1. Phase IB Trial of Carboxyamidotriazole Orotate (CTO) and Temozolomide for Recurrent Malignant Glioma (MG): A Novel Mechanism for Modulation of Multiple Oncogenic pathways Antonio M. P. Omuro 1, Thomas J. Kaley 1, Elena Pentsova 1, Lisa M. DeAngelis 1, Walter J. Urba 2, Matthew H. Taylor 3, Barry D. Anderson 4, Greg Gorman 5, Sean McLean 4, Rashida A. Karmali 6 1 Memorial Sloan-Kettering Cancer Center, New York, NY; 2 Earle A Chives Research Institute and Providence Cancer Center, Portland, OR; 3 Oregeon Health & Science University, Portland, OR; 4 Theradex, Princeton, NJ; 5 Samford University, Birmingham, AL; 6 Tactical Therapeutics,New York, NY I NTRODUCTION Multiple signal transduction pathways are activated in malignant glioma (MG) and glioblastoma (GBM). CTO is an oral inhibitor of non-voltage-dependent calcium signaling that modulates several receptor-mediated calcium – dependent signaling pathways, including EGFR, MEK, RAS, HDAC, HSP90, WNT/B-catenin, Akt, ERK, VEGF and Bcr-Abl. (Kohn, 1997; Berlin, 1997; Corrado 2012; Karmali, 2013). This proof-of-concept Phase IB trial follows completion of the CTO Phase I safety study at doses of 75-427mg/m 2 /day in solid tumors, in which a safe toxicity profile, predictable pharmacokinetics and responses in various refractory tumors with different mutations were observed. (ASCO 2013). A possible mechanism of resistance to targeted and chemo-therapeutics is the existence of redundant signaling pathways. CTO crosses the blood-brain barrier, in preclinical studies CTO alone has shown activity in melanoma and GBM xenografts, and robust synergism with temozolomide (TMZ) prompting this proof-of-concept Phase IB (Figure 1). (Karmali, 2011, Karmali 2013). S TUDY D ESIGN P HARMACOKINETICS R ESULTS C ONCLUSIONS CTO in doses from 219 to 625mg/m 2 /day in combination with TMZ (150mg/m 2 ) is safe; dose-escalation is at CTO 812 mg/m 2/ day. MTD has not been determined. Durable Partial Responses (DPR) (6-13+ cycles) have been observed in 4 of 17 refractory patients, some continuing in 14 th cycle (Figure 5). 9 of 17 patients received combination treatment beyond 2 cycles. 2 patients with DPR have Negative MGMT status (Figure 6 and 7); 1 patient has Positive MGMT status (Figure 8), providing evidence of synergy between CTO and TMZ in chemo-sensitive and chemo-insensitive MG and GBM. These signals of clinical activity in recurrent MG and GBM are encouraging, (Figure 4) and a Phase II trial is planned. Other studies started are CTO with TMZ and radiation therapy in newly diagnosed patients, and CTO with bevacizumab, in patients with MG and GBM.     Figure 8: MRI Images of Patient 004-55 (MGMT+) Baseline (L); Cycle 4 (R ) Figure 7: MRI Images of Patient 004-48 (MGMT-) Baseline (L); Cycle 10 (R) Figure 6: MRI Images of Patient 004-45 (MGMT-) Baseline (L); Cycle 12 (R) Figure 1: Response of SC U251 Human CNS Tumor to Combination Treatment with TMZ and CTO Study Enrollment Cohort 1 (219mg/m 2 /day), n= 4 Cohort 2 (285mg/m 2 /day), n= 3 Cohort 3 (370mg/m 2 /day), n= 3 Cohort 4 (481mg/m 2 /day), n= 3 Cohort 5 (625mg/m 2 /day), n= 4 Total Enrollment: 17 Patients Treatment-Emergent Adverse Events N(%) Safety evaluable patients14 (100%) No. of patients with TEAEs14 (100%) Constipation 7 ( 50.0%) Fatigue 7 ( 50.0%) Nausea 6 ( 42.9%) Vomiting NOS 5 ( 35.7%) Headache NOS 4 ( 28.6%) Headache NOS 4 ( 28.6%) Dizziness 3 ( 21.4%) Dry skin 3 ( 21.4%) Dysgeusia 2 ( 14.3%) Convulsions NOS 2 ( 14.3%) Diarrhoea NOS 2 ( 14.3%) Myalgia 2 ( 14.3%) Hypophosphataemia 2 ( 14.3%) Anxiety 2 ( 14.3%) Micturition urgency 2 ( 14.3%) CharacteristicsN(%) Age (Years) Median51 Range27-77 Sex Male9 (53%) Female8 (47%) Summary of Adverse Events N(%) Safety evaluable patients14 (100%) Patients14 (100%) With Any Adverse Event14 (100%) With Possibly, Probably, Or Definitely CTO Related Adverse Events 10 ( 71.4%) With Possibly, Probably, Or Definitely TMZ Related Adverse Events 13 ( 92.9%) With Severity Grade 3, 4 or 5 4 ( 28.6%) With Severity Grade 3, 4 or 5 for CTO Related Adverse Events 1 ( 7.1%) With Any Serious Adverse Events 4 ( 28.6%) Who Died Due to Adverse Events 1 ( 7.1%) Key Inclusion Criteria -Histologically proven, recurrent MG -Measurable tumor on a gadolinium- enhanced MRI -ECOG 0, 1, 2 -Life expectancy > 8 Weeks -No CYP3A4 inhibitors or inducers Study Treatment -CTO administered daily, 28-day cycle -TMZ administered days 1-5 of each cycle Evaluations -Response: Gadolinium-enhanced MRI every two cycles -Safety: Adverse events, vital signs, ECG, clinical laboratory tests, physical exams -Pharmacokinetics, pharmacogenomics Study Objectives -Determine the safety and MTD of CTO and TMZ -Determine the Tumor Response of MG and GBM according to the MacDonald Criteria -Determine the pharmacokinetics of CTO and TMZ when co-administered -Confirm the proof-of –concept with evidence of synergism between CTO and TMZ -Investigate effect of CTO and TMZ on growth of tumors with various genotypes (MGMT +/-) -Investigate the effect of CTO and TMZ on gene expression in anagen hair from treated patients Study Design -Combination of escalating dose of CTO with fixed dose of TMZ (150mg/m 2 ) -“3+3” design, CTO administered orally at a starting dose of 219mg/m 2 /day Figure 6: MRI Images of Patient 004-56 Baseline (L); Cycle 12 (R) C YCLES References: Berlin, J., et al, J. Clin Oncol 1997, 15: 781-789 Corrado, C., et al, PLos ONE 2012, 7: 1-13 Karmali, RA., et al, Cancer Therapy 2011, 8: 71-80 Karmali, RA, et al, Mol Cancer Ther 12:11s,2013, Abs A233 Kohn E.C., et al, J. Clin Oncol 1997, 15: 1985-1993. Figure 5: Duration of Treatment Figure 4: Change in Tumor Burden (%) Table 3: TEAEs in >10% of Patients Table 4: Summary of Adverse Events Table 1: Summary of CohortsTable 2: Patient Demographics Unpredictable pharmacokinetics were observed at different CTO doses and steady state and C max CAI plasma levels. Unclear if this is due to large inter-patient variability and complexity of disease, or due to co-administration of TMZ; TMZ levels were consistent across all dose levels. * Values are cohort means with standard error