were lower than rates for other tumor types Lohr et al., PNAS 2012 (DLBCL); Stransky et al., Science 2011 (H&N); Chapman et al., Nature 2011 (CRC); Bass et al., Nature Genet 2011 (CRC); Berger et al., Nature 2011 (PR); Berger et al., Nature 2012 (Mel)

42 2013

43 SMO in skull base meningiomas overall: 7/62 anterior skull base meningiomas (11%) 6/18 olfactory groove 1/21 tuberculum sellae Clark V et al, Science 2013 Gill C et al, submitted

44 AKT in skull base meningiomas

Phase II trial of SMO/AKT1/FAK inhibitors in progressive

Recurrent or progressive meningiomas n = 24; (n = 12 Gr1; n = 12

12 Gr2/3) SMO mutation NF2 mutation AKT mutation SMO inhibitor:

inhibitor: Afuresertib Complete response, partial response or

45 Phase II trial of SMO/AKT1/FAK inhibitors in progressive meningiomas with SMO/AKT1/NF2 mutations Alliance protocol A Recurrent or progressive meningiomas n = 24; (n = 12 Gr1; n = 12 Gr2/3) n = 24; (n = 12 Gr1; n = 12 Gr2/3) n = 24; (n = 12 Gr1; n = 12 Gr2/3) SMO mutation NF2 mutation AKT mutation SMO inhibitor: Vismodegib FAK inhibitor: GSK Brain MRI every 2 months AKT inhibitor: Afuresertib Complete response, partial response or stable disease: Continue on therapy Progressive disease or significant toxicity: Off study

46 Alliance cooperative group centers 316 sites open as of spring 2016

47 Some themes for surgeons Targeted therapy in genomically simple tumors Target the pathway, not just the mutation Attention to novel endpoints and diagnostic techniques Neoadjuvant setting to decrease treatment toxicity (surgery, XRT)

48 Acknowledgements Scott Plotkin, Priscilla Brastianos, Will Curry, Dan Cahill, Mike Vogelbaum, Susan Chang

Randomized phase II trials Effective cytotoxic chemotherapy was expected to cause imaging responses Targeted agents might be cytostatic and/or cause imaging responses that do

49 Randomized phase II trials Effective cytotoxic chemotherapy was expected to cause imaging responses Targeted agents might be cytostatic and/or cause imaging responses that do not reflect true antitumor activity (e.g. bevacizumab) Historical control groups no longer appropriate -> different endpoints, randomized control group (larger trials, ~120 pts)

50 Methylation status and outcome based on TMZ therapies *** Yin et al PLOS 2014

52 Role of the surgeon For many of these tumors neurosurgeons provide initial therapy, provide tissue for diagnosis and laboratory studies, and follow patients throughout their disease cycle Preclinical and translational studies and clinical trial design

53 Adamantinomatous cranio: CTNNT1 - chromosome 3 No treatments ~60% NF % target beta catenin

54 WRS 0% WRS 8%->98% 7 yr duration

55 1. single drug (BRAF) 2. significant response 3. rapid recurrence during drug holiday 4. treatment failure at 7 months

58 Histological subtypes by age SEER Shankar GM, Barker FG unpublished

59 Probability Probability of oligo-containing histology vs. literature on chemo for oligos Probability of oligo diagnosis 40% 30% 20% 10% 0% SEER % oligos PubMed # articles on chemo for oligos Number of articles on chemo for oligos Year of diagnosis Year of diagnosis SEER, PubMed data; Barker FG et al unpublished

60 110 steps, 191 days

61 NCTN Funding Distribution: Pre-2014 vs beyond

62 Audit, DSMB, Institutional performance, Accrual, Ethics, COI, Disparities, Care delivery, Pharmacogenomics, Biorepository, Imaging, Radiation QC, Sequencing.. 21,000 patients accrued and treated per year

63 Targeted therapy era Tailoring therapy to specific molecular pathology personalized medicine Phase 0: tiny trials with a drug discovery function Phase I Randomized Phase II finding activity with time-to-event endpoints Phase III

Radioterapia no Tratamento dos Gliomas de Baixo Grau

Radioterapia no Tratamento dos Gliomas de Baixo Grau Dr. Luis Souhami University Montreal - Canada Low Grade Gliomas Relatively rare Heterogeneous, slow growing tumors WHO Classification Grade I Pilocytic