Fatima Karzai

A phase I study of TRC105 anti-endoglin (CD105) antibody in metastatic castration-resistant prostate cancer

TRC105 is a chimeric immunoglobulin G1 monoclonal antibody that binds endoglin (CD105). This phase I open‐label study evaluated the safety, pharmacokinetics and pharmacodynamics of TRC105 in patients with metastatic castration‐resistant prostate cancer (mCRPC).

Racial Disparities in the Association Between Variants on 8q24 and Prostate Cancer: A Systematic Review and Meta-Analysis

Recent studies implicate single nucleotide polymorphisms (SNPs) within the 8q24 region as a risk factor for prostate cancer (PCa). New developments suggest that 8q24 encodes regulators of the nearby MYC gene, a known oncogene. In order to better understand the implications of SNPs in this region, we performed meta-analyses, stratified by race, of seven SNPs and one microsatellite marker previously identified as risk loci on the 8q24 region of the genome. In addition, we reviewed the literature examining the possible associations between these polymorphisms and clinicopathological features of PCa. The results of the meta-analyses indicate that rs6983267, rs1447295, rs6983561, rs7837688, rs16901979, and DG8S737 are significantly associated with a higher risk for PCa for at least one race, whereas the variants rs13254738 and rs7000448 are not. The degree of association and frequency of the causative allele varied among men of different races. Though several studies have demonstrated an association between certain 8q24 SNPs and clinicopathological features of the disease, review of this topic revealed conflicting results.

A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma

&NA; TRC105 is a chimeric monoclonal antibody that targets CD105 (endoglin). Heavily pretreated patients with metastatic urothelial carcinoma received TRC105 at 15 mg/m2 every 2 weeks on a 28‐day cycle. Treatment was not associated with significant toxicities, but did not improve 6‐month progression‐free survival. Exploratory analyses suggest interplay between immunosuppressive subsets and TRC105, which warrants further study. Background: In this trial we assessed the efficacy and tolerability of TRC105, a chimeric monoclonal antibody that targets CD105 (endoglin) in patients with advanced, previously treated urothelial carcinoma (UC). Patients and Methods: Patients received TRC105 15 mg/kg every 2 weeks on days 1 and 15 of each 28‐day cycle. The primary end point was progression‐free survival (PFS) at 6 months. Secondary end points included safety, toxicity, and overall survival (OS). CD105 expression was evaluated using immunohistochemistry (IHC) in a separate cohort of 50 UC patients. Biomarker studies included immune subsets, circulating tumor cells (CTCs), circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and osteopontin. Results: Of 13 patients enrolled, 12 were evaluable for OS and PFS. The 3‐month PFS probability was 18.2% (median PFS, 1.9 months [95% confidence interval (CI), 1.8‐2.1 months). This met the criterion for ending accrual on the basis of the 2‐stage design. Median OS was 8.3 months (95% CI, 3.3‐17.0 months). IHC for CD105 scores was not associated with T stage (P = .26) or presence of lymph nodes (P = .64). Baseline levels of regulatory T and B cells, CEPs, and changes in CEC level after TRC105 exhibited trends toward an association with PFS or OS. CTCs pre‐ and post‐TRC105 were detected in 4 of 4 patients. Conclusion: Although TRC105 was well tolerated, it did not improve 6‐month PFS in heavily pretreated patients with advanced UC. CD105 staining was present in 50% of UC tumors at different intensities. Our observations on the pharmacodynamic significance of immune subsets, CECs, and CTCs warrant further study.

Phase II trial of docetaxel, bevacizumab, lenalidomide and prednisone in patients with metastatic castration-resistant prostate cancer.

To determine the safety and clinical efficacy of two anti‐angiogenic agents, bevacizumab and lenalidomide, with docetaxel and prednisone.

Beyond PSA: managing modern therapeutic options in metastatic castration-resistant prostate cancer.

Prostate cancer remains a significant cause of cancer-related deaths in men in the United States. Significant advances in the treatment of metastatic castration-resistant prostate cancer have been made in recent years with the arrival of new therapeutic targets and options. The definition of progression of disease must be thought of in the context of clinical symptoms and radiographic evidence rather than as changes in prostate-specific antigen (PSA). Ultimately, the use of PSA criteria alone should not be used to determine the progression of disease; instead, PSA should be evaluated in combination with other clinical data.

Somatic VHL Mutation in a Patient With MEN1-Associated Metastatic Pancreatic Neuroendocrine Tumor Responding to Sunitinib Treatment: A Case Report

Multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) are autosomal-dominant diseases caused by germline mutations in tumor-suppressor genes. A patient with a germline MEN1 mutation and a somatic VHL mutation in the tumor has not been reported. Herein, we report on a patient with MEN1 and a metastatic nonfunctioning pancreatic neuroendocrine tumor (PNET) with a somatic VHL mutation. This patient underwent a pancreaticoduodenectomy for a grade 2 PNET obstructing her pancreatic duct. The patient developed liver and regional lymph node metastases as well as growth of a PNET in the remnant pancreas. As part of a clinical trial for mutation-targeted therapy, a biopsy of the metastatic tumor was obtained. The clinical diagnosis, confirmed by OncoVAR-NET and molecular profiling analysis, revealed MEN1 with a germline deletion in exon 2 and a c.402 deletion C, p.Phe134LeufsX51. In addition, a somatic mutation in the VHL gene—a nonsense mutation, c.529A>T, p.Arg177Ter—was identified by hybrid capture sequencing. The mutations were confirmed by Sanger sequencing. Comparative genomic hybridization showed loss of heterozygosity in both the MEN1 and VHL genes. The patient was treated with sunitinib and had a partial response to treatment. This case illustrates not only that a second hit occurs in tumor suppressor genes but that somatic mutations are also possible in additional tumor suppressor genes. This suggests that targeted therapy selection should include analysis of somatic mutations even when the susceptibility gene is known.

