bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
A phase Ib, open-label, dose-finding study of ruxolitinib in patients (pts) with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF) and baseline platelets (PLTs) 50 to <100 x 109/l.
Authors: Gisslinger Heinz , McMullin Mary Frances , Jaekel Nadja , Miller Carole Brennan , Verstovsek Srdan , Harrison Claire N , Barosi Giovanni , Kiladjian Jean-Jacques , Al-Ali Haifa-Kathrin , Weber Denis , Hu Jing , Sirulnik L. Andres , Vannucchi Alessandro M.
Published: March 2020

TPS6642^

Background: Ruxolitinib, a potent and selective oral JAK1/2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 studies in pts with PMF, PPV-MF, or PET-MF. There is considerable experience in pts who develop thrombocytopenia on study, and ruxolitinib is well-tolerated with dose adjustment. However, there is limited experience in pts with baseline thrombocytopenia as those with low PLTs (< 100 x 109/L) were excluded from the phase 3 protocols. EXPAND (Evaluating RuXolitinib in Patients with Low Baseline PlAtelet CouNts Diagnosed With Myelofibrosis) will evaluate the safety of ruxolitinib and establish the maximum safe starting dose (MSSD) in thrombocytopenic pts with MF. Methods: This is a phase 1b, open-label, dose-finding study (NCT01317875) in pts with PMF, PPV-MF, or PET-MF and baseline PLT 50-100 x 109/L. A Bayesian logistic regression model with escalation with overdose control will be used to guide dose-escalation decisions. The study consists of 2 phases: dose-escalation and safety-expansion. The starting dose is ruxolitinib 5 mg twice daily (BID) with a maximum of 15 mg BID. In the dose-escalation phase, cohorts will be: 5 mg BID, 5 mg am/10 mg pm, 10 mg BID, 10 mg am/15 mg pm, and 15 mg BID; only pts with PLT 75-100 x 109/L (1st stratum) will initially be enrolled. Once safety is established at the first 2 dose levels (5 mg BID; 5 mg am/10 mg pm), pts with PLT 50-75 x 109/L will be included (2nd stratum). Each dose level in the 2nd stratum will be open only if both that dose and the following one are deemed safe in the 1st stratum. In the safety-expansion phase, 20 pts (10 from each stratum) additional to those treated at the MSSD during dose escalation will be treated at the respective MSSD for their stratum. In cohort 1 (n = 4), 3 pts were evaluable as they completed > 28 days of treatment; 1/4 pts discontinued after 6 doses due to disease progression. No dose-limiting toxicities were observed. The second cohort (5 mg am/10 mg pm) has completed enrollment (n = 3) and is ongoing.
Randomized phase II open-label study of abiraterone acetate (AA) plus low-dose prednisone (P) with or without exemestane (E) in postmenopausal women with ER+ metastatic breast cancer (MBC) progressing after letrozole or anastrozole therapy.
Authors: O'Shaughnessy Joyce , Yu Margaret K. , Kearney Jill , Larsen Julie S. , Molina Arturo , Johnston Stephen R. D.
Published: March 2020

TPS666

Background: AA plus P treatment in men with metastatic castration-resistant prostate cancer has demonstrated a survival advantage over P alone. Circulating adrenal steroids including DHEA and DHEA-sulfate can stimulate proliferation of breast cancer cell lines in a low-estrogen environment. Thus, it is hypothesized that depletion of adrenal androgens as well as estrogens by AA, a potent CYP17 inhibitor, inhibits tumor growth by disruption of ER-dependent growth signaling. In a previously reported phase I study of AA in patients (pts) with breast cancer (Basu, ASCO 2011), 2/21 pts who were ER+ were on study for ≥ 11 months; 1 had a confirmed PR and continued on treatment > 14 months. Mechanism-based adverse event of grade 3/4 hypokalemia occurred in 4 pts and was managed with potassium supplementation and low dose corticosteroids. Methods: In the current study, 300 postmenopausal women with ER+ Her2- MBC progressing after letrozole or anastrozole are randomized to either AA 1000 mg + P 5 mg daily or AA + P + E 25 mg daily vs E. Disease must have been sensitive to a non-steroidal aromatase inhibitor (AI) prior to study entry. Subjects are stratified by number of prior therapies and by AI use in adjuvant or metastatic setting. Central review of tissue is required prior to randomization. Gene expression profiling (GEP) (AR, ER, PR, Her2, CYP17, Ki-67, CYP 19, and 3-β-HSD) will be performed on FFPE archival tissue. Pre- and post-treatment circulating tumor cells and fresh tumor biopsies will also be obtained for GEP in a subset of pts. Primary endpoint is PFS. Secondary endpoints are OS, ORR, patient reported outcomes, changes in endocrine markers, and PK characterization of AA and E. Subjects randomized to E may crossover to AA + P at time of disease progression. One interim analysis is scheduled after 50% of PFS events have occurred. After review of interim data, the Data Review Committee will make recommendations regarding study continuation. 23pts from 45 active sites have been randomized as of January 24,2012. (ClinicalTrials.gov Identifier: NCT01381874)
Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE): An international, randomized, double-blind, placebo-controlled phase III clinical trial.
Authors: Goss Paul Edward , Barrios Carlos H. , Bell Richard , Finkelstein Dianne M , Iwata Hiroji , Martin Miguel , Braun Ada H. , Ke Chunlei , Maniar Tapan , Coleman Robert Edward
Published: March 2020

