bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/IB study of paclitaxel in combination with VS-6063, a focal adhesion kinase (FAK) inhibitor, in patients (pts) with advanced ovarian cancer.
Authors: Jones Suzanne Fields , Moore Kathleen N. , Patel Manish R. , Infante Jeffrey R. , Poli Anne , Keegan Mitchell , Padval Mahesh , Burris Howard A.
Published: March 2020

TPS2620

Background: Blockade of FAK reduces tumor growth and metastasis through inhibition of tumor cell survival, proliferation and invasion as well as tumor angiogenesis. Furthermore, treatment with FAK inhibitors reduces the proportion of cancer stem cells (CSCs) in a dose dependent manner while paclitaxel treatment enriches for CSCs. (Kolev VN San Antonio Breast Cancer Symposia 2012 abstr P6-11-09). The ability of CSCs to survive exposure to chemotherapy but remain susceptible to novel drugs suggests a unique therapeutic approach whereby standard of care chemotherapy may be sequentially combined with targeted drugs to kill surviving CSCs and thus prevent tumor recurrence and metastasis. VS-6063 (previously PF-04554878) is a potent oral inhibitor of FAK and proline-rich tyrosine-kinase -2. The phase I first-in-man trial explored doses ranging from 12.5 -750 mg twice daily (BID). (Jones SF J Clin Oncol 2011 29:1 suppl; abstr 3002) Dose-limiting toxicities consisted of headache, fatigue, and unconjugated hyperbilirubinemia at various dose levels. A maximum tolerated dose was not defined, but doses > 100 mg BID consistently yielded concentrations above the preclinically predicted minimal efficacious concentration. Seven pts demonstrated stable disease lasting approximately 6 months or greater, including 3 heavily-pretreated ovarian cancer pts (2 platinum resistant). Methods: Pts with advanced or refractory ovarian cancer (≤ 4 prior regimens) will be enrolled. In the phase I portion, VS-6063 is administered continuously at a starting dose of 200mg BID with paclitaxel 80 mg/m2 on days 1, 8, and 15 every 28 days, and will be escalated to 400mg BID if tolerated. Pharmacokinetics will be analyzed. An additional 15 pts with biopsiable disease will be enrolled at the recommended dose. A 10-day run-in with VS-6063 alone will be used to obtain paired tumor biopsies in order to examine the effects on pFAK expression, CSCs, and other biomarkers. Patients will continue treatment until disease progression. Clinical trial information: NCT01778803.
A phase I dose-escalation study of TKM-080301, a RNAi therapeutic directed against polo-like kinase 1 (PLK1), in patients with advanced solid tumors: Expansion cohort evaluation of biopsy samples for evidence of pharmacodynamic effects of PLK1 inhibition.
Authors: Northfelt Donald W. , Hamburg Solomon I. , Borad Mitesh J. , Seetharam Mahesh , Curtis Kelly Kevelin , Lee Peter , Crowell Brynne , Vocila Linda , Fredlund Paul , Gilbert Mark J. , Mast Catherine Patricia , Semple Sean C. , Judge Adam D. , MacLachlan Ian , Ramanathan Ramesh K.
Published: March 2020

TPS2621

Background: TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1, a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis. Anti-tumor activity, RNA interference and pharmacodynamic effects of PLK1 inhibition have been conclusively demonstrated in preclinical models. Demonstration of pharmacodynamic effects of PLK1 inhibition in patient biopsy samples is an exploratory objective of this first-in-human study. Methods: TKME080301 is being evaluated in an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKME080301 as a 30-minute intravenous infusion on Days 1, 8 and 15 of a 28-day cycle. Treatment can continue until disease progression, based on overall clinical benefit. Tumor response is determined according to RECIST criteria. Primary study objectives include determination of safety, maximum tolerated dose and dose limiting toxicities. Secondary objectives include characterization of pharmacokinetics and the preliminary assessment of anti-tumor activity. Five cohorts have been enrolled and a tentative Phase 2 dose has been identified. An expansion cohort of 10 patients began enrolling in February, 2013. The focus of the expansion cohort will be to collect additional safety and pharmacokinetic data at the tentative Phase 2 dose, as well as pharmacodynamic data from mandatory biopsy samples. Pre- and post-dose biopsy samples will be evaluated for potential evidence of PLK1 inhibition using 5’ RACE (rapid amplification of cDNA ends) polymerase chain reaction (to identify the predicted PLK1 mRNA cleavage product), histology (to assess for the presence of aberrant mitotic figures) and immunohistochemistry. An update on enrollment and pharmacodynamic evaluations will be presented. Clinical trial information: NCT01262235.
Phase I dose escalation study of recombinant interleukin-21 (rIL-21; BMS-982470) in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced or metastatic solid tumors.
Authors: Chow Laura Quan Man , Gordon Michael S. , Logan Theodore F. , Antonia Scott J. , Bhatia Shailender , Thompson John A. , Brahmer Julie R. , Solberg Gretchen , Bittner Rachel , Fontana David , Grosso Joseph , Cohen Lewis J. , Ahlers Christoph Matthias , Wigginton Jon M. , Drake Charles G.
Published: March 2020

