Browsing by Author "Albany, Costantine"

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    A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer
    (Wiley, 2021) Albany, Costantine; Fazal, Zeeshan; Singh, Ratnakar; Bikorimana, Emmanuel; Adra, Nabil; Hanna, Nasser H.; Einhorn, Lawrence H.; Perkins, Susan M.; Sandusky, George E.; Christensen, Brock C.; Keer, Harold; Fang, Fang; Nephew, Kenneth P.; Spinella, Michael J.; Medicine, School of Medicine
    Purpose: Germ cell tumors (GCTs) are cured with therapy based on cisplatin, although a clinically significant number of patients are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMAs), we conducted a phase I trial combining the next-generation HMA guadecitabine (SGI-110) with cisplatin in recurrent, cisplatin-resistant GCT patients. Methods: Patients with metastatic GCTs were treated for five consecutive days with guadecitabine followed by cisplatin on day 8, for a 28-day cycle for up to six cycles. The primary endpoint was safety and toxicity including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Results: The number of patients enrolled was 14. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by 100 mg/m2 cisplatin. The major DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients, including one with primary mediastinal disease, completed the study and qualified as complete responses by serum tumor marker criteria with sustained remissions of 5 and 13 months and survival of 16 and 26 months, respectively. The overall response rate was 23%. Three patients also had stable disease indicating a clinical benefit rate of 46%. Conclusions: The combination of guadecitabine and cisplatin was tolerable and demonstrated activity in patients with platinum refractory germ cell cancer.
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    Cisplatin-associated neuropathy characteristics compared to those associated with other neurotoxic chemotherapy agents (Alliance A151724)
    (Springer, 2021) Albany, Costantine; Dockter, Travis; Wolfe, Eric; Le-Rademacher, Jennifer; Wagner-Johnston, Nina; Einhorn, Lawrence; Lafky, Jackie; Smith, Ellen; Pachman, Deirdre; Staff, Nathan; Ma, Cynthia; Loprinzi, Charles L.; Costello, Brian A.; Medicine, School of Medicine
    Purpose: The current project was developed to obtain natural history information regarding cisplatin-induced peripheral neuropathy in males with testicular/germ cell cancers and to compare such neuropathy data with similarly obtained data in patients receiving other chemotherapy drugs in similarly conducted clinical trials. Methods: Patients without baseline neuropathy symptoms, who were initiating cisplatin-based chemotherapy, completed the EORTC CIPN 20 patient-reported instrument to evaluate chemotherapy-induced peripheral neuropathy (CIPN). Results were compared with EORTC CIPN 20 data obtained from independent study sets regarding patients receiving (1) paclitaxel, (2) combined paclitaxel and carboplatin, (3) oxaliplatin, or (4) a combination of doxorubicin and cyclophosphamide (AC). The last study set of patients on AC was selected to evaluate the use of EORTC CIPN 20 data in patients receiving chemotherapy not known to cause CIPN. Results: Cisplatin-induced neuropathy was more similar to neuropathy in patients receiving oxaliplatin than in those receiving paclitaxel. The cisplatin and oxaliplatin groups exhibited the coasting phenomenon and more prominent upper extremity symptoms than lower extremity symptoms during chemotherapy administration weeks. In contrast, paclitaxel-treated patients did not, on average, exhibit the coasting phenomenon; additionally, lower extremity symptoms were more prominent during the weeks when paclitaxel was administered. Cisplatin-induced neuropathy was less severe than was seen in patients in the other two groups, potentially because the cisplatin-receiving patients were younger. Patients receiving AC did not report substantial EORTC CIPN 20 changes. Conclusion: Understanding neuropathy similarities and differences with various chemotherapy agents may help elucidate CIPN processes and facilitate means to prevent and/or treat established CIPN.
