Sharad A. Ghamande

PRECEDENT: A Randomized Phase II Trial Comparing Vintafolide (EC145) and Pegylated Liposomal Doxorubicin (PLD) in Combination Versus PLD Alone in Patients With Platinum-Resistant Ovarian Cancer

PURPOSE Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined. PATIENTS AND METHODS Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups. RESULTS The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806). CONCLUSION Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma.

OBJECTIVE Patients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma. METHODS This Phase II, multicenter, single-arm, open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma, who had received one or two prior chemotherapy regimens. Patients received pilaralisib 600mg capsules or 400mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free survival (PFS) >6months and safety. Molecular profiling in archival tumor tissue and circulating tumor DNA were performed to identify molecular markers associated with response or resistance to pilaralisib. RESULTS 67 patients were enrolled, of which 50 and 17 patients had received one or two prior regimens, respectively. Complete or partial tumor responses occurred in two patients each (ORR 6.0%); three had tumors with normal PTEN expression and PIK3R1 mutations and one had a tumor with PTEN protein deficiency. However, there was no association between molecular alterations and clinical activity. Rate of PFS>6months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (40.3%), diarrhea (37.3%) and fatigue (28.4%). The most commonly reported treatment-related grade ≥3 AEs were rash (9.0%), diarrhea (4.5%) and increased alanine aminotransferase (4.5%). CONCLUSIONS Pilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma.

A Phase 2, randomized, double-blind, placebo-controlled trial of clinical activity and safety of subcutaneous A6 in women with asymptomatic CA125 progression after first-line chemotherapy of epithelial ovarian cancer

OBJECTIVES A6 is a novel peptide that interferes with single-chain urokinase plasminogen activator activity and has shown anti-angiogenic, anti-migratory, and anti-invasive properties. We evaluated clinical efficacy and safety of subcutaneously administered A6 in women with epithelial ovarian cancer. METHODS Women with epithelial ovarian, fallopian tube, or primary peritoneal cancer in clinical remission after first-line chemotherapy with 2 consecutive increases of CA125 values above normal but with no disease on physical examination or imaging studies were randomly assigned to receive daily subcutaneous injections of placebo, low-dose A6 (150 mg), or high-dose A6 (300 mg) until disease progression or end of study participation. Primary endpoints were time to clinical progression of disease and safety of A6. Secondary endpoints were changes in serum CA125 and biomarkers of the urokinase system. RESULTS Data are available for 24 women (placebo, n=12; low-dose, n=8; high-dose n=4). A6 therapy was associated with a statistically significant delay in time to clinical progression (log-rank p-value 0.01) with a median of 100 days (95% CI: 64,168) for women who received A6 compared with 49 days (95% CI: 29,67) for women who received placebo. The treatments appeared to be well tolerated. Treatment was not associated with CA125 response (p=0.44). On-treatment values for plasma urokinase plasminogen activator receptor were statistically significantly lower in the A6 groups compared with placebo (p=0.02). CONCLUSIONS A6 therapy increases time to clinical disease progression and appears to be well tolerated in this patient population.

Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with or without oral phenoxodiol, a sensitizer of platinum cytotoxicity: the phase III OVATURE multicenter randomized study

BACKGROUND Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients. PATIENTS AND METHODS A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life. RESULTS The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1-21.0] versus 20.1 weeks for group 2 (95% CI = 13.1-33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0-45.3) versus 45.7 weeks (95% CI 35.6-58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity. CONCLUSIONS Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies.