TPS670

Background: Bone is a common site of distant recurrence in women with early-stage breast cancer, and represents approximately 40% of all first recurrences. Tumor cells in bone release growth factors and cytokines that stimulate osteoclast-mediated bone resorption through the RANK ligand (RANKL) pathway. In preclinical studies, RANKL inhibition significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is a fully human monoclonal antibody that binds to RANKL with high affinity and specificity. It is approved for the prevention of skeletal-related events in patients with established bone metastases from a variety of solid tumors. The purpose of the D-CARE trial is to evaluate the ability of denosumab to prolong bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. Methods: Approximately 4,500 women with stage II or III breast cancer, at high risk for recurrence and with known hormone and HER-2 receptor status, are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned. Exclusion criteria include: a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization or any intravenous BP use. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. All patients receive vitamin D (≥ 400 IU) and calcium (≥ 500 mg) supplements. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Safety, quality of life assessments, breast density, and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and is expected to complete in October 2016. Paul Goss and Dianne Finkelstein supported in part by the Avon Foundation New York.
Vinorelbine plus cisplatin versus gefitinib in resected non-small cell lung cancer haboring activating EGFR mutation (WJOG6410L).
Authors: Tada Hirohito , Takeda Koji , Nakagawa Kazuhiko , Okamoto Isamu , Mitsudomi Tetsuya , Ichinose Yukito , Sugio Kenji , Tsuboi Masahiro , Nakanishi Yoichi ,   West Japan Oncology Group
Published: March 2020

TPS7110

Background: Vinorelbine plus cisplatin after completely resected stage II-III non-small cell lung cancer (NSCLC) is a standard therapy. Stage IV non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR) is quite sensitive to tyrosine kinase inhibitors (TKIs). Three randomized trials demonstrated that gefitinib is superior to platinum based chemotherapy in progression free survival. Retrospective analysis of adjuvant TKIs therapy for patient with resected lung cancer harboring EGFR mutation showed favorable trend toward improvement in disease free survival (DFS) and overall survival (OS). (J Thorac Oncol. 2011;6: 569–575) BR19 comparing adjuvant gefitinib vs. placebo for completely resected NSCLC without any selection of biomarker was closed early and did not show any benefit of adjuvant gefitinib, even in the EGFR mutation positive cohort. The randomized trial in adjuvant therapy with erlotinib vs. placebo for patients with overexpression of EGFR protein has complete enrolment already. We conduct the first randomized phase III trial comparing adjuvant gefitinib with chemotherapy in patients with completely resected stage II-III NSCLC harboring EGFR mutations. Methods: Patients who have undergone complete resection and have EGFR mutation, deletions in exon 19, or L858R point mutation at exon 21 and without T790M mutation are randomly assigned gefitinib 250mg a day for 2 years or vinorelbine 25mg/m2 days 1 and 8, plus cisplatin 80mg/m2 day 1, every 3 weeks for 4 courses. The primary endpoint is DFS and secondary endpoints are OS and safety. On the basis of previous studies, we assume the hazard ratio of DFS is 0.65. To demonstrate this improvement in DFS, 230 patients in total would be needed during 3-year accrual period. This trial has begun from September 12 among 22 institutes in Japan. Until now (January 31. 2012), 13 cases have been enrolled. Five cases were enrolled in latest 1 month.
ASPIRATION: Phase II study of continued erlotinib beyond RECIST progression in Asian patients (pts) with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).
Authors: Park Keunchil , Tsai Chun-Ming , Ahn Myung-ju , Yu Chong-Jen , Kim Sang-We , Sriuranpong Virote , Kuo Han Pin , Lee Jong-Seok , Kang Jin Hyoung , Lin Meng-Chih , Geater Sarayut Lucien , Chang Gee-Chen , Seetalarom Kasan , So Ping Fai Peter , Lai Ruay-Sheng , Cheng Ashley Chi Kin , Cho Eun Kyung , Chen Shang-Hung , Hsia Te-Chun , Mok Tony
Published: March 2020