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    Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer
    (American Society of Clinical Oncology, 2021-07-22) Taza, Fadi; Holler, Albert E.; Fu, Wei; Wang, Hao; Adra, Nabil; Albany, Costantine; Ashkar, Ryan; Cheng, Heather H.; Sokolova, Alexandra O.; Agarwal, Neeraj; Kessel, Adam; Bryce, Alan; Nafissi, Nellie; Barata, Pedro; Sartor, A. Oliver; Bastos, Diogo; Smaletz, Oren; Berchuck, Jacob E.; Taplin, Mary-Ellen; Aggarwal, Rahul; Sternberg, Cora N.; Vlachostergios, Panagiotis J.; Alva, Ajjai S.; Su, Christopher; Marshall, Catherine H.; Antonarakis, Emmanuel S.; Medicine, School of Medicine
    Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. Methods: We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. Results: A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. Conclusion: PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.
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    Epigenetic Targeting of Platinum Resistant Testicular Cancer
    (Bentham Science Publishers, 2016) Sonnenburg, Daniel; Spinella, Michael J.; Albany, Costantine; Department of Medicine, Indiana University School of Medicine
    The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, little is known of the epigenetic alterations in testicular cancer and particularly in platinum refractory germ cell tumors. Germ cell derived testicular cancers, as compared to somatic tumors, appear to have a unique epigenetic profile that features more extensive DNA hypomethylation. Emerging data from clinical specimens suggest that epigenetic aberrations, especially DNA hypermethylation, can contribute to chemotherapy resistance and poor clinical outcomes in testicular germ cell tumors. Recent data indicate that testicular cancer cells, even those resistant to platinum, are highly sensitive to low doses of demethylating agents. Based on these promising preclinical studies, we suggest that DNA methylation inhibitors in combination with chemotherapeutic agents may offer a path to overcome acquired drug resistance in testicular cancer, laying the foundation and rationale for testing this class of epigenetic drugs in the clinical setting. In this mini-review we provide a brief overview of the promise of DNA methylation therapy to treat patients with refractory cancer of the testes.
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    Hypermethylation and global remodelling of DNA methylation is associated with acquired cisplatin resistance in testicular germ cell tumours
    (Taylor & Francis, 2021-10) Fazal, Zeeshan; Singh, Ratnakar; Fang, Fang; Bikorimana, Emmanuel; Baldwin, Hannah; Corbet, Andrea; Tomlin, Megan; Yerby, Cliff; Adra, Nabil; Albany, Costantine; Lee, Sarah; Freemantle, Sarah J.; Nephew, Kenneth P.; Christensen, Brock C.; Spinella, Michael J.; Medicine, School of Medicine
    Testicular germ cell tumours (TGCTs) respond well to cisplatin-based therapy. However, cisplatin resistance and poor outcomes do occur. It has been suggested that a shift towards DNA hypermethylation mediates cisplatin resistance in TGCT cells, although there is little direct evidence to support this claim. Here we utilized a series of isogenic cisplatin-resistant cell models and observed a strong association between cisplatin resistance in TGCT cells and a net increase in global CpG and non-CpG DNA methylation spanning regulatory, intergenic, genic and repeat elements. Hypermethylated loci were significantly enriched for repressive DNA segments, CTCF and RAD21 sites and lamina associated domains, suggesting that global nuclear reorganization of chromatin structure occurred in resistant cells. Hypomethylated CpG loci were significantly enriched for EZH2 and SUZ12 binding and H3K27me3 sites. Integrative transcriptome and methylome analyses showed a strong negative correlation between gene promoter and CpG island methylation and gene expression in resistant cells and a weaker positive correlation between gene body methylation and gene expression. A bidirectional shift between gene promoter and gene body DNA methylation occurred within multiple genes that was associated with upregulation of polycomb targets and downregulation of tumour suppressor genes. These data support the hypothesis that global remodelling of DNA methylation is a key factor in mediating cisplatin hypersensitivity and chemoresistance of TGCTs and furthers the rationale for hypomethylation therapy for refractory TGCT patients.