TPS3112

Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2. Nivolumab, a PD-1 receptor blocking antibody, has shown durable antitumor activity in pts with various solid tumors in two phase I clinical trials. The cytokine rIL-21 has also shown antitumor activity in selected solid tumors. We hypothesized that combining rIL-21-induced stimulation of T-cell and NK-cell function in conjunction with T-cell checkpoint blockade using nivolumab could enhance biologic activity resulting in improved clinical outcomes, as compared with either agent alone. We describe a novel phase I study investigating the biologic activity and clinical outcomes of the combination in pts with advanced solid tumors. Methods: This ongoing study (N=160) includes a dose escalation phase (Part 1) using a 3 + 3 design followed by an expansion phase (Part 2). In Part 1 (N=60), successive pt cohorts with advanced solid tumors are being treated with escalating doses of rIL-21 (10, 30, 50, 75, or 100 µg/kg IV) on two distinct schedules (Arms A and B) in combination with fixed-dose nivolumab (3 mg/kg q 2 weeks) in 6 week cycles. Arm A administers rIL-21 on a weekly schedule, given on day 1 in weeks 1–4 of the 6 week cycle. Arm B administers rIL-21 at 3x per week during weeks 1 and 3 of the 6 week cycle. In Part 2, pts with renal cell carcinoma (N=50) or non-small cell lung carcinoma (N=50) will each be randomized to treatment at the maximum tolerated dose (MTD) or maximum administered dose, if no MTD is determined, for Arm A or Arm B. Therapy for pts who are stable or responding in Parts 1 and 2 may be continued for up to 2 years or until treatment discontinuation criteria are met. Primary objectives are to evaluate the safety of rIL-21 + nivolumab, and to define the MTD of the 2 schedules. Secondary and exploratory objectives include a preliminary assessment of the antitumor activity, pharmacokinetics, immunoregulatory activity (peripheral blood, tumor) and immunogenicity of this combination. Clinical trial information: NCT01629758.
An exploratory study of the biologic effects of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) treatment in patients (pts) with advanced (unresectable or metastatic) melanoma (MEL).
Authors: Sosman Jeffrey Alan , Martin-Algarra Salvador , Wolchok Jedd D. , Sharfman William Howard , Bhatia Shailender , Hodi F. Stephen , Hwu Wen-Jen , Gajewski Thomas , Slingluff Craig L. , Kaufman Howard , Gupta Manish , McGirr Analia , Horak Christine E. , Ahlers Christoph Matthias , Wigginton Jon M. , Urba Walter John
Published: March 2020

TPS3114

Background: Programmed death-1 (PD-1) is an immune checkpoint receptor expressed by T cells that negatively regulates T-cell activity and may promote tumor immune evasion by binding to its ligands (PD-L1/L2) on tumor cells and/or antigen-presenting cells. Nivolumab is a fully human IgG4 PD-1 receptor blocking monoclonal antibody that has shown antitumor activity in phase I trials in pts with solid tumors, including advanced MEL. Objective responses were observed in pts whose diseases were refractory to multiple prior therapies. We describe an ongoing exploratory, open-label, multicenter translational study designed to further investigate the immunoregulatory activity and mechanisms of action of nivolumab in advanced MEL, including ipilimumab (anti-CTLA-4) naïve and refractory pts. Methods: This study is enrolling advanced MEL pts who are either ipilimumab naive (n=40) or refractory (n=40). Eligible pts must not have received >3 prior therapies for metastatic disease and must consent to pre-and on-treatment biopsy (after 2 doses of nivolumab [Day 28]) of an accessible tumor. Nivolumab will be administered IV every 2 weeks (wks) at a dose of 3mg/kg and may continue for up to 13 cycles (104 wks) until clinically significant progression or treatment discontinuation criteria are met. Tumor responses will be assessed every 8 wks using RECIST 1.1 criteria. The primary objective is to investigate the pharmacodynamic (immunoregulatory) activity of nivolumab in the peripheral blood (PB), tumor, and tumor microenvironment. Secondary objectives include evaluation of safety and tolerability, preliminary antitumor activity, and immunogenicity of nivolumab, as well as the association between tumor PD-L1 expression and clinical efficacy. Exploratory objectives include characterization of pharmacokinetics (PK) and evaluation of the potential association between selected PB and/or tumor biomarkers and PK, clinical safety, and efficacy (eg, progression-free and overall survival). Clinical trial information: NCT01621490.
A pilot study of preoperative, single-dose ipilimumab (Ipi) and/or cryoablation (Cryo) in women (pts) with early stage/resectable breast cancer (ESBC).
Authors: Diab Adi , Solomon Stephen Barnett , Sacchini Virgilio , Comstock Christopher , Maybody Majid , Durack Jeremy C. , Sung Janice S. , Blum Brian , Neville Deirdre A. , Kotin Alan , Yuan Jianda , Patil Sujata , Morris Elizabeth Ann , Brogi Edi , Morrow Monica , Wolchok Jedd D. , Hudis Clifford , Allison James , Norton Larry , McArthur Heather L.
Published: March 2020

TPS3120

Background: Intratumoral cryo combined with immune modulation generates a potent systemic anti-tumor immune response that might improve recurrence-free survival in ESBC. Cryo-mediated tumor destruction results in necrosis and immunogenic cell death which exposes dendritic cells (DC) to sufficient quantities of tumor antigens and inflammatory cytokines to induce their maturation and activation and elicit tumor specific T cell responses. To further amplify this immune response we use ipi, a human monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 (CTLA4). In preclinical murine models, the combination of cryo with CTLA4 blockade successfully mediates rejection of metastatic prostate cancer lesions and prevents growth of secondary tumors. We therefore hypothesize that this strategy could confer long-term immunity for pts with ESBC. In this study, we evaluate the safety of pre-op cryo and/or immune modulation with single dose ipi (at 10 mg/kg) in pts with ESBC. Methods: Pts are sequentially assigned to receive pre-op: cryo alone (Group A), ipi alone (B), or ipi with cryo (C). Cryo is administered 7-10 d prior to surgery. Ipi is administered 8-15 d prior to surgery (1-5 d prior to cryo). If at least 5/6 pts in each group proceed with surgery without delay, the regimen will be considered safe/tolerable.Primary aim: To evaluate the safety of pre-op cryo and/or ipi (10mg/kg) in pts with ESBC.Seconday aims: To characterize pre- and post-intervention radiographic and immunological (peripheral blood and tumor tissue) correlates. Eligibility: Pts ≥18y of age with operable ≥1.5 cm invasive ESBC, no history of autoimmune disease and planned mastectomy. Study status: As of January 25, 2013 7/7 pts were enrolled to Group A (expanded after 1 pt had suspected incomplete cryo) and 5/6 pts were enrolled to Group B. Enrollment to Group C will open when the pts in Group B meet the safety endpoint 30 d (+/-10 d) after surgery. Toxicity evaluation continues for 12 wks after ipi administration for Groups B and C. Clinical trial information: NCT01502592.
A phase II study of live-attenuated Listeria monocytogenes immunotherapy (ADXS11-001) in the treatment of persistent or recurrent cancer of the cervix (GOG-0265).
Authors: Huh Warner King , Brady William E. , Moore Kathleen N. , Lankes Heather A. , Monk Bradley J. , Aghajanian Carol , Dizon Don S. , Fracasso Paula M.
Published: March 2020