TPS7614

Background: First-line erlotinib (an EGFR tyrosine-kinase inhibitor) significantly increased progression-free survival (PFS) vs chemotherapy in phase III trials of pts with EGFR mutation-positive NSCLC. Discontinuation of erlotinib on RECIST disease progression (PD) may lead to rapid disease flare-up; continued erlotinib beyond RECIST PD may extend clinical benefit by slowing progression of this life-threatening disease. We describe ASPIRATION, a large, Asian, multicenter, single-arm, open-label, phase II trial (NCT01310036), which will increase understanding of first-line erlotinib and erlotinib continuation beyond RECIST PD in pts with EGFR-mutated NSCLC. Methods: Pts (n=204) ≥18 yrs with stage IV/recurrent NSCLC, ≥1 measurable lesion (≥10mm), ECOG performance status (PS) 0-2 and positive EGFR mutation status established by local pathology laboratory (that underwent voluntarily QA/QC) are eligible. All pts receive erlotinib 150mg/day. Tumor response is evaluated using RECIST (v1.1). The primary endpoint is PFS. At investigator's discretion, pts may continue on erlotinib beyond RECIST PD, e.g. if they have slow PD (>6 months of partial response/stable disease), asymptomatic minimal PD, or new brain metastasis controlled locally. Pts should not continue erlotinib if they have extracranial PD with symptoms; rapid PD and/or worsening of PS; or life-threatening complications. Pts continuing erlotinib who present with second RECIST PD will discontinue. Secondary endpoints include objective response rate, disease control rate, overall survival, and safety. For the exploratory biomarker study, pre-treatment tumor tissue blocks are collected; remaining tissue (after EGFR mutation testing for eligibility) will be analyzed centrally to study the association of biomarkers and clinical outcomes. Pre-treatment and post-treatment plasma and serum samples will be obtained at various time points for biomarker assays, including EGFR mutations and other candidate NSCLC biomarkers. Recruitment began in Apr 2011; the estimated final data collection for the primary endpoint is Dec 2014.
Prophylactic cranial irradiation after reaching complete response, partial response, or stable disease in non-small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (ProACT).
Authors: Tufman Amanda , Belka Claus , Kuenzel Heike , Huber Rudolf M.
Published: March 2020

TPS7617

Background: Patients with non-small cell lung cancer (NSCLC) who respond to treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) seem to be at increased risk of central nervous system relapse, and may benefit from prophylactic cranial irradiation (PCI) more than other NSCLC patients. Methods: This study investigates the safety and efficacy of combining PCI with EGFR TKIs in stage IV NSCLC. Patients with stage IV NSCLC, no evidence of brain metastases, and an indication for first or later line therapy with an EGFR TKI will be enrolled. Those with complete response (CR), partial response (PR), or stable disease (SD) following 6 weeks of therapy and no evidence of brain metastases on MRI will be treated with PCI. Neurocognitive function, depression indices, quality of life, symptoms, and ability to function independantly will be assessed at baseline, before PCI, and at 6 week and then 3 month intervals following PCI. MRI will be repeated 6 weeks following PCI and at 3 month intervals, and serum markers of blood brain barrier permeability (neuron-specific enolase (NSE), protein S100 beta) will be assessed at all visits. Safety data will be formally reviewed after the first 10 patients. The primary endpoint for efficacy is overall survival. Secondary endpoints include progression free survival, site of progression, quality of life and neurological disability. Planed subgroup analyses based on mutation status, line of treatment with TKIs, comorbidity, precise histology and molecular biology will be carried out.
Phase I/II study of investigational agent MLN8237 (alisertib) plus rituximab with or without vincristine in patients (pts) with relapsed/refractory (rel/ref) aggressive diffuse large B-cell lymphoma (DLBCL)/transformed follicular lymphoma (TFL).
Authors: Persky Daniel Oscar , Kelly Kevin R. , Lee Peter , Park Steven I. , Zhang Bin , Leonard E. Jane , Benaim Ely , Friedberg Jonathan W.
Published: March 2020