Metabolic syndrome in prostate cancer: impact on risk and outcomes

Androgen-deprivation therapy (ADT) is a fundamental element of treatment for nonlocalized prostate cancer and for patients with high-risk disease who are not candidates for radical treatment. ADT has been linked to metabolic syndrome, which involves changes in metabolic factors. While distinct from classic metabolic syndrome, this type does include changes in body composition, lipid profiles and insulin resistance. The constellation of risk factors may be associated with cardiovascular morbidity and the onset of diabetes mellitus. Physicians should discuss in detail the risk and benefits of ADT, as well as any needed lifestyle modifications with patients before beginning therapy.

Use of supportive measures to improve outcome and decrease toxicity in docetaxel-based antiangiogenesis combinations.

128 Background: We have recently completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P). Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90410 trials we attempted to contrast and compare our studies with the failed phase III trials. METHODS Among the first 52 pts on the ART-P, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21-day cycle (C). We later enrolled 11 more pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. Patients on CALGB 90410 received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and on MAINSAIL received D 75 mg/m2, L 25 mg daily for 14 days of every 21-day cycle with daily P. Patients on CALGB 90410 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. RESULTS Median number of Cs in ART-P was 16 (3-38). PFS was 22 months and median OS has not been reached. Pts with measurable disease had 1 CR and 25 PR (86.7% RR). Two patients (3%) had deep vein thromboses. Of 1,219 cycles given, 14 cycles were complicated by febrile neutropenia (FN) (1.1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90410 trial, median OS was 22.6 months with median PFS of 9.9 months. Median number of Cs was 8, and 19 pts developed thromboses/emboli (3.6%). In addition, 7% of patients developed FN and treatment related deaths were reported at 4%. CONCLUSIONS The use of supportive care allows the ART-P combination to be given for more cycles than were given in MAINSAIL and CALGB 90401 potentiating a longer PFS, RR and possibly OS with an improved toxicity profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. CLINICAL TRIAL INFORMATION NCT00942578.

A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening

Purpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high-throughput and mechanistic analysis. Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested >20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin. Results: All PDX models proliferated as organoids in culture. Greater than 50% could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously reported conditions. In addition, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2−/− organoids, similar to responses observed in patients. Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically characterized platform to investigate the mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC. Clin Cancer Res; 24(17); 4332–45. ©2018 AACR.

Abstract CT058: A phase 2 open-label study to evaluate the efficacy and safety of VT-464 in patients with androgen receptor positive triple-negative breast cancer patients, and men with ER positive breast cancer

Background: The androgen receptor (AR) is expressed in 20-30% of patients with triple negative breast cancer (TNBC). In phase 2 trials androgen blockade with bicalutamide demonstrated a clinical benefit rate (CBR = Partial Response + Complete Response + Stable Disease) of 19% at 24 weeks and enzalutamide showed a CBR of 35% at 16 weeks. VT-464 is an oral non-steroidal, small molecule that is a potent anti-androgen through both inhibition of CYP17 lyase and through direct inhibition of AR. Studies in breast cancer cell lines have shown that VT-464 inhibits growth in a soft agar assay of MCF7 (ER positive/low AR expression), tamoxifen-resistant MCF7, and MDA-MB-453 (ER negative/AR positive) cells in a dose dependent manner and with higher potency than enzalutamide. Patients with AR+ TNBC may benefit from treatment with VT-464. In addition, since VT-464 will deplete androgen available for aromatization, men with ER-positive (ER+) breast cancer may benefit from use of VT-464. Methods: This is a Phase 2, open label study evaluating the potential benefit of VT-464 in female patients with TNBC with AR 1 to 9% (cohort 1) and AR ≥ 10% (cohort 2), and men with ER+ breast cancer (cohort 3) (NCT02130700; NIH 14-c-0090). VT-464 will be administered once daily in continuous 28-days cycles. Due to differences in drug metabolism, women with TNBC will receive VT-464 450mg by mouth daily while men with ER+ breast cancer will receive VT-464 600mg by mouth daily. In the two female TNBC cohorts the primary endpoint is CBR at 16 weeks. In the ER+ male breast cancer cohort the primary endpoint is progression free survival at 24 weeks. Secondary objectives include evaluation of response rate and the safety profile of the drug in both populations. Women with TNBC with > 1% AR expression per IHC are eligible. Males with ER+ breast cancer, who have failed at least one prior endocrine therapy and are undergoing gonadal suppression using LHRH agonists or antagonists are eligible for the study. All patients must be at least 18 years old and have a ECOG of 0 to 1. Consenting patients must have biopsiable disease which will be used for genomic and transcriptomic evaluation before and after treatment with VT-464. Correlative studies including serum hormone levels, circulating tumor cells, and immune subset will be analyzed. Patients must also have adequate hematopoietic, hepatic and renal function. Exclusions include symptomatic CNS metastases, radiotherapy within 28 days of study entry and active HIV, hepatitis B or hepatitis C infection. This trial opened in December 2016. While no patients have been enrolled at this time, multiple patients are currently being screened. Citation Format: Alexandra Zimmer, Margaret E. Gatti-Mays, Stan Lipkowitz, Fatima Karzai, James Gulley, William Dahut, Seth Steinberg, William D. Figg, Ravi Madan. A phase 2 open-label study to evaluate the efficacy and safety of VT-464 in patients with androgen receptor positive triple-negative breast cancer patients, and men with ER positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT058. doi:10.1158/1538-7445.AM2017-CT058