TPS3121

Background: This is a GOG/NCI-sponsored phase II study (NCT01266460, GOG 0265) of ADXS11-001 in patients with persistent or recurrent cancer of the cervix. ADXS11-001 is a live attenuated Listeria monocytogenes (Lm) immunotherapy bioengineered to secret a HPV-E7 fusion protein targeting HPV-E7 transformed cells. A previous phase I dose escalation study determined the safety of ADXS11-001 in patients with late stage cervical cancer (Maciag PA. Vaccine. 2009 Jun 18;27(30):3975-83). The primary objectives of this study are to evaluate the tolerability and safety of ADXS11-001, and to assess the activity of ADXS11-001 in patients with persistent or recurrent cancer of the cervix. Secondary objectives are progression-free survival, overall survival and objective tumor response. Methods: Patient eligibility criteria: Females age ≥ 18 years with persistent or recurrent squamous or non-squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix with documented disease progression (disease not amenable to curative therapy). Patients must have measurable disease as defined by RECIST 1.1; at least one “target lesion” as defined by RECIST 1.1; have had one prior systemic chemotherapeutic regimen for management of their disease; have adequate organ function and must be free of active infection and not on antibiotics. This protocol is a 2-stage design with 12-month survival as the primary endpoint and with a planned sample size of up to 67 patients. Patients will receive ADXS11-001 at a dose of 1x109 CFU on Day 1 and repeat every 28 days for 3 total doses in the absence of disease progression or unacceptable toxicity, with each dose followed at 72 hours by a 7 day course of ampicillin, 500 mg QID. Tumor tissue and serum samples may be collected periodically for translational research. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years. As of January 31, 2013, enrollment has been completed in the 6-patient safety lead-in portion of the study. Clinical trial information: NCT01266460.
ICE CREAM: Irinotecan cetuximab evaluation and the cetuximab response evaluation among patients with G13D mutation.
Authors: Segelov Eva , Wilson Kate , Gebski Val , Waring Paul Michael , Tabernero Josep , Wasan Harpreet , Ciardiello Fortunato , Desai Jayesh , Underhill Craig , Karapetis Christos Stelios , Khasraw Mustafa , Nott Louise M. , Joubert Warren Lance , Pavlakis Nick , Van Hazel Guy , Chantrill Lorraine A. , Price Timothy Jay , Jefford Michael , Haydon Andrew Mark , Shapiro Jeremy David
Published: March 2020

TPS3649

Background: Patients with metastatic colorectal cancer (mCRC) whose disease has progressed despite oxaliplatin and irinotecan containing regimens may benefit from the use of EGFR-inhibiting monoclonal antibodies if the tumor contains no mutations in the KRASgene (i.e. WT). However, it is unknown whether antibodies used in this setting, such as cetuximab, are more efficacious alone or in combination with irinotecan, as suggested by the BOND study which did not select for KRASstatus. This international trial will also evaluate prospectively the activity of cetuximab in the subgroup of patients with mCRC with a specific KRASmutation in codon G13D. In selected retrospective analyses, tumors bearing this mutation appear to derive similar response from cetuximab as WT. Trials involving small molecular subsets (in this case approx. 5% of patients with mCRC, or 18% of patients with KRAS mutations) will provide framework for future collaborations. Methods: This randomised phase II study of cetuximab +/- irinotecan will recruit patients with metastatic colorectal cancer (mCRC) with either KRAS WT (n=50) or G13D mutation (n=50) over 2 years from sites in Australia (12), and three international sites (G13D mutations only): Spain (1), England (1), and Italy (1). The trial will prospectively select the KRAS WT arm for the “quadruple WT" genotype (no mutations also in BRAF, NRAS, PIK3CA exon20). Primary objective is 6 month progression free survival. Secondary objectives are response rate, overall survival, quality of life, and translational research including markers that may predict response such as amphiregulin and epiregulin determined by immunohistochemistry. Eligibility: Patients with histologically confirmed CRC with either “quadruple WT" genotype or KRAS G13D mutation; unresectable metastatic disease; measurable or evaluable disease; ECOG 0-2; life expectancy at least 12 weeks, and disease progression, or intolerance of thymidylate synthase inhibitor and irinotecan and oxaliplatin containing regimens. Status: Opened to accrual November 2012, at 31 Jan 2013 3/100 patients have been enrolled, all with G13D mutations. Clinical trial information: ACTRN12612000901808.
Phase II clinical trial of biomarker-directed therapy for localized pancreatic cancer.
Authors: Tsai Susan , Ritch Paul S. , Erickson Beth , Kelly Tracy R. , Quebbeman Edward , Evans Douglas B. , Mackinnon Alexander C. , Christians Kathleen K.
Published: March 2020