Twelve serum proteins progressively increase with disease stage in squamous cell cervical cancer patients

Objective This study aimed to reliably identify serum protein profile alterations that may be useful for elucidation of the disease mechanism and/or finding new targets for treatment and intervention. Materials and Methods A total of 1057 women at 4 different squamous cell cervical cancer stages (noninvasive, invasive International Federation of Gynecology and Obstetrics stages I, II, and III) were included in this cross-sectional study. Forty-seven serum proteins were profiled using multiplex Luminex immunoassays. Results Serum concentration of serum amyloid A (SAA), C-reactive protein (CRP), soluble tumor necrosis factor receptor I and II (sTNFRI and sTNFRII), soluble interleukin 2 receptor &agr; (sIL2R&agr;), CXCL1, CXCL9, hepatocyte growth factor, squamous cell carcinoma antigen (SCCA), insulin-like growth factor binding protein 2, CA125, and carcinoembryonic antigen (CEA) were elevated significantly as disease progressed in cervical cancer patients. Serum levels are significantly different at early stage (I) for SAA, CRP, sIL2R&agr;, sTNFRII, SCCA, and CEA (P values ranged from 0.02 for CEA to 0.0001 for CRP and SCCA) and at late stages (II and III) for all 12 proteins (P values ranged from 8.78E-5 for CA125 to 3.49E-47 for SAA), as compared to the noninvasive stage. The areas under the curves of these proteins for disease state separation also improved with the advancement of the disease. The correlations between serum concentrations of these proteins also show different patterns at different clinical stages. These proteins are involved in multiple mechanisms including inflammation and immunity, angiogenesis, growth promotion, and metastasis. Conclusions A number of serum proteins are significantly different between patients at different stages of cervical cancer.

Serum Protein Profile at Remission Can Accurately Assess Therapeutic Outcomes and Survival for Serous Ovarian Cancer

Background Biomarkers play critical roles in early detection, diagnosis and monitoring of therapeutic outcome and recurrence of cancer. Previous biomarker research on ovarian cancer (OC) has mostly focused on the discovery and validation of diagnostic biomarkers. The primary purpose of this study is to identify serum biomarkers for prognosis and therapeutic outcomes of ovarian cancer. Experimental Design Forty serum proteins were analyzed in 70 serum samples from healthy controls (HC) and 101 serum samples from serous OC patients at three different disease phases: post diagnosis (PD), remission (RM) and recurrence (RC). The utility of serum proteins as OC biomarkers was evaluated using a variety of statistical methods including survival analysis. Results Ten serum proteins (PDGF-AB/BB, PDGF-AA, CRP, sFas, CA125, SAA, sTNFRII, sIL-6R, IGFBP6 and MDC) have individually good area-under-the-curve (AUC) values (AUC = 0.69–0.86) and more than 10 three-marker combinations have excellent AUC values (0.91–0.93) in distinguishing active cancer samples (PD & RC) from HC. The mean serum protein levels for RM samples are usually intermediate between HC and OC patients with active cancer (PD & RC). Most importantly, five proteins (sICAM1, RANTES, sgp130, sTNFR-II and sVCAM1) measured at remission can classify, individually and in combination, serous OC patients into two subsets with significantly different overall survival (best HR = 17, p<10−3). Conclusion We identified five serum proteins which, when measured at remission, can accurately predict the overall survival of serous OC patients, suggesting that they may be useful for monitoring the therapeutic outcomes for ovarian cancer.

