Marizomib (MRZ): Brain Penetrant Irreversible Pan-Proteasome Inhibitor

Transcription

1 MARIZOMIB (MRZ) WITH BEVACIZUMAB (BEV) IN WHO GRADE IV MALIGNANT GLIOMA (G4 MG): FULL ENROLLMENT RESULTS FROM THE PHASE 1, MULTICENTER, OPEN-LABEL STUDY Daniela Bota, MD, PhD 1, Annick Desjardins, MD, FRCPC 2, Warren Mason 3, MD, Howard Fine, MD 4, Santosh Kesari, MD, PhD 5, Steven D. Reich, MD 6, Anshu Vashishtha, MD, PhD 6, Nancy Levin, PhD 6 and Mohit Trikha, PhD 6 1 University of California, Irvine, Irvine, CA, 2 The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, 3 Princess Margaret Hospital, Toronto, ON, Canada, 4 Weill Cornell Brain & Spine Center, New York, NY, 5 John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John s Health Center, Santa Monica, CA, 6 Triphase Accelerator, San Diego, CA

2 Marizomib (MRZ): Brain Penetrant Irreversible Pan-Proteasome Inhibitor 26S Proteasome: Regulates Protein Degradation Marizomib Poly-ubiquitinated proteins (proteasome substrates) Ub UbUb ATP ADP ATPases/ Cdc48 20S Free Ub for re-cycling 19S α β 19S 20S Lawasut et al., 2012 Curr Hematol Malig Rep;7:258 Six Protease activities β5, β5i β1, β1i β2, β2i Degraded protein Unique Proteasome Inhibitor Inhibits all proteasome subunits Binds irreversibly Brain penetrant Demonstrates anti-glioma activity in vitro and in vivo >300 patient safety database in hematologic and solid tumors, including multiple myeloma and malignant glioma 1

3 Study MRZ-108 Recurrent Glioblastoma Outline MRZ+BEV dose-escalation combination study followed by a MRZ monotherapy study WHO Grade IV malignant glioma, first or second relapse, clear progressive disease, completed standard radiation and temozolomide No prior anti-angiogenic agent or proteasome inhibitor treatment 4 weeks from surgical resection, 12 weeks from end of radiotherapy MRZ+BEV Cohorts MRZ 10 min IV (mg/m 2 ) Days 1,8,15 q 28 days BEV IV (mg/kg) q 14 days Patients Expansion of RP2D MRZ Mono Cohort 0.8 None Ongoing 2

4 MRZ-108: Demographics Median age, years (range) 55 (27 76) Male, % 64% (23/36) Karnofsky Performance Status (KPS) 100 9% (3/35) 90 37% (13/35) 80 45% (16/35) 70 9% (3/35) Prior Therapies Surgery, Radiation / Temozolomide 100% (36/36) Immunotherapy 14% (5/36) Other Investigational Drug or Device 8% (3/36) Median months from last RT (range) 7.8 ( ) 3 Preliminary Data as of 12 September 2016

5 Treatment Related Grade 3 AEs by Patient MRZ Dose 0.55 mg/m 2 Cohort 1 (N=6) 0.7 mg/m 2 Cohort 2 (N=3) 0.8 mg/m 2 Cohorts 3 & 4 (N=27) Preferred Term BEV MRZ BEV MRZ BEV MRZ TOTAL (N=36) Ataxia Confusional State Delusion Fatigue Hallucination Headache Insomnia Embolism Hypertension Intracranial Hemorrhage Embolism Optic Nerve Disorder Proteinuria Fall Dyspnea Hyponatremia Two Gr 4 AEs: Cohort 4, appendicitis perforated (not related); optic nerve disorder (BEV-related) One Gr 5 AE: Cohort 4, intracranial hemorrhage (BEV-related) One DLT: Cohort 1, fatigue (MRZ-related) 4 Preliminary Data as of 12 September 2016

6 MRZ+BEV: Best Reduction in Tumor Area (N=33) Reduction in Tum or Area (% ) Tumor Area Measured by MRI *PR confirm ed on * * * * * * * * * m g/m m g/m 2 2 consecutive M RIs m g /m 2 * * * * * Best RANO Response # Patients Efficacy Evaluable (N=33) CR (1) + PR CR * (3) + PR (10) 14 42% SD (including 2 unconfirmed PR) 13 39% PD 6 18% *PR with no measurable target lesion 5 Preliminary Data as of 27 October 2016

7 MRZ+BEV Improved PFS & OS at 6 & 9 Months Compared With Historical BEV Monotherapy Studies 6 mo PFS 9 mo PFS Study Treatment All Pts Unmethylated Methylated All Pts Unmethylated Methylated MRZ-108 MRZ+BEV 34% 34% 29% 22% 23% TBD Taal (BELOB) Heiland (Freiburg, BEV Monotherapy 16% 8% 33% 8% 0% 22% Field (CABARET) 18% NR NR 6% NR NR Germany) 12% 10% 38% 0% 0% 22% Wick (EORTC P2) 14% 10% 25% 9% 10% 9% 6 mo OS 9 mo OS Study Treatment All Pts Unmethylated Methylated All Pts Unmethylated Methylated MRZ-108 MRZ+BEV 73% 63% 73% 55% 44% 73% Taal (BELOB) Field (CABARET) BEV Monotherapy 61% NR NR 39% NR NR 62% 50% 83% 45% 12% 67% Heiland (Freiburg, Germany) 18% 25% 58% 30% 12% 40% NR: Not Reported 6 Preliminary Data as of 27 October 2016

8 MRZ+BEV Improved PFS & OS in Unmethylated MGMT Compared With Historical BEV Monotherapy Studies 6 mo PFS 9 mo PFS Study Treatment All Pts Unmethylated Methylated All Pts Unmethylated Methylated MRZ-108 MRZ+BEV 34% 34% 29% 22% 23% TBD Taal (BELOB) Heiland (Freiburg, BEV Monotherapy 16% 8% 33% 8% 0% 22% Field (CABARET) 18% NR NR 6% NR NR Germany) 12% 10% 38% 0% 0% 22% Wick (EORTC P2) 14% 10% 25% 9% 10% 9% 6 mo OS 9 mo OS Study Treatment All Pts Unmethylated Methylated All Pts Unmethylated Methylated MRZ-108 MRZ+BEV 73% 63% 73% 55% 44% 73% Taal (BELOB) Field (CABARET) BEV Monotherapy 61% NR NR 39% NR NR 62% 50% 83% 45% 12% 67% Heiland (Freiburg, Germany) 18% 25% 58% 30% 12% 40% 7 Preliminary Data as of 27 October 2016

9 Summary: MRZ+BEV in Recurrent Glioblastoma Well tolerated, no DLTs at 0.8 mg/m 2 (RP2D) RANO response 42% (Efficacy Evaluable) Durable ( 6 months) clinical responses in 10 patients to date 3 patients remain on study PFS 6 months: 34% OS 9 months: 55% Apparent improvement in PFS and OS in unmethylated MGMT patients 8 Preliminary Data as of 26 October 2016

10 Future Directions MRZ monotherapy study in recurrent glioblastoma ongoing 1 PR, 2 SD; 2 possible pseudo-progression MRZ well tolerated, AE profile similar to MRZ+BEV study Newly diagnosed glioblastoma study ongoing MRZ + RT / TMZ and MRZ + TMZ adjuvant dose escalation in progress Translational research Define molecular mechanism of benefit in unmethylated MGMT Identify additional biomarkers of response to MRZ 9