TPS4147

Background: Several candidate biomarkers exist for the common chemotherapeutic agents used to treat pancreatic cancer (PC) (Table). The predictive value of these markers in the treatment of PC has not been established. This is the first prospective clinical trial utilizing biomarker-directed therapy for localized pancreatic cancer. Methods: Patients with localized pancreatic cancer undergo endoscopic ultrasound-guided fine needle aspiration (FNA) for confirmation of diagnosis and immunohistochemical profiling . Six biomarkers (STREET profile) were selected based on their relevance to accepted pancreatic chemotherapy regimens (table). The treatment algorithm selected for each individual patient is based on the clinical stage of resectability (resectable/borderline resectable) and the STREET profile results. Neoadjuvant therapy is followed by restaging (CT and serum Ca19-9) and in the absence of disease progression, patients undergo surgery. Post-surgical (adjuvant) therapy is determined by the STREET profile of the resected specimen. The primary endpoint is an increase in the rate of surgical resection 20% compared with historical controls treated with best available neoadjuvant therapy which was not biomarker-directed. Secondary endpoints include assessment of overall and progression-free survival, comparative STREET profiling of pre- and post-treatment specimens, and changes in radiographic response. Eligbility Criteria: Patients with resectable or borderline resectable pancreatic cancer undergo endoscopic ultrasound-guided fine needle aspiration (FNA) for confirmation of diagnosis and immunohistochemical profiling. Enrollment: 26 of planned 100 patients have been enrolled. Clinical trial information: NCT01726582. [Table: see text]
Next study (JCOG1109): A three-arm randomized phase III study comparing preoperative CDDP+5-FU(CF) versus docetaxel+CF versus CF-radiation followed by esophagectomy with D2-3 lymphadenectomy for locally advanced esophageal squamous cell cancer.
Authors: Kato Ken , Igaki Hiroyasu , Ito Yoshinori , Mizusawa Junki , Tsubosa Yasuhiro , Nakagawa Satoru , Daiko Hiroyuki , Hironaka Shuichi , Udagawa Harushi , Hayashi Kazuhiko , Nozaki Isao , Yano Masahiko , Kimura Yusuke , Matsushita Hisayuki , Abe Tetsuya , Okabe Hiroshi , Nakamura Kenichi , Fukuda Haruhiko , Hirao Motohiro , Kitagawa Yuko
Published: March 2020

TPS4152

Background: Based on the results of JCOG9907, preoperative cisplatin plus 5- fluorouracil (CF) followed by esophagectomy with D2-3 lymphadenectomy has become standard care for advanced esophageal cancer in Japan, while the standard therapy in Western countries is preoperative chemoradiotherapy. A new clinical question has thus arisen of whether CF plus docetaxel (DCF) or CF plus radiotherapy (CF-RT) shows a survival benefit over preoperative CF even with intensive surgery. Methods: Eligibility criteria include histologically proven thoracic esophageal squamous cell carcinoma with stage IB/II/III (excluding T4) based on the 7th UICC-TNM, age 20 to 75, and performance status 0 to 1. No prior chemotherapy, radiotherapy, or hormonal therapy is allowed. Adequate organ function and written informed consent are required. Patients are randomized into any of the following three arms by a minimization method balancing the arms in terms of institution and tumor depth (T1–2 versus T3). Patients in arm A (CF) receive two courses of cisplatin at 80 mg/m2 on day 1 and fluorouracil at 800 mg/m2 on days 1–5, repeated every three weeks. Patients in arm B (DCF) receive three courses of docetaxel at 70 mg/m2, cisplatin at 70 mg/m2 on day 1, and fluorouracil at 750 mg/m2 on days 1–5, repeated every three weeks. Patients in arm C (CF-RT) receive two courses of cisplatin at 75 mg/m2 on day 1 and fluorouracil at 1000 mg/m2 on days 1–4, repeated every four weeks concurrently with radiotherapy at 41.4Gy/23fr. This trial is designed to demonstrate the superiority of preoperative DCF and/or CF-RT over CF in terms of overall survival. We assumed three-year survival with preoperative CF to be 63% and expected a 10% increase in three-year survival for DCF and CF-RT. The sample size was calculated as a total of 501 patients (167 patients per arm) with a study-wise one-sided alpha level of 5%, power of 70% for each pair comparison, an accrual period of 6.25 years, and a follow-up period of three years. This trial was registered as UMIN000009482 and started in December 2012. Clinical trial information: UMIN000009482.
POWER: An open-label, randomized phase III trial of cisplatin and 5-FU with or without panitumumab (P) for patients (pts) with nonresectable, advanced, or metastatic esophageal squamous cell cancer (ESCC).
Authors: Moehler Markus Hermann , Ringshausen Ingo , Hofheinz Ralf , Al-Batran Salah-Eddin , Mueller Lothar , Thuss-Patience Peter C. , Borchert Kersten , Karatas Aysun , Keller Ralph , Klein Anja , Kranich Anne , Brenner Baruch , Lorenzen Sylvie , Lutz Manfred P. , Greil Richard , Tabernero Josep , Van Cutsem Eric , Graeven Ullrich
Published: March 2020