Abstract 2320: Clinical epigenetic resensitization of platinum-resistant, recurrent ovarian cancer patients with SGI-110, a novel, second-generation, subcutaneously administered hypomethylating agent (HMA)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Epigenetic changes have been implicated in acquired resistance to platinum. SGI-110 is a second generation SQ HMA with improved pharmaceutical properties compared to decitabine. Here we report the clinical results and pharmacodynamic analyses of the phase 1 study of SGI-110 in combination with carboplatin in patients with recurrent platinum resistant high-grade serous, epithelial ovarian cancer (EOC), primary peritoneal carcinoma (PPC) or fallopian tube (FT) cancer. Methods: SGI-110 was administered SQ QD x 5 followed by carboplatin IV on Day 8 of a 28-day cycle. Patients were required to have either measurable disease according to RECIST v1.1 or detectable disease (modified Rustin) with clinical response assessed using the applicable criteria. Safety assessments were graded using CTCAE v4. Results: Twenty patients (18 EOC, 1 PPC, 1 FT) were enrolled and treated in the phase 1 portion of the trial. Median age was 55.8 years (38-72); ECOG PS of 0/1/2 was 10/10/0, respectively. Median number of prior regimens was 7 (1-9). The starting doses were SGI-110 45 mg/m2 SQ QD x 5 and carboplatin AUC5 in the first cohort of 6 patients. Four DLTs of myelosuppression (neutropenia and thrombocytopenia) in the first cohort led to dose reduction to SGI-110 30 mg/m2 and carboplatin AUC4 with granulocyte-CSF permitted at the discretion of the physician. No DLTS were observed in 14 patients and this dose was recommended for the subsequent phase 2 study. Grade 3/4 AEs regardless of relationship to the combination ≥ 10% included anemia, leukopenia, neutropenia, thrombocytopenia, nausea, vomiting, constipation, small intestinal obstruction, infusion related reaction and pulmonary embolism. Three PRs and 9 SDs as best response were observed in 20 patients for an overall response rate and clinical benefit rate of 15% and 60%, respectively. All PRs and 3 SDs were accompanied by CA-125 decrease. LINE-1 hypomethylation, a marker of global DNA methylation, was recorded in PBMCs with SGI-110 30 mg/m2 (avg: -19.5%, n=14) and 45 mg/m2 (avg: -17.4%, n=6). Gene specific methylation of RASSF1A and BRCA-1 measured by pyrosequencing was significantly decreased at C2D8 compared to baseline in paired tumor biopsies/ascites (n=9). Gene re-expression measured by quantitative RT-PCR was observed in tumor biopsies. Conclusions: Priming treatment with SGI-110 prior to carboplatin induced clinical responses in a heavily-pretreated platinum resistant ovarian cancer population with expected and manageable safety profile. Potent LINE-1 demethylation and demethylation and re-expression of silenced tumor genes were recorded. The phase 2 portion of the trial is currently ongoing with patients randomized to either the RP2D dose combination or a physician choice of 1 of 4 treatment options (topotecan; liposomal doxorubicin; weekly paclitaxel; or weekly gemcitabine). Citation Format: Gini Fleming, Sharad Ghamande, Yvonne Lin, Angeles Alvarez Secord, John Nemunaitis, Merry-Jennifer Markham, Kenneth Nephew, Fang Fang, Shweta Gupta, Sue Naim, Gavin Choy, Simone Jueliger, Pietro Taverna, Yong Hao, Harold Keer, Mohammad Azab, Daniela Matei. Clinical epigenetic resensitization of platinum-resistant, recurrent ovarian cancer patients with SGI-110, a novel, second-generation, subcutaneously administered hypomethylating agent (HMA). [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 2320. doi:10.1158/1538-7445.AM2014-2320

Multiplex glycan bead array for high throughput and high content analyses of glycan binding proteins

Glycan-binding proteins (GBPs) play critical roles in diverse cellular functions such as cell adhesion, signal transduction and immune response. Studies of the interaction between GBPs and glycans have been hampered by the availability of high throughput and high-content technologies. Here we report multiplex glycan bead array (MGBA) that allows simultaneous analyses of 384 samples and up to 500 glycans in a single assay. The specificity, sensitivity and reproducibility of MGBA are evaluated using 39 plant lectins, 13 recombinant anti-glycan antibodies, and mammalian GBPs. We demonstrate the utility of this platform by the analyses of natural anti-glycan IgM and IgG antibodies in 961 human serum samples and the discovery of anti-glycan antibody biomarkers for ovarian cancer. Our data indicate that the MGBA platform is particularly suited for large population-based studies that require the analyses of large numbers of samples and glycans.The low throughput or content of current methods for the analysis of glycans-glycan binding proteins (GBPs) interactions hampers their clinical applications. Here, the authors conjugate synthesized glycans to Luminex beads to detect GBPs and apply it for the discovery of ovarian cancer biomarkers.

