bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized, open-label, phase II study of MDV3100 alone or in combination with leuprolide and dutasteride as neoadjuvant therapy to prostatectomy in intermediate and high-risk prostate cancer.
Authors: Montgomery Robert B. , Joshua Anthony , Hannah Alison L. , Peterson Amy C. , Lopez Christian , Gleave Martin Edwin , Taplin Mary-Ellen 
Published: March 2020

TPS4695 Background: MDV3100 is a potent androgen receptor (AR) signaling inhibitor (ARSI) that inhibits AR signaling via three mechanisms: inhibition of androgen binding to AR, inhibition of AR nuclear translocation, and inhibition of nuclear AR-DNA binding. In vivo, MDV3100 induces significant prostate cancer apoptosis, an effect not seen with anti-androgens. To date, the use of neoadjuvant androgen deprivation therapy has not led to an improvement in time to PSA progression (Soloway 2002; Aus 2002). While serum androgens may be suppressed using luteinizing hormone-releasing hormone agonists, intratumoral levels of androgens remain, driving continued AR signaling and prostate cancer survival. More effective inhibition of AR signaling may improve local and systemic disease control. Methods: MDV3100-07 will assess the effect of 6 mos of neoadjuvant AR blockade with AR inhibition alone (MDV3100) or in combination with maximal suppression of androgens (MDV3100 +leuprolide [L] + dutasteride [D]). Eligible patients will have treatment-naive localized prostate cancer and be candidates for radical prostatectomy. Patients must have either PSA > 10 ng/mL or Gleason score ≥ 7 (4 + 3) with ≥3 cores containing tumor. Patients with evidence of metastatic/nodal disease are excluded. All patients receive MDV3100 (160 mg/d PO); those randomized to MDV3100+L+D therapy also receive L (22.5mg IM q3m) and D (0.5 mg/day PO). Serum/tumor androgen levels will be serially assessed. Tissue from the diagnostic and prostatectomy specimens will be evaluated for androgen levels, AR signaling profiles, and selected markers of apoptosis and mitotic indices. The primary efficacy endpoint is pathological complete response (pCR) rate at time of radical prostatectomy. For each arm, the percent of patients who achieve a pCR will be compared to the percent pCR in patients treated with neoadjuvant leuprolide, estimated to be 5% in a mixed low-to-intermediate risk population. Target Accrual: 40 pts will be randomized 1:1 to MDV3100 or MDV3100+L+D therapy. Keywords:MDV3100, prostate cancer, androgen receptor, anti-androgen, Phase 2, neoadjuvant.
Prospect: A randomized, double-blind, phase III efficacy trial of PROSTVAC.
Authors: Bandman Olga , Delcayre Alain , Laus Reiner , Godfrey Wayne Russell , Kantoff Philip W. , Schlom Jeffrey , Gulley James L. 
Published: March 2020

TPS4699 Background: PROSTVAC is a candidate cancer vaccine comprised of two recombinant poxviral vectors: vaccinia (V) and fowlpox (F), each with insertions of four human genes: PSA and three costimulatory molecules (TRICOM) - LFA-3, B7.1 and ICAM-1. This off the shelf vaccine demonstrated a statistically significant overall survival (OS) benefit of 8.5 months while displaying a favorable side effect profile in patients (pts) with asymptomatic to minimally symptomatic prostate cancer (mCRPC) in a randomized, placebo –controlled 122-pt Phase II trial. Data from this Phase II trial supported the design of a Phase III protocol that will rigorously test the hypothesis of OS benefit, as well as expand our understanding of immune system response to cancer vaccines. Methods: 1200 pts will be randomized in a double-blind fashion to three arms: PROSTVAC, PROSTVAC+GM-CSF, or Placebo, at 1:1:1 ratio. A five-month treatment regimen will include a priming vaccination with PROSTVAC-V, and six booster vaccinations with PROSTVAC-F. Eligible pts will have asymptomatic or minimally symptomatic mCRPC, and progression despite androgen ablation and be chemotherapy-naïve. Pts with rapidly progressing disease will be excluded, as well as pts with risk factors for developing vaccinia-associated complications. The projected trial size is 400 pts per arm for at least 85% power. Primary endpoint is OS. The final analyses will be event-driven and will compare each active arm independently with placebo. Pts will be followed for 12 months after the projected number of events in each arm is realized. Secondary endpoint is proportion of event-free pts at 6 months compared to placebo. A number of exploratory endpoints are planned, including immune response to immunizing antigen, non-vaccine-contained prostate antigens, tumor-associated antigens; changes in baseline biomarker levels and CTC levels, as well as characterization of T cell subpopulations. The thorough immune monitoring program would provide basis for future studies on the effects of cancer immunotherapy on immune system and facilitate search for potential biomarkers of such effects. The trial is currently open for enrollment. ClinicalTrials.gov registry number: NCT00450463.
OPSALIN: A phase II placebo-controlled randomized study of ombrabulin in patients with platinum-sensitive recurrent ovarian cancer treated with carboplatin (Cb) and paclitaxel (P).
Authors: Pujade-Lauraine Eric , Vergote Ignace B. , Allard Aurore , Rey Augustin A. , Sessa Cristiana , Birrer Michael J. 
Published: March 2020