TPS4158

Background: More than 50% of pts with esophageal cancer have locally advanced or metastatic disease at the time of initial diagnosis. For this group chemotherapy is increasingly used intending local and distant tumor control, improvement of quality of life (QoL) and longer survival. Previous data suggested that EGFR-targeting antibodies may be safely combined with cisplatin and 5-FU, and in addition may increase the efficacy of the standard cisplatin/5-FU regimen [Lorenzen et al, Ann Oncol2009; 20(10): 1667-1673]. Methods: In this open-label, randomized (1:1), multicenter, multinational phase III trial pts with nonresectable, advanced or metastatic ESCC, not eligible for definitive radiochemotherapy, are included. Pts have measurable or non-measurable disease according to RECIST 1.1 and an ECOG PS 0-1. Previous chemotherapy of ESCC in the metastatic setting, concurrent radiotherapy involving target lesions and previous exposure to EGFR-targeted therapy are excluded. Pts receive either CTX (cisplatin 100 mg/m² on day 1 and 5-FU 1000 mg/m²/d on day 1-4) or CTX + P (9 mg/kg on day 1). Cycles are repeated every 3 weeks until progression of disease. Tumor assessment is performed every 9 weeks. The primary objective is to demonstrate superiority of CTX + P over CTX alone in terms of overall survival. Secondary endpoints are progression-free survival, 1-year survival, response rate, safety and tolerability, and QoL. A translational analysis in tumor tissue and serum samples is included. 300 pts are planned to be enrolled for a power of 90% to reject the null hypothesis in which the median overall survival in the control and experimental groups are 6 and 9 months, respectively. 18 pts have been enrolled to date. A Data Monitoring Board will review safety data after 40, 100 and 200 pts. The clinical trial registry number is NCT1627379. Clinical trial information: NCT01627379.
Phase IIb randomized trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), a targeted oncolytic vaccinia virus, plus best supportive care (BSC) versus BSC alone in patients with advanced hepatocellular carcinoma who have failed sorafenib treatment (TRAVERSE).
Authors: Heo Jeong , Chao Yee , Jonker Derek J. , Baron Ari David , Habersetzer Francois , Burke James , Breitbach Caroline , Patt Richard H. , Lencioni Riccardo , Homerin Michel , Limacher Jean-Marc , Lusky Monika , Hickman Theresa , Longpre Lara , Kirn David H.
Published: March 2020

TPS4161^

Background: Pexa-Vec is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony stimulating factor (GM-CSF). Direct oncolysis plus GM-CSF expression stimulates tumor vascular disruption and anti-tumor immunity (Nature Rev Cancer, 2009). Pexa-Vec was well-tolerated in Phase 1 trials and was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol, 2008 and Nature, 2011). A randomized high vs low dose Phase 2 trial in 30 patients with advanced HCC, demonstrated prolonged survival in the high-dose Pexa-Vec arm (median survival 14.1 mo vs. 6.7 mo; Hazard Ratio 0.39, p=0.02) (AASLD Annual Meeting, 2011, LB1). Methods: TRAVERSE is a Phase 2b randomized, open-label, multi-center trial in patients with advanced HCC who have failed sorafenib treatment. Approximately 120 patients will be randomized 2:1 to Pexa-Vec plus BSC versus BSC, respectively. Randomization will be stratified by region (Asian vs. non-Asian); sorafenib intolerant vs refractory; and presence vs absence of extra-hepatic disease. The primary objective is to determine overall survival. Main inclusion criteria are advanced HCC having failed sorafenib (intolerance or radiographic progression during or < 3 months following last sorafenib), Child-Pugh A-B7 (no ascites), acceptable hematologic function. Assuming a median overall survival of 4.0 months with BSC and a target hazard ratio of 0.57 (corresponding to an experimental arm median survival of 7.0 months), 73 events (deaths) will provide 70% power at 1-sided alpha = 0.05 to detect a difference in overall survival between the treatment groups using a stratified logrank test. Patients randomized to Pexa-Vec will receive a dose of 109 plaque forming units (pfu) IV on Day 1 followed by five IT treatments between Day 8 and Week 18. Enrollment has begun on this study with clinical trial registry number of NCT01387555. Clinical trial information: NCT01387555.
The Borealis-2 clinical trial: A randomized phase II study of OGX-427 plus docetaxel versus docetaxel alone in relapsed/refractory metastatic urothelial cancer.
Authors: Rosenberg Jonathan E. , Hahn Noah M. , Regan Meredith M. , Jacobs Cindy , Stewart Patricia S. , Choueiri Toni K.
Published: March 2020

TPS4588^

Background: Heat shock protein 27 (Hsp27) is over-expressed in many cancers including bladder, lung, prostate, and breast. Increased Hsp27 has been associated with inhibition of chemotherapy-induced apoptosis, increased tumor cytoprotection, and development of treatment resistance. OGX-427 is an antisense oligonucleotide designed to bind Hsp27 mRNA, inhibiting production of the Hsp27 protein. Inhibition of Hsp27 has been shown to increase apoptosis, inhibit tumor growth, and sensitize tumor cells to chemotherapy in a variety of malignancies, including urothelial cancer. Results of preclinical and phase 1 studies suggest that addition of OGX-427 to chemotherapy is well tolerated and may improve treatment efficacy. BOREALIS-2 is a randomized, multicenter, phase 2 study of OGX-427 in combination with docetaxel (DOC) vs. DOC alone in locally advanced/metastatic bladder cancer patients who received at least one line of prior platinum-based therapy. The primary objective is to evaluate overall survival. Secondary objectives include comparisons of safety and tolerability, disease response, and serum levels of Hsp27 and other pathway-related proteins. Associations between clinical outcomes, levels of Hsp27 and other proteins, and circulating tumor cells will be evaluated. Methods: Patients (N=200) are randomized in a 1:1 ratio following stratification (time from prior systemic chemotherapy; Bellmunt criteria). Up to 2 prior systemic therapies are allowed. Treatment-arm patients receive three loading doses of OGX-427 (600 mg) followed by up to ten 21-day treatment cycles (OGX-427 1000 mg on Days 1, 8, and 15 and DOC 75 mg/M2 IV on Day 1). Control-arm patients receive DOC 75 mg/M2 IV on Day 1 of each cycle. Treatment may continue until disease progression, unacceptable toxicity, completion of 10 cycles, or patient withdrawal. Patients who discontinue DOC due to toxicity after ≥2 cycles and do not have disease progression may receive maintenance therapy with OGX-427. One interim futility analysis will be performed. The trial will not be stopped early based on efficacy. Clinical trial information: NCT01780545.
ASPEN: A randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma.
Authors: Armstrong Andrew J. , Halabi Susan , Eisen Tim , Stadler Walter Michael , Jones Robert R , Vaishampayan Ulka N. , Garcia Jorge A. , Hawkins Robert E. , Kollmannsberger Christian K. , Lusk Christine , Broderick Samuel , George Daniel J.
Published: March 2020