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    Incorporating DNA Methyltransferase Inhibitors (DNMTis) in the Treatment of Genitourinary Malignancies: A Systematic Review
    (Springer, 2018-02) Chovanec, Michal; Taza, Fadi; Kalra, Maitri; Hah, Noah; Nephew, Kenneth P.; Spinella, Michael J.; Albany, Costantine; Medicine, School of Medicine
    Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hypermethylation in promoters of critical tumor suppressor genes is the basis for the idea that treatment with hypomethylating agents may lead to the restoration of a “normal” epigenome and produce clinically meaningful therapeutic outcomes. The aim of this review article is to summarize the current state of knowledge of DNMT inhibitors in the treatment of genitourinary malignancies. The efficacy of these agents in genitourinary malignancies was reported in a number of studies and suggests a role of induced DNA hypomethylation in overcoming resistance to conventional cytotoxic treatments. The clinical significance of these findings should be further investigated.
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    Life-Threatening Docetaxel Toxicity in a Patient With Reduced-Function CYP3A Variants: A Case Report.
    (Frontiers, 2021) Powell, Nicholas R.; Shugg, Tyler; Ly, Reynold C.; Albany, Costantine; Radovich, Milan; Schneider, Bryan P.; Skaar, Todd C.
    Docetaxel therapy occasionally causes severe and life-threatening toxicities. Some docetaxel toxicities are related to exposure, and inter-individual variability in exposure has been described based on genetic variation and drug-drug interactions that impact docetaxel clearance. Cytochrome P450 3A4 (CYP3A4) and CYP3A5 metabolize docetaxel into inactive metabolites, and this is the primary mode of docetaxel clearance. Supporting their role in these toxicities, increased docetaxel toxicities have been found in patients with reduced- or loss-of-function variants in CYP3A4 and CYP3A5. However, since these variants in CYP3A4 are rare, little is known about the safety of docetaxel in patients who are homozygous for the reduced-function CYP3A4 variants. Here we present a case of life-threatening (grade 4) pneumonitis, dyspnea, and neutropenia resulting from a single dose of docetaxel. This patient was (1) homozygous for CYP3A4*22, which causes reduced expression and is associated with increased docetaxel-related adverse events, (2) heterozygous for CYP3A4*3, a rare reduced-function missense variant, and (3) homozygous for CYP3A5*3, a common loss of function splicing defect that has been associated with increased docetaxel exposure and adverse events. The patient also carried functional variants in other genes involved in docetaxel pharmacokinetics that may have increased his risk of toxicity. We identified one additional CYP3A4*22 homozygote that received docetaxel in our research cohort, and present this case of severe hematological toxicity. Furthermore, the one other CYP3A4*22 homozygous patient we identified from the literature died from docetaxel toxicity. This case report provides further evidence for the need to better understand the impact of germline CYP3A variants in severe docetaxel toxicity and supports using caution when treating patients with docetaxel who have genetic variants resulting in CYP3A poor metabolizer phenotypes.
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    Long-Term Survival of Good-Risk Germ Cell Tumor Patients After Postchemotherapy Retroperitoneal Lymph Node Dissection: A Comparison of BEP × 3 vs. EP × 4 and Treating Institution
    (Elsevier, 2017) Cary, Clint; Jacob, Joseph M.; Albany, Costantine; Masterson, Timothy A.; Hanna, Nasser H.; Einhorn, Lawrence H.; Foster, Richard S.; Urology, School of Medicine
    Background Patients with International Germ Cell Cancer Collaborative Group (IGCCCG) good-risk testicular cancer might receive either 4 cycles of etoposide and cisplatin (EP × 4) or 3 cycles of bleomycin, etoposide, and cisplatin (BEP × 3). We sought to examine differences in survival after retroperitoneal lymph node dissection (PC-RPLND) between patients who received EP × 4 compared with BEP × 3. Patients and Methods The Indiana University Testis Cancer database was queried to identify IGCCCG good-risk PC-RPLND patients who received either EP × 4 or BEP × 3 induction chemotherapy. The primary outcome was overall survival (OS). Kaplan–Meier plots were generated for the EP × 4 and BEP × 3 groups and compared using the log rank test. Cox regression analysis was used to determine risk of mortality. Results A total of 223 patients met inclusion criteria between 1985 and 2011. Induction chemotherapy consisted of EP × 4 in 45 (20%) patients and BEP × 3 in 178 (80%). Most patients (78%) received their chemotherapy at outside institutions and were subsequently referred for PC-RPLND. The location of treating institution did not influence outcomes significantly when similar chemotherapy regimens were compared in this good-risk cohort. The 10-year OS for the EP × 4 and BEP × 3 groups were 91% and 98%, respectively (log rank P < .01). The adjusted risk of death in the EP × 4 group showed a nonsignificant trend of 3 times greater compared with the BEP × 3 group (hazard ratio, 3.1; 95% confidence interval, 0.8-12.0; P = .10). Conclusion The regimen of BEP × 3 resulted in a trend toward improved survival, however, this did not reach statistical significance. The location of treating institution seems less important in this risk group of patients.
