Ejadi, Samuel

9082 Background: Human tumors, including melanoma, are complex mixtures of individual, molecularly distinct subpopulations, or clones of cancer cells. Effective cancer therapy will likely require targeting of all tumor subsets within a given cancer. Understanding the tumor complexity and the ability to identify points of therapeutic vulnerability within the individual tumor subsets will be essential for development of effective personalized cancer therapies. Methods: We have developed an approach that combines identification of individual tumor subsets using a multiparameter nuclear flow cytometry coupled with a high-resolution genomic analysis using the array-based comparative genomic hybridization (aCGH). Melanoma nuclei were isolated from tumor tissues and subjected to flow cytomery using melanocyte-specific antibodies (to separate melanoma cells from stroma) and DNA content, to separate individual tumor subpopulations. DNA extracted from isolated nuclear subpopulations was extracted and analyzed by aCGH. This approach was adopted for both fresh-frozen and paraffin-embedded clinical specimens. Results: We initially demonstrate the feasibility of the outlined approach by successful separation of melanoma from stromal nuclei and separation of individual melanoma nuclear subpopulations by DNA content. aCGH analysis of the DNA derived from isolated tumor subpopulations allowed successful identification of potentially targetable molecular aberrations in individual subsets of tumor cells. Notably, such aberrations were often not detected in unsorted, bulk tumors analyzed by the same high-resolution aCGH approach. Conclusions: We demonstrate a feasible approach to in-depth molecular analysis of tumor subpopulations within a clinical cancer tissue. This approach allows identification of potentially targetable molecular aberrations within individual tumor subsets, thus opening a possibility for a broad tumor targeting through design of individually-tailored therapeutic approaches. No significant financial relationships to disclose.

Abstract Background: MRX34 is a liposomal nanoparticle formulation with an encapsulated mimic of the naturally occurring microRNA-34 (miR-34), which is lost or expressed at reduced levels in many tumors. miR-34 inhibits key oncogenic pathways by repressing multiple important oncogenes including BCL2, E2F3, HDAC1, MET, MEK1, CDK4/6, PDGFR-ɑ/β, SIRT1, WNT1/3, NOTCH-1, β-catenin, CD44, Nanog and AXL. miR-34 also represses the expression of PD-L1 and DGKζ, thereby possibly triggering an anti-tumor immune response and cancer cell death. A multicenter Phase 1 clinical trial of MRX34 is being conducted in patients with advanced malignancies. Methods: Eligible patients were enrolled in a standard 3 + 3 dose escalation study and were given a MRX34 starting dose of 10 mg/m2, administered intravenously (IV) twice weekly (BIW) for 3 weeks in 28-day cycles. Enrollment is ongoing into a second MRX34 dosing schedule, daily x 5 (QD x 5) in 21-day cycles. The primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for the two dosing schedules. Secondary objectives include assessments of safety, tolerability and the pharmacokinetic profile of MRX34 after intravenous dosing as well as to assess any biological and clinical activity. Results: As of July 2015, 75 patients with advanced solid tumors were enrolled and evaluable: 44 Caucasians, 47 males, a median age of 61 years and a median of 4 prior treatments. Histologies included 30 hepatocellular carcinoma (HCC), 7 pancreatic cancer, 4 cholangiocarcinoma, 3 each of bladder, breast, colorectal, cervix and lung. The remaining 19 patients represented various other malignancies <3 patients each. The 110 mg/m2 was deemed to be the MTD for the BIW dosing schedule. The MTD has not been determined yet for the QD x 5 schedule and dose escalation is continuing. The current dose levels are 70 mg/m2 QD x 5 for HCC and 93 mg/m2 QD x 5 for other solid tumors. The following treatment-emergent, all-causality adverse events (AEs) were most frequent among 47 patients in BIW cohorts vs 28 patients in QD x 5 cohorts: fever (64% vs 61%), fatigue (57% vs 39%), chills (57% vs 36%), back pain (55% vs 36%), nausea (49% vs 39%), diarrhea (43% vs 11%), headache (34% vs 14%), vomiting (32% vs 11%), anorexia (26% vs 14%), abdominal pain (23% vs 21%), dyspnea (23% vs 14%), insomnia (23% vs 14%), and dehydration (23% vs 4%). Most frequent grade 3/4 laboratory abnormalities were: lymphopenia (36% vs 71%), neutropenia (26% vs 36%), hyponatremia (26% vs 7%), AST elevation (26% vs 29%), leukopenia (23% vs 36%), hyperglycemia (19% vs 36%), thrombocytopenia (17% vs 29%), anemia (11% vs 21%), alkaline phosphatase elevation (11% vs 21%), and ALT elevation (9% vs 21%). One patient with HCC and another patient with melanoma achieved confirmed partial responses per RECIST. Conclusions: MRX34 has a manageable safety profile with confirmed partial responses in two patients with advanced HCC and melanoma. Due to better tolerability, QD x 5 schedule has been chosen for further study. Following MTD determination, enrollment will soon begin into the QD x 5 expansion cohorts for selected tumors. Citation Format: Muhammad Shaalan Beg, Andrew Brenner, Jasgit Sachdev, Samuel Ejadi, Mitesh Borad, Yang-Kon Kang, Ho Lim, T-Y Kim, Andreas Bader, Jay Stoudemire, Susan Smith, Sinil Kim, David Hong. Safety, tolerability, and clinical activity of MRX34, the first-in-class liposomal miR-34 mimic, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C43.