TPS5112 Background: Most women with ovarian cancer have disease recurrence after responding to their first treatment with platinum-based chemotherapy and are considered to have platinum-sensitive disease if the relapse-free period is more than 6 months. Although CbP is standard first-line chemotherapy for ovarian cancer, patients with platinum-sensitive recurrent disease are often retreated with CbP. Ombrabulin (AVE8062) is a vascular disrupting agent and analogue of combretastatin A4 that damages established tumor vasculature causing tumor necrosis and has synergistic antitumor activity with platinum agents in tumor models in vivo (Cancer Sci. 2003;94:200). A phase I study showed that treatment with vivo ombrabulin plus CbP is feasible in patients with advanced solid tumors (NCI-AACR-EORTC 2010;Abs 386). We initiated OPSALIN, a phase II randomized trial, to evaluate whether the addition of ombrabulin to CbP improves outcomes in patients with platinum-sensitive recurrent ovarian cancer (NCT01332656; EFC10260). Methods: Eligibility criteria include age of at least 18 years, ECOG PS 0–2, measurable carcinoma of the ovarian epithelium, fallopian tube, or primary peritoneum that is platinum sensitive, and completion of only one previous line of platinum-based chemotherapy. Exclusion criteria include uncontrolled brain metastases, peripheral neuropathy >grade 1, and a prior history of cardiovascular disease. Patients are being randomized (1:1) to receive either ombrabulin 35mg/m2 or placebo plus CbP every 3 weeks. Assigned treatment will continue until disease progression or death, unacceptable toxicity, or consent withdrawal. The primary endpoint is progression-free survival stratified by the time of first disease recurrence (6–12 months or >12 months). Secondary endpoints include safety, response rate, overall survival, pharmacokinetics, and analysis of predictive/prognostic biomarkers. Planned randomization is a total of 150 patients at approximately 45 sites globally. Sixty-five patients have been randomized as of January 2012.
LUX head and neck 2: A randomized, double-blind, placebo-controlled, phase III study of afatinib as adjuvant therapy after chemoradiation in primarily unresected, clinically high-risk, head and neck cancer patients.
Authors: Burtness Barbara , Bourhis Jean , Vermorken Jan Baptist , Dai Luyan , Lind Charlotte , Ehrnrooth Eva , Cohen Ezra E. W. 
Published: March 2020

TPS5599 Background: Locally advanced squamous cell cancer of the head and neck (SCCHN) is treated with curative intent, but recurrence and death are common. SCCHN frequently over-expresses EGFR (ErbB1). Co-expression of other HER family members such as HER2 (ErbB2) may contribute to resistance to EGFR inhibition, which is the only validated targeted therapy in SCCHN. Methods: The trial investigates if adjuvant afatanib, an irreversible ErbB family blocker, which has shown preclinical activity against all ErbB dimers including EGFR and HER2, reduces the risk of recurrence in high-risk patients who have no evidence of disease following platinum-based chemoradiation with or without neck dissection. Patients are eligible who have received definitive chemoradiation to a minimum of 66 Gy, with concurrent cisplatin (≥200 mg/m2) or carboplatin (≥AUC 9), for SCC of the oral cavity, oropharynx, or hypopharynx or larynx. Patients with base of tongue or tonsil cancer and ≤10 pack years of tobacco use, as well as those with nasopharynx, sinus or salivary gland cancer, are excluded. Adequate bone marrow, liver and kidney function is required. Prior therapy with investigational agents or EGFR inhibitors is not permitted. Randomization must take place within 16 weeks of the completion of chemoradiation with or without subsequent neck dissection. Patients are randomized 2:1 to afatinib 40 mg po qd or placebo, and treatment continues for 18 months in the absence of disease recurrence, second primary tumors, or intolerance to the study medication. Dose escalation to 50 mg qd is undertaken in patients with no side effects, and stepwise dose reduction to 30 or 20 mg po qd for diarrhea, skin toxicity or other adverse events is permitted. The primary endpoint is disease-free survival (DFS). The study is planned to accrue approximately 669 patients worldwide, with a 90% power to detect a hazard ratio of 0.72. Secondary endpoints are DFS at 2 years, overall survival, health-related quality of life, and safety.
Phase II trial of neoadjuvant chemotherapy for HPV-associated squamous cell carcinoma of the oropharynx followed by reduced-dose radiotherapy/chemoradiotherapy for responders or standard dose chemoradiotherapy for nonresponders.
Authors: Mehrotra Bhoomi , Schwartz David L. , Frank Douglas , Saltman Benjamin , Roy Rajasree , Lebowicz Yehuda Z. , Savona Steven R. 
Published: March 2020

