bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II clinical trial of six mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumors.
Authors: Nicum Shibani , Brooks Claire E , Wharton Rose , Boyle Lucy , Kaye Stanley B. , Gourley Charlie , Hall Marcia , Montes Ana , Pearson Sarah R , Julier Patrick , Midgley Rachel A , Schuh Anna , Dutton Susan J. ,   6MP Collaborative Group
Published: March 2020

TPS5615 Background: BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumor cells with these mutations demonstrate increased sensitivity to cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor, AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin (Issaeva 2010). Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers. This multi-center phase II single arm trial was set up to investigate the activity and safety of 6MP with methotrexate in patients with breast or ovarian cancer who are known to have a BRCA mutation. Methods: Two-stage Simon compromise design (Jung 2001, Jung 2004) with α=0.20, power=90% to detect an increase in activity from 10 to 20%. 1st stage: if ≤ 3/30 evaluable patients respond at 8 weeks the trial will be stopped for futility; 2nd stage: if ≥9/65 evaluable patients respond at 8 weeks the treatment will be regarded as potentially effective and a phase III trial will be considered if the treatment appears safe and well-tolerated. 65 patients with BRCA defective cancer progressing after at least one prior chemotherapy or relapsed platinum resistant ovarian cancer, ECOG performance status 0-2 will be recruited and treated with daily 6MP (75mg/m2 ) and weekly methotrexate (20mg/m2) until progression. The starting dose was later reduced by 25% due to excess of expected toxicity. Patients with low TPMT activity or a low/low genotype are excluded due to the risk of increased toxicity. Prior treatment with a PARP inhibitor is permissible. Primary outcome: objective response at 8 weeks: complete, partial response or stable disease defined by RECIST 1.1. Secondary outcomes include safety, PFS, OS and quality of life. Of the 46 patients screened for TMPT activity between 15 Jun2009 and 05Dec 2012 from 12 UK sites, 31 patients were recruited. The pre-specified activity goal for the 1st stage was met and accrual into the 2nd stage continues. Clinical trial information: 2009-016846-16.
Phase II study of dalantercept, a novel inhibitor of ALK1-mediated angiogenesis, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Authors: Jimeno Antonio , Wirth Lori J. , Posner Marshall R. , Cohen Roger B. , Weiss Jared , Popa Elizabeta C. , Saba Nabil F. , Grossmann Kenneth F. , Sukari Ammar , Cohen Ezra E.W. , Argiris Athanassios , Condon Carolyn H , Wilson Dawn , McClure Ty , Alimzhanov Marat , Pearsall Scott , Attie Kenneth M. , Sherman Matthew L. , Pandya Shuchi Sumant 
Published: March 2020

TPS6098 Background: Despite advances in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), the prognosis remains poor with a need to develop novel therapeutic strategies. Targeting angiogenesis in SCCHN is an active area of clinical research. Activin receptor-like kinase 1 (ALK1) is a type 1 receptor in the TGF-ß superfamily which is selectively expressed on activated endothelial cells. ALK1 binds bone morphogenetic proteins (BMP) 9 and 10 (ligands for ALK1) and is primarily involved in the maturation stage of angiogenesis. Dalantercept is a human ALK1-Fc receptor fusion protein that binds BMP9/10 and acts as a ligand trap. In preclinical tumor models, dalantercept demonstrated a decrease in tumor vascularization and delayed tumor growth. In a completed phase I study, dalantercept demonstrated anti-tumor activity in patients with advanced solid tumors including SCCHN. Methods: An open label, multi-center, multiple dose, phase II study to evaluate dalantercept in patients with advanced SCCHN is ongoing. Dalantercept is being administered every three weeks via SC injection in a total of 45 patients to assess safety, tolerability, and efficacy. 13 patients were enrolled at the 0.6 mg/kg dose level. To date, 6 out of 30 planned patients have received dalantercept at the 1.2 mg/kg dose level. Key inclusion criteria are tumors arising from the oral cavity, oropharynx, hypopharynx, or larynx, at least one prior platinum-containing regimen, ECOG performance status </= 1, and measurable disease. Exclusion criteria include prior anti-angiogenesis therapy, significant pulmonary, cardiovascular, or bleeding risk. The primary efficacy endpoint is RR. Secondary endpoints include PFS, OS, TTP, DOR, DCR, and PD biomarkers on tumor and serum specimens including BMP9/10 and ALK1 expression. Clinical trial information: NCT01458392.
Seamless phase II/III trial design with survival and PRO endpoints for treatment selection: Case study of RTOG 1216.
Authors: Rosenthal David Ira , Zhang Qiang , Kies Merrill S. , Truong Minh-Tam , Jordan Richard , Harari Paul M. , Le Quynh-Thu 
Published: March 2020