TPS4590

Background: Currently no level 1 evidence exists to guide therapeutic decisions in patients with metastatic non-clear cell renal cell carcinoma. Case series and retrospective analyses suggest that strategies targeting either the VEGF or mTOR/TORC1 pathways have clinical activity in papillary, chromophobe, or poorly differentiated histologic subtypes. Methods: We are conducting an international, randomized phase 2 trial of patients with metastatic non-clear cell RCC; either papillary, chromophobe, or undifferentiated histology; any Motzer risk group; and who have had no prior systemic therapy. All patients contribute tissue to an international biorepository for correlative genomic, genetic, and protein biomarker studies, along with companion longitudinal plasma and urine angiome studies. Patients are randomized to either everolimus or sunitinib (1:1) at FDA approved dosing until progression. The primary endpoint is progression free survival. Trial status: Seventy-three out of a planned 108 subjects have been enrolled at the time of abstract submission: median age 64, 59 white, 10 black, 4 unknown race, and includes 42 papillary and 31 chromophobe/undifferentiated histologies, 49 men and 22 women. Accrual is anticipated to be completed by December 2013. Accrual distribution by country is currently 43 (USA), 27 (UK), and 3 (Canada). The first DSMB meeting was conducted after 40 subjects completed at least 6 months of therapy and concluded that there were no unexpected safety signals and that the study should proceed. Tissue (primary, some metastatic, urine, plasma, whole blood) has been collected on all patients to date through the Duke Center for Human Genetics Biorepository. Clinical trial information: NCT01108445.
A phase II trial of the aurora kinase A inhibitor MLN8237 in patients with metastatic castrate resistant and neuroendocrine prostate cancer.
Authors: Beltran Himisha , Rubin Mark A. , Mosquera Juan Miguel , Christos Paul J. , Calukovic Olivera , Karpenko Irene , Pinski Jacek K. , Danila Daniel Costin , Nanus David M. , Tagawa Scott T. ,   The Prostate Cancer Clinical Trials Consortium
Published: March 2020

TPS5096

Background: NEPC can rarely arise de novo but more commonly arises as a mechanism of resistance in the setting of advanced prostate cancer. Transformation to NEPC is likely promoted by potent hormonal therapies and is currently under-recognized. There is no effective therapy for NEPC and most patients (pts) survive less than one year. We have found that Aurora kinase A (AURKA) and N-myc (MYCN) are significantly overexpressed and amplified in NEPC compared to prostate adenocarcinoma, and cooperate to induce neuroendocrine (NE) differentiation in prostate cancer (Beltran et al, Cancer Disc 2011). In preclinical models, aurora kinase inhibition results in dramatic and preferential anti-tumor activity in NEPC. Methods: In this single arm, multi-institutional Phase II trial, pts with metastatic prostate cancer need to meet at least one NEPC entry criterion: 1) histologic diagnosis of small cell or NEPC, 2) >50% immunohistochemical staining for NE markers, 3) development of liver metastases in absence of PSA progression, or 4) serum chromogranin >5x normal or neuron specific enolase >2x normal. Study will be open at 10 institutions including PCCTC sites. After a mandatory on-study research biopsy, pts will be treated with MLN8237, an orally administered Aurora kinase A inhibitor at 50 mg twice daily for 7 days repeated every 21 days. The primary endpoint is objective response rate (ORR). Secondary endpoints include overall survival, progression free survival, PSA response rate, circulating tumor cell response, and serum NE marker response to therapy. A number of correlative studies including AURKA, MYCN, AR, and exome and RNAseq are embedded in this trial in order to molecularly define this aggressive and poorly characterized disease. A Simon 2-stage design will be employed with up to 60 subjects providing 80% power to determine if the true ORR is >30% and 95% power if the true ORR is <15%, assuming a 5% level of significance. A subset of at least 20% meeting histologic entry criteria is embedded.
TAXYNERGY (NCT01718353): A randomized phase II trial examining an early switch from first-line docetaxel to cabazitaxel, or cabazitaxel to docetaxel, in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Antonarakis Emmanuel S. , Giannakakou Paraskevi , Kirby Brian J. , Nicacio Leonardo V. , Eisenberger Mario A. , Nanus David M. , Tagawa Scott T.
Published: March 2020