TPS5601 Background: Recent studies have established an improved outcome for HPV associated oropharyngeal squamous cell cancers with 3 year OS rates approaching 90%. Given that current aggressive treatment modalities for HNC include IMRT and chemotherapy (CT), they adversely affect the long term QOL of these patients who are considered highly curable. The primary objective of our study is to confirm the activity (CR + PR at 3 months post completion RT/CRT) of induction TPF followed by dose reduced IMRT +/- concurrent CT, in nonsmokers with HPV associated, locally advanced SCC of H&N. Secondary objectives include: to define objective tumor RR to induction chemotherapy and to subsequent RT based treatment, per RECIST version 1.1 criteria, assess PFS and OS at 2 years,assess locoregional disease and distant disease control at 2 years, and monitoring of QOL instruments for HNC. Methods: Institutional IRB approval has been obtained for this study. Eligibility criteria include p16 expressing or ISH + SCC of the oropharynx, T1-3, N1-2, age > 17 years, adequate marrow and organ function and adequate PS. Exclusion criteria include T4 or N3 disease, significant smoking history > 10 pack year lifetime exposure. Patients would be treated with standard TPF induction for 3 cycles followed by risk assessment. Pts. achieving locoregional CR or CR/PR at primary site would receive dose reduced RT (66 Gy) +/- CT, while those with SD/PD would receive standard CRT with full dose XRT. Post therapy assessments include serial evaluation of functional quality-of-life, including M. D. Anderson Dysphagia Inventory (MDADI) and Oropharyngeal swallowing efficiency (OPSE) measures of swallowing function, treatment related symptoms, dietary status assessments and formal sialometric measurement of parotid function. Interim analysis would include RR assessment at 3 months post treatment in the first 12 patients who received dose reduced RT and compared with historical controls. Early stopping rules are built into the protocol. This study is currently open and patient accrual is ongoing.
A pilot study of raltegravir and cisplatin in head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Olson Garth T , Spafford Michael , Nuara Michael , Sampath Sagus , Lee Sang-Joon , Williamson Elizabeth A. , Wu Yuehan , Sklar Larry A. , Oprea Tudor I. , Hromas Robert 
Published: March 2020

