Citations

271 Background: MEDI-573 is a dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF-1R and insulin receptor-A (IR-A) signaling pathways, which play a role in breast and other epithelial cancers. By sparing IR-B and its hybrid receptors, MEDI-573 is expected to achieve antitumor activity without perturbing glucose homeostasis. Methods: In a 3 + 3 dose-escalation trial ( NCT00816361 ), patients with advanced solid tumors, KPS ≥ 60, received MEDI-573 as a weekly 1-hr IV infusion at 0.5, 1.5, 5, 10, or 15 mg/kg every 21 days. Objectives included determination of MTD, safety profile, pharmacokinetics (PK), pharmacodynamics, and tumor response. In a separate biomarker study, mRNA expression of IR-A and IR-B was compared in HR+/HER- breast cancers. Results: Patients included 13M/12F (17 evaluable for efficacy at data cutoff); median age 59 yrs (range 37-78). No DLTs, drug-related SAEs, or significant toxicity patterns were reported. Forty-five AEs were considered treatment-related (% of patients): decreased appetite (28%), fatigue (24%), nausea (20%), diarrhea (16%), and anemia (12%). Hyperglycemia occurred in 2 patients, 1 with evidence of prestudy insulin resistance. No other significant changes in plasma glucose levels occurred. MEDI-573 had dose-proportionality, with AUC of 415 ± 165, 597 ± 298, and 1940 ± 904 d*μg/mL at 5, 10, and 15 mg/kg, respectively. Suppression of free IGF-1 and -2 was fully achieved at doses ≥ 5 mg/kg. Stable disease spanning ≥ 12 wks (range 12-36+) was seen in 6/17 patients. No antidrug antibodies were reported. In a study to identify breast cancer subsets that are dependent on IGF signaling, the IR-A:IR-B ratio was significantly higher in HR+/HER2- breast cancer than matched adjacent normal tissues and in proliferative luminal B than in luminal A breast cancer. Conclusions: MEDI-573 showed acceptable safety and favorable PK profiles without significant changes in glucose levels. The IR-A:IR-B ratio supports a biomarker approach for MEDI-573 patient stratification. A biomarker-rich phase Ib/II study of MEDI-573 with an aromatase inhibitor in patients with advanced HR+/HER2- breast cancer opens in 2011.

Abstract Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel. Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively. Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors. Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.

Abstract Targeted therapies and immunotherapies have led to significant improvements in the treatment of advanced cancers, including metastatic melanoma. However, new strategies are desperately needed to overcome therapeutic resistance to these agents, as well as to identify effective treatment approaches for cancer patients that fall outside major targetable mutational subtypes (e.g., non–V600 BRAF melanoma). One such strategy is to extend the paradigm of individually tailored, molecularly targeted therapy into a broader spectrum of melanoma patients, particularly those bearing tumors without commonly recognized therapeutic targets, as well as having failed or were ineligible for immunotherapy. In this nontreatment pilot study, next-generation sequencing (NGS) technologies were utilized, including whole genome and whole transcriptome sequencing, to identify molecular aberrations in patients with non–V600 BRAF metastatic melanoma. This information was then rationally matched to an appropriate clinical treatment from a defined pharmacopeia. Five patients with advanced non–V600 BRAF metastatic melanoma were enrolled. We demonstrated successful performance of the following during a clinically relevant time period: patient tumor biopsy, quality DNA/RNA extraction, DNA/RNA-based sequencing for gene expression analysis, analysis utilizing a series of data integration methodologies, report generation, and tumor board review with formulated treatment plan. Streamlining measures were conducted based on the experiences of enrolling, collecting specimens, and analyzing the molecular signatures of patients. We demonstrated the feasibility of using NGS to identify molecular aberrations and generate an individualized treatment plan in this patient population. A randomized treatment study utilizing lessons learned from the conduct of this pilot study is currently underway. Mol Cancer Ther; 14(8); 1962–71. ©2015 AACR.