TPS8109

Background: DLBCL and TFL are aggressive subtypes of non-Hodgkin lymphoma (NHL), with poor prognosis in the rel/ref setting. Alternatives to standard rituximab-based treatments are needed. MLN8237 is an oral, selective inhibitor of Aurora A kinase – a key mitotic regulator overexpressed/amplified in various human cancers, including lymphomas (Hamada et al, 2003; Yakushijin et al, 2004; Qi et al, 2011). Emerging data from a phase 2 study suggest that MLN8237 has single agent activity in aggressive NHL (Friedberg et al, ASH 2011). MLN8237 + rituximab (MR) ± vincristine (MRV) has also shown activity in preclinical B-cell NHL models (Mahadevan et al, ASH 2011). Further clinical evaluation of these regimens in rel/ref B-cell NHL is warranted. Methods: This single-arm phase 1/2 study (ClinicalTrials.gov #NCT01397825) aims to assess the safety, efficacy, and pharmacokinetics of, and determine a recommended phase 2 dose (RP2D) and schedule for, MR and MRV in adults with CD20+ rel/ref DLBCL/TFL after 1–4 prior regimens (including ASCT) and ECOG PS 0–2. Pts with other aggressive B-cell lymphomas may also enroll in phase 1. ~100 pts will be recruited at 22 sites in the US, UK, Italy, and Spain, and study duration will be ~2 years. In part 1, a safety lead-in cohort will receive MR (table), with the RP2D determined as when <2 dose limiting toxicities (DLT) occur in 6 pts in cycle 1. MRV dose escalation (part 2) will then follow a 3+3 design. Phase 2 enrollment (part 3) will follow a Simon optimal 2-stage design, with pts receiving MRV at the RP2D determined in part 2. The primary phase 2 objective is overall response rate by IWG criteria. Responders may continue MLN8237 if clinical benefit is seen and if the regimen is tolerable. Enrollment as of 20 Jan 2012 is 6 evaluable pts. [Table: see text]
ELOQUENT-1: A phase III, randomized, open-label trial of lenalidomide/dexamethasone with or without elotuzumab in subjects with previously untreated multiple myeloma (CA204-006).
Authors: Dimopoulos Meletios A. , Facon Thierry , Richardson Paul Gerard Guy , Orlowski Robert Z. , San-Miguel Jesùs F. , Lonial Sagar , Anderson Kenneth Carl , Moreau Philippe , Reece Donna Ellen , Singhal Anil , Shazer Ronald L. , Kopit Justin , Palumbo Antonio Pierangelo
Published: March 2020