TPS5602 Background: Metnase is a recently characterized DNA repair component present in anthropoid primates. Metnase, the fusion of a SET histone methylase domain and a Transposase nuclease (Tn) domain, enhances DNA double-stranded break (DSB) repair. The Tn domain trims free DNA ends for optimal end-joining, and is required to re-start stalled replication forks. The SET domain di-methylates H3K36 at the DSB, recruiting non-homologous end-joining repair components. Cisplatin (CDDP), the central chemotherapy in HNSCC, covalently binds DNA leading to intra- and interstrand crosslinks (ICL). In addition to blocking strand transcription and segregation, the ICL stalls DNA replication fork progression leading to collapse and DSB. The role of Metnase in DNA repair, including overcoming the stalled replication fork, makes it a potential therapeutic target. We hypothesize that Metnase inhibition may be a useful adjunct to CDDP. 3D modeling of the Metnase Tn domain identified significant homology with human immunodeficiency virus 1 (HIV-1) integrase. A virtual screen of the Chem Div library identified the HIV-1 integrase inhibitor, raltegravir, as a lead compound for inhibiting the Metnase Tn domain. We designed a pilot study in HNSCC to evaluate potentiation of CDDP DNA damage by raltegravir. Methods: The primary objective of this window-of-opportunity study is to analyze biomarkers of DNA damage, fork arrest, and apoptosis in serial tumor biopsies from patients (pts) with HNSCC undergoing CDDP, with and without raltegravir. Eligible pts: 1) have HNSCC with tumor site amenable to repeat, awake biopsy; 2) are appropriate candidates for CDDP. Pts are treated with 2 doses of CDDP 30 mg/m2. One CDDP dose is administered with raltegravir 400 mg bid for 5 days, starting the day before CDDP. Pts undergo 3 research biopsies, at baseline and 48-72 hours after each CDDP. Serial biopsies will be evaluated for expression changes in γH2AX, Annexin V, pChk1, pChk2, and p53BP1 by immunohistochemistry. Numerical increase in biomarker expression in tumors exposed to CDDP-raltegravir vs. CDDP will justify development of a phase I/II study. Four of 12 pts have enrolled and completed all biopsies. Supported by a grant from the American Cancer Society.
An open-label randomized, multicenter, phase II study on neoadjuvant treatment with trastuzumab plus docetaxel versus trastuzumab plus docetaxel plus bevacizumab according to positron emission tomography (PET) value modification in patients with early stage HER2-positive breast cancer (AVATAXHER): Design description.
Authors: Cochet Alexandre , Kerrou Khaldoun , Nabholtz Jean-Marc A. , Cachin Florent , Pierga Jean-Yves , Champion Laurence , Ferrero Jean-Marc , Darcourt Jacques , Petit Thierry , Bourahla Khalil , Bougnoux Philippe , Baulieu Jean-Louis , Dupre Pierre-Francois , Salaun Pierre-Yves , Bachelot Thomas Denis , Mognetti Thomas , Coeffic David Emmanuel , Mesnard Nathalie , Coudert Bruno P. , Berriolo-Riedinger Alina 
Published: March 2020

TPS646 Background: For patients with early HER2+ breast cancer at diagnosis, addition of trastuzumab (T) to 6 cycles of preoperative docetaxel (D) can reach a pathological complete response (pCR) in ~50% of cases, and a high rate of conservative surgery. pCR can be predicted by changes of Fluorodeoxyglucose (FDG) tumor uptake evaluated by Positon Emission Tomography (PET) after one cycle of therapy. In order to increase this pCR rate, adding an antiangiogenic compound could be considered. Pre-clinical and phase I-II data support that the combination of bevacizumab (B) and T is synergistic and safe when patients are chemotherapy naïve. The neoadjuvant AVATAXHER trial (EUDRACT 2009-013410-26) investigates the potential increase of pCR rate by combining B with T and D for patients with HER2+ breast cancer who are not predicted for pCR by FDG PET. Methods: In this multicenter, open-label, phase II trial, 2 phases are planned after a selection period: phase I: all patients receive two cycles of therapy combining T (8 mg/kg at the first cycle, then 6 mg/kg) and D (100 mg/m2). FDG PET is also performed within 7 days before cycle 1 (baseline) and less than 3 days before cycle 2 in order to calculate changes of the tumor FDG uptake between baseline and after cycle 1 (ΔSUV). Phase 2: if ΔSUV≥70%, patients will continue to receive T and D for (cycles 3 to 6: D 100 mg/m2 + T 6 mg/kg); if ΔSUV<70%, patients are randomized 2:1 to arm A (cycles 3 to 6 D 100 mg/m2 + T 6 mg/kg + B 15 mg/kg) or arm B ( cycles 3 to 6: D 100 mg/m2 + T 6 mg/kg). The primary endpoint is pCR rate evaluated post-surgery 4 to 6 weeks after the last treatment of cycle 6. Enrolment began in May 2010 and 125 patients were to be recruited in 26 sites. According to the hypothesis that 60% of patients will have a ΔSUV<70%, it is presumed that 72 patients will be randomized. There are currently 107 patients included (as of 06 January 2012 ), 95 of them reached the phase 1; 52 of them (55%) showed a ΔSUV<70% and after randomization 34 were included in arm A and 18 in arm B.
An open-label, multicenter, expanded access study assessing the safety and efficacy of oral ruxolitinib administered to patients with primary myelofibrosis (PMF), post-polycythemia myelofibrosis (PPV MF) or post-essential thrombocythemia myelofibrosis (PET-MF).
Authors: le Coutre Philipp D. , Gisslinger Heinz , Zachee Pierre , Gupta Vikas , Perez Jose Ricardo , Schenk Nora , Vutukuru Suresh , Garcia-Hernandez Carmen , Tavares Renato , Bocchia Monica , Niederwieser Dietger 
Published: March 2020