TPS5100

Background: Docetaxel is the standard 1st-line chemotherapy for mCRPC, while cabazitaxel prolongs survival after docetaxel progression. The activity of cabazitaxel in the 1st-line setting is unknown, while the molecular mechanisms of taxane sensitivity/resistance have been understudied. Clinically, a ≥30% PSA decline within 3 months predicts survival in docetaxel- and cabazitaxel-treated men. Molecularly, emerging evidence suggests that sensitivity/resistance to taxanes relates to the ability of microtubules to traffic AR into the nucleus. Circulating tumor cells (CTCs) represent a real-time biomarker to assess drug-target engagement (DTE) which may be predictive of clinical outcome, and novel enrichment techniques present opportunities for molecular testing. Methods: This is a multicenter phase 2 trial for chemo-naïve mCRPC. 100 men will be randomized (2:1) to 1st-line docetaxel or cabazitaxel. Following 4 cycles, if a ≥30% PSA decline is not achieved, men will switch to the alternative taxane; others will remain on the initial taxane until progression (PCWG2) or unacceptable toxicity. CTCs will be obtained at screening, baseline, after 1 and 4 cycles of chemotherapy, at crossover and at progression to interrogate mechanisms of taxane sensitivity/resistance. CTCs will be enriched via a prostate-specific microfluidic device, enumerated, and analyzed via multiplex confocal microscopy for microtubule bundling and AR localization. TaqMan PCR (and RNA sequencing) will be used to detect AR variants, as preliminary data show that variant ARv567 predicts taxane sensitivity while ARv7 predicts resistance. The primary clinical endpoint of the trial is achievement of a ≥50% PSA reduction during the treatment continuum. The primary molecular endpoint is analysis of DTE in CTCs, and correlation with PSA responses. The study will have 80% power to detect a 25% increase in PSA response rate with tight interclass kappa coefficients for primary biomarkers. Secondary endpoints include radiographic and PSA progression-free survival, objective response rates, overall survival, and safety. Clinical trial information: NCT01718353.
A randomized phase II clinical trial of enzalutamide in combination with the therapeutic cancer vaccine, PSA tricom, in metastatic, castration resistant prostate cancer.
Authors: Singh Nishith K. , Kim Joseph W. , Heery Christopher Ryan , Dahut William L. , Couvillon Anna , Rauckhorst Myrna , McMahon Sheri , Schlom Jeffrey , Fojo Tito , Arlen Philip M. , Gulley James L. , Madan Ravi Amrit
Published: March 2020

TPS5104

Background: There is a strong rationale to combine therapeutic cancer vaccines with hormonal abrogation in prostate cancer. Androgen abrogation augments T-cell trafficking to prostate, decreases immune tolerance, increases production of naïve thymic T-cells, enhances cytotoxic T-cell repertoire. PSA TRICOM (PROSTVAC) is a therapeutic, viral-vector based, off-the-shelf, cancer vaccine of PSA & 3 co-stimulatory molecules in phase III testing. This was developed at the NCI in collaboration with Bavarian Nordic Immunotherapeutics. It has demonstrated safety and survival benefit in a randomized phase 2 trial of metastatic castrate resistant prostate cancer (mCRPC). Enzalutamide is a modern androgen receptor inhibitor (ARI) approved for the treatment of mCRPC. Data from the clinical trials with these therapies suggest good individual tolerability without any overlapping toxicities. Analysis of previous trials suggests that vaccines may enhance clinical outcomes with ARI. These data form the scientific basis for a combination approach of a cancer vaccine with ARI to control tumor progression in mCRPC. Methods: A randomized, phase 2, open-label clinical trial at the NCI will enroll 72 chemo-naïve, minimally symptomatic patients with mCRPC. They will be randomized (1:1) to enzalutamide (160 mg daily) alone, or enzalutamide with PSA TRICOM for treatment until radiographic progression. PSA-TRICOM will be administered in a core phase (with day 1, 15 and 29 then 4 additional monthly boosts) followed by continued boosts every 3 months. The primary end point will evaluate time to progression in each arm with secondary endpoints including overall survival and systemic immune responses (lymphocyte subsets, regulatory T-cells, regulatory T-cell function, cytokines, naïve thymic emigrants). If a therapeutic cancer vaccine can enhance the clinical efficacy of a hormonal agent such as enzalutamide, it may help define a new role for vaccines as an adjuvant to standard therapies. We will also evaluate this combination in a second trial in non-metastatic, castration-sensitive patients where this combination may yield its greatest clinical impact.
Phase II study of de-intensification of radiation and chemotherapy for low-risk HPV-related oropharyngeal squamous cell carcinoma.
Authors: Chera Bhishamjit S. , Qaqish Bahjat F. , Weissler Mark C , Hayes David N. , Shores Carol G. , Monroe Alan , Anderson Roger F. , Wu Justin , Grilley-Olson Juneko E. , Weiss Jared , Hackman Trevor , Zanation Adam M , Mendenhall William M. , Amdur Robert J
Published: March 2020