TPS8113

Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells. In a MM xenograft mouse model, the combination of Elo + lenalidomide (Len) significantly reduced tumor volume in a synergistic manner compared with either agent alone. In a phase 2 study (N=73) of Elo (10 or 20 mg/kg) in combination with Len and low-dose-dexamethasone (Dex) in pts with RR MM, the 10 mg/kg dose group (n=36) demonstrated objective response rates (ORR) of 92% in all pts, and 100% in pts who had received only 1 prior therapy (n=16). The higher response rate in pts with fewer prior lines of therapy provides a rationale for investigating this combination earlier in the disease course. This randomized, open-label, phase 3 trial will determine if the addition of Elo to Len/Dex improves progression-free survival (PFS) in pts with newly diagnosed, untreated MM. Methods: Pts (N=750) with newly diagnosed symptomatic MM ineligible for stem cell transplant will be randomized in a 1:1 ratio to receive 28-day cycles of Len 25 mg PO (days1-21) and Dex 40 mg PO (days 1, 8, 15 and 22) with or without Elo. Elo dose and schedule is 10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles and on days 1 and 15 of cycles 3-18 followed by 20 mg/kg on day 1 of cycle 19 onward. Dex 8 mg IV + 28 mg PO is used during the weeks with Elo. Treatment will continue until disease progression, death, or withdrawal of consent. Pts will be followed up for response every 4 weeks until progressive disease and for survival every 16 weeks. The primary endpoint is PFS (90% power for a hazard ratio [experimental to control arm] of 0.74) and the secondary endpoints are ORR and overall survival. Exploratory endpoints are safety, time to response, duration of response, time to subsequent therapy, health-related quality of life, and pharmacokinetics and immunogenicity of Elo. Potential biomarkers will also be assessed. As of January 1, 2012, 13 pts were enrolled and 9 pts were treated. NCT01335399.
Recruitment in a randomized, double-blind, placebo-controlled study to assess siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in patients with multicentric Castleman’s disease.
Authors: Van Rhee Frits , Capra Marcelo , Wong Raymond , Vermeulen Jessica , Safer Karim , Todorovic Marija , Rhoten Patricia , Van De Velde Helgi
Published: March 2020

TPS8117

Background: Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder in which dysregulated production of interleukin (IL)-6 results in lymph node enlargement and debilitating symptoms, including systemic inflammatory manifestations (eg, fever, fatigue, weight loss), autoimmune phenomena, and markedly abnormal laboratory findings (eg, anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis, increases in acute-phase proteins such as CRP, ESR, fibrinogen). There is currently no approved systemic treatment for MCD in the US or EU. Siltuximab (CNTO 328) is a chimeric mAb with high affinity for soluble IL-6. In a previous phase 1 study, high objective tumor response rate (64%) has been observed in patients with MCD (van Rhee F et al. Blood 2008;112:1008), and the long-term safety profile looks favourable (Kurzrock R et al. Blood 2011;118:3959). These results have prompted a randomized, double-blind, placebo-controlled study to definitively assess the efficacy and safety of siltuximab in combination with best supportive care (BSC) compared with BSC in patients with MCD. Methods: Eligibility includes HIV- and HHV-8-negative, symptomatic, measurable MCD patients. Patients with prior lymphoma or prior exposure to treatment targeting IL-6 or its receptor are excluded. Patients can be enrolled when receiving stable doses of corticosteroids (<1 mg/kg/d of prednisone or equivalent). Patients will be randomized in a 1:2 ratio to placebo + BSC or to 11 mg/kg siltuximab + BSC and will receive siltuximab/placebo in a 1-hour IV infusion every 3 weeks. The primary objective is to evaluate durable tumor and symptomatic response in the intent-to-treat population. Secondary objectives include additional efficacy measures, safety, patient reported outcomes, and pharmacologic assessment. Status: 67/78 patients have been randomly assigned. This is the first randomized, placebo-controlled study to be conducted in MCD. The rarity of the disease has posed unique challenges, and various enrollment strategies have been successfully implemented, with projected completion of enrollment in March 2012.
The HERBY study: A phase II open label, randomized, multicenter, comparative study of bevacizumab (Bv)-based therapy in pediatric patients with newly diagnosed supratentorial high-grade glioma (HGG).
Authors: Grill Jacques , Hargrave Darren R , Varlet Pascale , Jaspan Tim , Jones Chris , Massimino Maura , Cañete Adela , Azizi Amedeo A. , Le Deley Marie-Cécile , Saran Frank , Morgan Paul , Zahlmann Gudrun , Viviers Louis , Bachir Jeanette , Shang Aijing , Rousseau Raphael F. , Vassal Gilles ,   on behalf of the European Innovative Therapies for Children with Cancer (ITCC) Consortium, The SIOP-E Brain Tumour Group and the Australian Children's Cancer Trials Group
Published: March 2020