TPS6640 Background: Myelofibrosis (MF) can be primary in origin or can progress from polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). MF is characterized by cytopenias, reactive bone marrow fibrosis, splenomegaly, and constitutional symptoms including weight loss, fever, and night sweats. MF is associated with dysregulation of the Janus kinase pathway, irrespective of JAK2V617F mutation status. Recently, ruxolitinib (INCB018424) was approved for the treatment of MF on the basis of results from 2 phase 3 trials (COMFORT-I and -II). These trials demonstrated marked reductions in splenomegaly and symptom burden, and improvements in health-related quality of life (QoL) measures. Methods: JAK Inhibitor rUxolitinib in Myelofibrosis Patients (JUMP) is a global, phase 3b expanded access trial (NCT01493414) designed to assess the safety and efficacy of ruxolitinib in adult pts with PMF, PPV-MF or PET-MF who are treatment naïve, and are intolerant of, or had progressed on any prior therapy. Inclusion criteria: peripheral blast count of <10%, adequate liver and renal function and intermediate-2 or high risk MF according to IPSS criteria or intermediate-1 risk MF with palpable spleen length ≥ 5 cm. The primary endpoint is to assess the safety of ruxolitinib. Additional endpoints include the proportion of pts with a > 50% reduction in palpable spleen length, % change in white blood cell and platelet counts from baseline (BL), and change in packed red blood cell transfusion requirements. Changes from BL in QoL scores will be assessed using validated ECOG PS, FACT-Lymphoma, and FACIT instruments. Pts with a BL platelet count > 200,000/μL will receive oral ruxolitinib 20 mg BID; pts with a BL platelet count of 100,000/μL to 200,000/μL will receive 15 mg BID; dose modifications are permitted for safety and efficacy. Global enrollment is open and currently includes 277 pts. This is planned to be the largest study ever conducted in pts with MF. [Table: see text]
A randomized phase II, open-label trial of orally administered SAR302503 in patients with polycythemia vera (PV) or essential thrombocythemia (ET) who are resistant or intolerant to hydroxyurea.
Authors: Tefferi Ayalew , Cortes Jorge E. , Hochhaus Andreas , Kiladjian Jean-Jacques , Mesa Ruben A. , Pardanani Animesh Dev , Lebedinsky Claudia , Neumann Frank , Hsu Karl , Vannucchi Alessandro M. 
Published: March 2020

TPS6641 Background: Hydroxyurea is widely used to treat patients with high-risk PV and ET. However, some patients are either clinically resistant to hydroxyurea or have unacceptable side effects, supporting the need for active therapeutic options in this setting. SAR302503 is an orally administered selective JAK-2 inhibitor that reduced symptom burden and provided a durable clinical benefit, including a reduction in the JAK2V617F allele burden, with an acceptable safety profile in a Phase 1/2 trial of patients with primary myelofibrosis (MF), post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789; Pardanani, ASH 2011; Abs 3838). Based on the results in MF, in October 2011 we initiated a Phase 2 trial to evaluate SAR302503 for the treatment of patients with PV and ET who are resistant or intolerant to hydroxyurea (NCT01420783; ARD12042). Methods: Eligibility criteria include age of at least 18 years, ECOG PS 0–2, and hydroxyurea resistant PV or ET as defined by European LeukemiaNet Consensus Criteria (Blood 2009;113:4829). Patients are being randomized (1:1:1) to receive 100, 200, or 400 mg of SAR302503 orally once daily in consecutive 28-day cycles for at least 8 cycles in the absence of progression or unacceptable toxicity. The primary end points will be assessed after the completion of 8 cycles and are: for PV, the proportion of patients maintaining a hematocrit below 45% without phlebotomy for at least 3 months; for ET, the proportion of patients with a platelet count lower than 400 × 109/L for at least 3 months. Secondary objectives include safety, response rate, pharmacokinetics, pharmacodynamics as measured by JAK2V617F allele burden and STAT3 phosphorylation inhibition, assessment of disease-related symptoms, and quality of life. Enrollment of the planned total of 90 patients is ongoing at approximately 45 sites globally. Twelve patients have been enrolled as of January 2012.