A phase i clinical trial of guadecitabine and carboplatin in platinum-resistant, recurrent ovarian cancer: Clinical, pharmacokinetic, and pharmacodynamic analyses

Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC). Experimental Design: Guadecitabine was administered once daily on days 1 to 5 followed by carboplatin i.v. on day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4. Results: Twenty patients were enrolled and treated. Median age was 56 years (38–72 years). The median number of prior regimens was 7 (1–14). In the first cohort (N = 6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTs were observed in the subsequent 14 patients. Grade ≥3 adverse events ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small-intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR), and 6 patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene reexpression in paired tumor biopsies/ascites were recorded. Conclusions: Guadecitabine and carboplatin were tolerated and induced clinical responses in a heavily pretreated platinum-resistant ovarian cancer population, supporting a subsequent randomized phase II trial. Clin Cancer Res; 24(10); 2285–93. ©2018 AACR.

Abstract A89: A phase I study of the novel DNA topoisomerase-1 inhibitor, TLC388 (Lipotecan®), administered intravenously to patients with advanced solid tumors.

Introduction: TLC388 (Lipotecan) is a potent Topoisomerase-1 inhibitor and it can disrupt both Sonic Hedgehog and HIF1-α pathways to overcome cancer drug resistance and inhibit angiogenesis induced by tumor hypoxia. This phase I first-in-human study of Lipotecan examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles of TLC388 in patients with advanced incurable solid tumors. Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent safety assessments regularly and tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2 for all treated patients. Results: The enrollment for this study has been concluded and 54 previously-treated patients with advanced or metastatic solid tumors received Lipotecan. The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts (11 dose levels). MTD was reached at 50 mg/m2, following the emergence of two DLTs at 60 mg/m2: one grade 3 febrile neutropenia and one toxicity that precluded treatment within the 14 days specified by the protocol. Other DLTs occurred in other dose levels include hyponatremia (grade 3 and 4; 40 mg/m2) and thrombocytopenia (grade 4; 40 mg/m2). To date, all the subjects except one have completed the study. Lipotecan given at this dosing schedule was well-tolerated and no cumulative toxicity was observed. Non-hematological toxicity was generally mild, including fatigue (41%), nausea (37%), diarrhea (28%), vomiting (14%) and constipation (14%). Anemia was the most frequently reported hematological toxicity (67.0%). Neutropenia (30%), thrombocytopenia (28%), and leukopenia (26%) were also reported. Grade 3 or grade 4 hematological toxicity included neutropenia (28%), anemia (22%), leucopenia (17%), and thrombocytopenia (13%). Other G3/4 non-hematological side effects included hyponatremia (11%), abdominal pain (7%), fatigue (6%), and hypokalaemia (6%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 5 cycles (range of 2–18 cycles), and experienced stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 9 patients (26%), including renal (chromophobe and clear cell types), docetaxel refractory prostate, salivary gland, sorafenib refractory hepatic, and vaginal cancers. One minor response occurred in a heavily pretreated 70-year-old male with stage II B thymoma cancer metastatic to lung, liver and lymph nodes who was treated for 18 courses and remains on the study. PET-CT scan revealed reduction in his tumor size by 27% at the end of cycle 16. His disease had progressed through prior treatment with cyclophosphamide, cisplatin and doxorubicin. Pharmacokinetics of TLC388 were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R-TLC388 and 996 (1333) L/m2 for S,S-TLC388, and 7420 (8151) L/h-m2 for S,R-TLC388 and 4949 (5678) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.76 (1.15) hours for S,R-TLC388 and 0.75 (1.13) hours for S,S-TLC388. Conclusions: Lipotecan administered doses up to 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support Phase 2 disease-specific investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A89.