TPS9596

Background: Despite therapeutic advances, outcomes in pediatric HGG remain poor. The phase I study (Glade-Bender et al., J Clin Oncol. 2008) indicated that Bv is well tolerated in children with refractory solid tumors and yielded pharmacokinetic (PK) data that support further studies of Bv in childhood cancer. Reports of Bv used in children with solid tumors showed safety profiles consistent with data from adults. Methods: 120 evaluable patients aged 3-18 years with newly diagnosed histologically confirmed WHO grade 3or 4 HGG are randomized to receive standard combined modality therapy as currently adopted worldwide by the pediatric neuro-oncology community with or without Bv. Treatment consists of 6 weeks of concomitant TMZ and local radiotherapy, followed by a 4-week TMZ treatment break and 48 weeks of adjuvant TMZ with or without Bv every other week. Primary endpoint is event-free survival (EFS). Progression is based on RANO criteria. Secondary endpoints are overall survival (OS), safety, feasibility, and tolerability. PK sampling is performed during cycles 1-4 of the adjuvant TMZ phase on all patients randomized to receive Bv. Health-related quality of life, neurocognitive functions, MGMT methylation status, functional changes in tumor based on magnetic resonance diffusion & perfusion imaging and spectroscopy are explored as well as the correlation of biomarkers with clinical activity and adverse events. All randomized patients will be followed for at least 3 years. Analysis of EFS and secondary endpoints will be performed after the 120 patients evaluable for EFS have been followed for 1 year. Multimodal imaging will provide a platform to develop new imaging criteria for pediatric neuro-oncological treatment response. An updated OS and safety analysis will be performed 3 years after the last patient has been randomized. The first patient was randomized in October 2011; completion of the study is expected in 2016.
RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM).
Authors: Gilbert Mark R. , Dignam James , Won Minhee , Blumenthal Deborah T. , Vogelbaum Michael A. , Aldape Kenneth D. , Colman Howard , Chakravarti Arnab , Jeraj Robert , Armstrong Terri S. , Wefel Jeffrey Scott , Brown Paul D. , Jaeckle Kurt A. , Schiff David , Atkins James Norman , Brachman David , Werner-Wasik Maria , Komaki Ritsuko , Sulman Erik P. , Mehta Minesh P.
Published: March 2020

1

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Hyaluronidase synthase 3 (HAS3) variant and anthracycline-related cardiomyopathy: A report from the Children’s Oncology Group.
Authors: Sun Can-Lan , Wang Xuexia , Liu Wei , Armenian Saro , Hankonarson Hakon , Hageman Lindsey , Ding Yan , Landier Wendy , Keller Frank G. , Neglia Joseph Philip , Desai Sunil J. , Sklar Charles A. , Castellino Sharon M. , Cherrick Irene , Dreyer Zoann , Yasui Yutaka , Relling Mary V. , Bhatia Smita
Published: March 2020

10004

Background: The strong dose-dependent association between anthracyclines and cardiomyopathy limits the therapeutic potential of this extremely effective class of agents, demanding identification of those at highest risk, such that anthracycline exposure may be tailored. Methods: In a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy in cancer survivors by using the ITMAT/Broad/CARe cardiovascular SNP-array to profile common SNPs in 2100 genes considered most relevant to de novo cardiovascular disease. All cases of cardiomyopathy fulfilled American Heart Association (AHA) criteria for cardiac compromise and were confirmed echocardiographically. Results: Using a matched case-control design (93 cases, 194 controls, all non-Hispanic white survivors of childhood cancer) we identified a common SNP rs2232228 in hyaluronan synthase (HAS3) gene that exerts a substantial modifying effect on anthracycline dose-dependent risk of cardiomyopathy. Among individuals with GG genotype, cumulative anthracycline exposure was not associated with cardiomypathy risk at any dose. Individuals with AA genotype, exposed to >250mg/m2 anthracyclines, had an 8.5-fold increased cardiomyopathy risk (95%CI, 2.0-35.6, p=0.004). Replication in an independent set of 76 patients (adult-onset and childhood cancer; all races) with anthracycline-related cardiomyopathy revealed the odds of cases with AA genotype in the high-dose anthracycline group to be 4.5-times higher (95%CI, 1.1-18.4, p=0.04). Hyaluronan (HA) – produced by HAS3 – is a ubiquitous component of extracellular matrix (ECM). ECM is involved in tissue remodeling; the extent of cardiac remodeling/repair after anthracycline-induced cardiac injury is possibly modulated by variability in HA production. Conclusions: The significant modifying effect of HAS3 genotype on the dose-dependent association between anthracycline and cardiomyopathy risk suggests that, upon confirmation in prospective studies, genotyping HAS3 may be considered when evaluating risk of anthracycline-related cardiomyopathy.