Abstract Background First identified as an estrogen-inducible gene in a breast cancer cell line, LIV-1 is a multispan transmembrane protein of the solute-carrier family 39 with putative zinc transporter and metalloproteinase activity. As a downstream target of STAT3, it promotes the epithelial-to-mesenchymal transition that is important in the malignant progression to metastasis. LIV-1 is expressed in a number of cancers with the highest prevalence and level of expression in breast, prostate, and melanoma. Additionally, LIV-1 has been linked with malignant progression to metastasis and associated with lymph node involvement in breast cancer. Normal tissue expression is predominantly limited to hormonally regulated tissues, including breast and prostate. In metastatic breast cancer tissue samples, the current validated immunohistochemistry assay for LIV-1 has detected moderate to high expression in 82% of samples tested, with 88% positivity in hormone receptor-positive tumors and 73% in triple-negative tumors. SGN-LIV1A is an antibody-drug conjugate (ADC) composed of a humanized anti-LIV-1 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, SGN-LIV1A shows target-specific internalization and cytotoxic activity against LIV-1-positive neoplastic cell lines. Significant dose-dependent tumor regression was demonstrated in mouse xenograft models. Methods The primary objective of this first-in-human phase 1, open label, multicenter study is to evaluate the safety and tolerability, and to identify the maximum tolerated dose of SGN-LIV1A using a 3+3 dose-escalation study design. Pharmacokinetics, immunogenicity, and antitumor activity will also be evaluated (ClinicalTrials.gov #NCT01969643). Enrollment to this US-based trial began in late 2013. Eligible patients are adult females who have hormone receptor-positive/HER2-negative or triple-negative metastatic breast cancer. Tumor tissue must be positive for expression of LIV-1 per central assessment. Patients must have received at least 2 prior cytotoxic regimens in the metastatic setting and have measurable disease per RECIST v1.1. Pre-existing neuropathy ≥ Grade 2 is not permitted. SGN-LIV1A is administered intravenously every 3 weeks at protocol-defined doses starting at 0.5 mg/kg. Patients who achieve an objective response or stable disease per RECIST v1.1 are eligible to continue treatment until disease progression. At the completion of dose escalation, expansion cohorts may be opened to enroll patients with specific breast cancer subtypes to further define safety and antitumor activity. Tumor biopsies are being obtained at baseline and after one cycle of treatment to evaluate the role of LIV-1 expression, target saturation, and other tumor-specific measurements in the antitumor activity of SGN-LIV1A. Citation Format: Andres Forero, Howard Burris III, Patricia LoRusso, Jennifer Specht, Kathy Miller, Monica Mita, Minetta C Liu, Shanu Modi, Lajos Pusztai, Django Sussman, Ana Kostic. SGN-LIV1A: A phase 1 trial evaluating a novel antibody-drug conjugate in patients with LIV-1-positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-3-01.