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    Low CD34+ Cell Doses Are Associated with Increased Cost and Worse Outcome after Tandem Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Germ Cell Tumors
    (Elsevier, 2018) Hyder, Mustafa A.; Goebel, W. Scott; Ervin, Kirsten D.; Schwartz, Jennifer E.; Robertson, Michael J.; Thakrar, Teresa C.; Albany, Costantine; Farag, Sherif S.; Medicine, School of Medicine
    Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumor (GCT) patients. Studies, predominantly in lymphoma, showed that CD34+ cell doses > 5.0 × 106/kg/single transplant led to decreased resource utilization. Because most GCT patients have received prior cisplatin-based treatment, collecting >10 × 106 CD34+ cells/kg is challenging. We analyzed the effect of CD34+ cell dose on resource utilization and outcome in 131 GCT patients, median age 29.5 years (range, 16 to 58), undergoing tandem ASCT. Of 262 individual transplants performed, 120 were performed as inpatient and 142 as planned outpatient. Overall, median CD34+ dose per transplant was 3.1 × 106/kg (range, .8 to 16.0), with no significant difference between inpatient and outpatient transplants. Patients were divided into quartiles based on the CD34 cell dose infused: Q1, .8 to 1.9 × 106/kg; Q2, 2.0 to 2.9 × 106/kg; Q3, 3.0 to 4.1 × 106/kg; and Q4, 4.2 to 16.0 × 106/kg. For all patients higher CD34+ cell doses were associated with significantly shorter times to neutrophil (P <.001) and platelet recovery (P <.001). For inpatient transplants higher CD34+ doses were significantly associated with shorter length of hospital stay (P <.001); fewer days of filgrastim (P <.001), i.v. antibiotic (P = .012), and antifungal (P = .03) usage; and fewer RBC (P = .001) and platelet units transfused (P <.001), resulting in overall lower cost of care (P < .001). Of the 142 planned outpatient transplants, 100 admissions were required for a median length of hospital stay of 7.0 days (range, 1 to 18). Although there was no significant difference in the rates of hospitalization between patients in different CD34+ cell dose quartiles, a significant trend was observed for shorter hospitalization (P = .01) and fewer RBC (P = .002) and platelet (P = .005) transfusions with higher CD34+ cell dose quartiles. Patients receiving CD34+ cell doses in the lowest dose quartile (Q1) had significantly worse progression-free survival and overall survival compared with patients receiving higher CD34+ cell doses. Overall, resource utilization, including cost of care, is significantly reduced when patients receive higher CD34+ cell doses, indicating greater efforts to improve peripheral blood stem cell collection in this population are needed.
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    Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy
    (Hindawi, 2015-09) Ranganath, Praveen; Einhorn, Lawrence; Albany, Costantine; Medicine, School of Medicine
    Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect of multiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of these side effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for a curable neoplasm has also turned into an excellent testing ground to develop effective strategies to prevent chemotherapy induced nausea and vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)3 receptor antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and delayed CINV. Mechanism and pattern of CINV with multiday chemotherapy may differ from those in single day chemotherapy and therefore efficacy of antiemetic drugs as observed in single day chemotherapy may not be applicable. There are only few randomized clinical trials with special emphasis on multiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose, and duration of the newer agents and combinations in multiday cisplatin based chemotherapy.