TPS6097

Background: The prognosis is excellent for low-risk human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC). Current standard chemoradiotherapy (CRT) regimens cure most patients but cause significant acute (mucositis) and long-term toxicities (xerostomia and dysphagia). Toxicity is primarily determined by the dose of radiotherapy and the intensity of chemotherapy. The aim of this study is to evaluate the pathological complete response (pCR) rate of low-risk HPV-associated OPSCC after de-intensified CRT. Methods: The major inclusion criteria are: 1) T0-T3, N0-N2c, M0, 2) HPV or p16 positive, and 3) </= 10 pack-years smoking history. Patients receive 60 Gy of intensity modulated radiotherapy (IMRT) with concurrent weekly intravenous cisplatinum (30 mg/m2). CT scans are obtained 4 to 8 weeks after completion of CRT to assess response. All patients have a surgical resection of any clinically apparent residual primary tumor or biopsy of the primary site if there is no evidence of residual tumor and a selective neck dissection to encompass at least those nodal level(s) that were positive pre-treatment, within 4 to 14 weeks after CRT. Longitudinal assessments of quality of life (EORTC QLQ-C30 & H&N35, NDII), patient reported outcomes (PRO-CTCAE, EAT-10), and swallowing evaluations (modified barium swallow) are obtained prior to, during, and after CRT. The primary endpoint of this study is the rate of pCR after CRT. The null hypothesis is that the pCR rate for de-intensified CRT is at least 87%, the historical rate (based on the reported 3-year local regional control rate of 87% in the RTOG 0129). Power computations were performed for N=40, with a type I error of 14.2% if the true pCR rate is 0.87. The study will be done in 3 stages with 15+15+10 patients with interim analyses at 15 and 30 patients. The trial will be stopped if the pCR rate is </= 9/15 and 21/30. The null hypothesis will be accepted if the pCR rate is >/= 33/40. Clinical trial information: NCT01530997.
Ph III randomized studies of the oral pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer (BC) after aromatase inhibitor (AI; BELLE-2) or AI and mTOR inhibitor (BELLE-3) treatment.
Authors: Iwata Hiroji , Baselga José , Campone Mario , Arteaga Carlos L. , Cortes Javier , Jonat Walter , De Laurentiis Michelino , Ciruelos Eva , Janni Wolfgang , Bachelot Thomas , Lonning Per Eystein , Ma Cynthia , O'Regan Ruth , Di Tomaso Emmanuelle , Bharani-Dharan Bharani , Duval Vincent , Lau Helen , Germa Caroline , Urban Patrick , Di Leo Angelo
Published: March 2020

TPS650^

Background: The PI3K/Akt/mTOR pathway is commonly dysregulated in BC and linked to resistance to endocrine therapy, including AIs. Buparlisib is an oral inhibitor of class I PI3K isoforms (α, β, γ, δ), showing near complete tumor regression in an in vivo model of ER+ BC in combination with fulvestrant. Preliminary clinical activity in BC pts has been observed with buparlisib as a single agent and in combination with letrozole (Mayer et al. ASCO 2012). Methods: BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060) are 2 Ph III randomized, double-blind, placebo-controlled trials of oral buparlisib (100 mg/d) in combination with fulvestrant (500 mg) given on D1 and 15 of Cycle 1 and D1 of each 28-day cycle thereafter in postmenopausal women with HR+/HER2– locally advanced/metastatic BC. Additional eligibility criteria: disease progression on/after AI treatment for BELLE-2; prior treatment with AI and progression on mTOR inhibitor in combination with endocrine therapy (as last therapy prior to study entry) for BELLE-3; ≤1 previous line of chemotherapy for advanced disease; available archival tumor tissue for PI3K-related biomarker analysis. Randomization to either arm (1:1 for BELLE-2 and 2:1 for BELLE-3) is stratified according to PI3K pathway activation status (activated vs non-activated vs unknown) and visceral disease status (present vsabsent). Study treatment is given until disease progression or discontinuation for any reason. Co-primary endpoints in both trials: PFS in full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints: overall survival (OS) in full and PI3K pathway-activated populations; other secondary endpoints: PFS and OS in PI3K non-activated/unknown population, overall response rate, clinical benefit rate, safety (CTCAE 4.03), PK, and patient-reported outcomes (EORTC QLQ-C30 and QLQ-BR23). Estimated enrollment is 842 pts for BELLE-2 and 615 for BELLE-3. As of January 2013, 96 pts were randomized to BELLE-2 and 1 pt to BELLE-3. Recruitment is ongoing globally. Clinical trial information: NCT01610284 and NCT01633060.
UNIRAD: Multicenter, double-blind, phase III study of everolimus plus ongoing adjuvant therapy in ER+, HER2- breast cancer.
Authors: Bachelot Thomas Denis , Chabaud Sylvie , Martin Anne-Laure , Lemonnier J , Campone Mario , Andre Fabrice
Published: March 2020

TPS653

Background: Advances in adjuvant treatment and highly effective endocrine therapies have resulted in better prognosis and survival among patients (pts) with hormone-receptor-positive (HR+; ER+ and/or PgR+) breast cancer (BC). Despite this, high risk pts (>3N+ and/or T3/4) are likely to relapse during/after adjuvant therapy. In a pivotal phase 3 trial (BOLERO-2), everolimus (EVE, an oral mammalian target of rapamycin [mTOR] inhibitor), plus exemestane demonstrated clinical efficacy in postmenopausal pts with HR+, human epidermal growth factor receptor-2–negative (HER2–) advanced BC progressing on non-steroidal aromatase inhibitors. Administering EVE earlier, concurrent with adjuvant endocrine therapy (ET) may lower relapse rates, especially in pts with high and/or persistent nodal involvement after neoadjuvant therapy. This study (UNIRAD) will evaluate the safety and effectiveness of adding EVE to adjuvant ET in pts with ER+, HER2–non-metastatic BC, who are disease-free following 3y of adjuvant ET. Methods: This multi-center, double-blind, phase 3 study will randomize adult (≥18y) women with non-metastatic ER+, HER2- BC, any T, pN+(≥4 if initial therapy and ≥1 after neoadjuvant therapy), who are disease-free following 3y of adjuvant ET to EVE (10mg/d) plus ongoing ET versus placebo (PBO) plus ongoing ET for a total adjuvant therapy duration of 5y. Stratification is by country, ET (tamoxifen or aromatase inhibitors), previous adjuvant versus neoadjuvant therapy, and age (≤70 versus >70y). Follow-up will continue for 5y after treatment. The primary endpoint is disease-free survival (DFS) with EVE versus PBO. Secondary endpoints include overall survival (OS), event-free survival, distant metastasis-free survival, DFS and OS in selected subgroups, safety, incidence of secondary cancers, quality of life, and predictive value of mTOR activation markers on DFS. Results: Accrual to the UNIRAD study will begin in March 2013 (planned N = 1984). Updated information will be presented. Clinical trial information: 2012-003187-44.