Abstract Despite remarkable therapeutic advances in malignant melanoma, an incomplete understanding of melanoma's extraordinary genetic diversity, complex disease course and ability to resist treatment continues to impede rational, curative clinical intervention. This is particularly true for the understudied “dark matter” of the melanoma genome, i.e. cases that lack mutations in the three most commonly-mutated melanoma genes (BRAF, NRAS, NF1) and that display extensive mutational heterogeneity. Clearly a pressing need exists for transformative approaches to melanoma medicine. We have therefore broadened our traditional focus on melanoma in human patients to include canine melanoma as a model of human disease. Given canine melanoma's clinicopathological resemblance to human non-cutaneous triple-negative subtypes, study of this disease in each species may inform the other. Further, the accelerated clinical course of canine melanoma and flexibility in veterinary clinical trial design may allow for evaluation of novel treatment designs that would not be possible in human cancer trials. Thus, we have undertaken a first-in-dog genomic characterization study of canine melanomas from a cohort of 37 dogs to further explore the landscape of this comparative model. This analysis combines comprehensive genomics (whole genome, whole genome long-insert, RNA sequencing, and array comparative genomic hybridization) in 7 matched canine melanoma/normal tissues with targeted analysis in an additional 27 tumors and 3 cell lines. These canine tumors display striking patterns of mutation and subtype heterogeneity resembling that of their non-cutaneous human counterparts with the majority being BRAF, NRAS, and NF1 wild type and lacking recurrent single nucleotide variants. Despite heterogeneity at the single nucleotide level, shared patterns of structural variation and gene expression exist and these patterns suggest core pathways that may define therapeutic vulnerabilities in these disease subtypes. These data provide the genomic framework for further clinical pursuit of melanoma in the canine model as a paradigm for drug development. Citation Format: William P. Hendricks, Victoria Zismann, Berry Button, Christophe Legendre, Waibhav Tembe, Holly Yin, Michael Bittner, Donald Berry, Matthew Huentelman, Chand Khanna, Patricia LoRusso, Matthew Breen, Aleksandar Sekulic, Jeffrey Trent. The genomic landscape of canine melanoma reveals broad mutational heterogeneity and recurrent patterns of structural variation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3417. doi:10.1158/1538-7445.AM2014-3417

Abstract Enzymatic degradation of hyaluronan (HA), a key component of the extracellular matrix (ECM), can enhance tumor perfusion, improve delivery of chemotherapeutics, and enhance the effects of anti-tumor agents. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational therapeutic agent under clinical development for the treatment of patients with solid tumors that may accumulate HA. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Twenty-six patients with advanced solid tumors were enrolled in a Phase 1 multi-center trial. Patients received weekly or twice weekly doses of IV PEGPH20 (0.5 - 5 μg/kg) for the first 4-week cycle, followed by once-weekly dosing for the subsequent 4-week cycles. Serial blood samples were drawn from each patient, and plasma concentrations were measured by an ultrasensitive hyaluronidase activity assay to assess PEGPH20 pharmacokinetics (PK). Plasma levels of HA catabolites were measured using a quantitative HPLC method to characterize PEGPH20 pharmacodynamics (PD). Other measures of PD activity were evaluated in selected patients, including DCE-MRI, DW-MRI, 18FDG-PET, textural analysis on CT, and histochemical staining of HA in tumor biopsies collected both before and after PEGPH20 treatment. Peak plasma PEGPH20 concentrations increased with dose, and plasma pharmacokinetics (PK) were well described by a linear PK model. Pre-treatment plasma HA levels were typically <1 μg/mL and increased in a dose-dependent fashion after PEGPH20 treatment. Increased plasma HA corresponded with decreased HA staining in patients with available tumor biopsies. DCE-MRI analysis indicated early (24-48 hr) and rapid increase in tumor perfusion compared to baseline in 4 patients with serial MRI assessments. Pharmacodynamic activity was also demonstrated when pre-treatment 18FDG-PET scans were compared with images collected at scheduled times after PEGPH20 dosing. Reduction in FDG uptake exceeding 25% was demonstrated in 3 of 4 patients after one cycle of treatment, consistent with a partial metabolic response. These data are consistent with the mechanism of action reported in preclinical models, and results support continued evaluation of PEGPH20 in combination with anti-tumor agents via modification of the ECM. Citation Format: Ping Jiang, Daniel C. Maneval, Ramesh K. Ramanathan, Jeffrey R. Infante, Mitesh Borad, Alberto Bessudo, Patricia LoRusso, Barry J. Sugarman, Deborah Carson, Marie A. Printz, Curtis B. Thompson, Paneer Selvam, Joy Zhu, Ronald Korn, H Michael Shepard, Gregory I. Frost. Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2013-3375

Abstract Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210–7. ©2014 AACR.

Abstract Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity. Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. Clin Cancer Res; 20(18); 4747–57. ©2014 AACR.