TPS6099 Background: Clinical trial results from phase II trials to select an experimental treatment arm for separate phase III trial comparison can require years. Cancer clinical trials also now aim at both survival and PRO/functional outcomes, especially in head and neck (HN) studies. We developed a unique seamless phase II/III trial design to save on sample size and trial duration. The initial multi-arm phase II trial selects the most effective regimen among multiple experimental arms by first comparing each of the new treatments to a common control arm, using chosen endpoints, such as progression free survival. The winner will be tested for overall survival in the phase III study. Methods: We propose a phase II/III design to test the efficacy of experimental arms of postoperative radiation (RT) + docetaxel or RT + docetaxel + cetuximab in patients with HN squamous cancer. These are compared to the control arm of RT + cisplatin in the phase II part. Only one arm will be selected to go on to phase III depending on efficacy (PFS), PRO and safety outcomes. One experimental arm must be sufficiently better than the common control arm and the winner not having increased toxicity or functional cost to be selected for phase III inclusion. If not, the trial is halted for futility. Patients in the phase II selected arm and the control arm are included in phase III testing. Group sequential method is used to design each component. Separate interim efficacy and futility analyses are built in such that each endpoint can be monitored as in separate phase II, III trials. Once sample sizes are derived, operating characteristics for the seamless II/III design are evaluated through simulations under the null and various alternative hypotheses. Savings on sample size and time are compared to typical separate phase II and III designs and to the design testing only the arm of RT + docetaxel + cetuximab in phase II. Conclusion: The phase II/III RTOG 1216 HNC trial offers cost effectiveness, operational efficiency and scientific innovation.
Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy with or without one year of everolimus in patients with high-risk, hormone receptor- (HR) positive and HER2-neu-negative breast cancer: SWOG/NSABP S1207.
Authors: Chavez-Mac Gregor Mariana , Barlow William E. , Gonzalez-Angulo Ana M. , Rastogi Priya , Mamounas Eleftherios P , Ganz Patricia A. , Schott Anne , Paik Soonmyung , Lew Danika , Bandos Hanna , Hortobagyi Gabriel N. 
Published: March 2020

TPS657 Background: Abnormalities of the PI3kinase/AKT/mTOR signaling pathway are common in breast cancer. This pathway has been associated with endocrine resistance. Everolimus, an mTOR-inhibitor, has been shown to increase the biological activity endocrine therapies. S1207 proposes to evaluate the role of everolimus in combination with endocrine therapy in the adjuvant setting. Methods: S1207 is randomized phase III double-blinded, placebo-controlled clinical trial. The primary objective is to assess whether the addition of one year of everolimus to standard adjuvant endocrine therapy improves DFS. Secondary objectives include OS, DRFS, safety, adherence, and quality of life. Submission of tissue specimens/blood samples is required. Patients will be randomly assigned to receive standard adjuvant endocrine therapy in combination with one year of everolimus (10 mg PO daily) or in combination with one year of matched placebo. Eligibility Criteria: Patients with histologically confirmed invasive breast cancer HR-positive and HER2-negative with a) node-negative disease with tumors >2cm and a recurrence score (RS) >25; b) 1-3 positive lymph nodes RS >25; c) >4 positive lymph nodes are eligible after they have completed adjuvant chemotherapy; d) Patients with >4 positive lymph nodes after neoadjuvant chemotherapy are also eligible. Patients must have completed surgery, chemotherapy, and radiation therapy (if indicated) before registration. Statistical methods/ target accrual: Parallel randomization design with equal allocation to the two treatment groups with stratification by 4 risk groups. All analyses are intent-to-treat. The study plans to randomize 3,500 patients over a 3.5-year accrual period. All patients will be followed for 10 years to assess survival and late adverse events. The first interim analysis would be after 39% of the expected events (n=295) have been observed or approximately 3.5 years after initiation of the study. Support: NCI U10-CA-37377, -12027, -69651; Breast Cancer Research Foundation; Novartis. Clinical trial information: NCT01674140.
Predictors of accrual success for cooperative group trials: The Cancer and Leukemia Group B (Alliance) experience.
Authors: Gordon David Hirsch , Liu Qianying , Kleinman Ben , Karrison Theodore , Kelly Michael , Fleming Gini F. 
Published: March 2020

TPS6645 Background: Clinical trials that fail to meet accrual waste patient, physician, and institution resources. We explored factors that predict for poor accrual to cooperative group trials in order to improve trial design and target resources to support or increase accrual when needed. Methods: Twenty trial characteristics were collected for Cancer and Leukemia Group B (CALGB) trials that closed between 06/01/02 and 06/01/12. We evaluated accrual in two ways: (1) logistic regression applied to accrual success/failure as a binary outcome; (2) treated the ratio of actual to expected accrual rate as a continuous response and applied linear regression to the square root of the ratio. Results: 110 trials (phase III=27, phase I/II=83) were examined. 89 (80.9 %) met the accrual goal, 21 (19.1%) did not. For trials that met their accrual goal, time to accrual ranged from 0.5 to 8.8 years and was non-normally distributed, with 57% accruing within 3 years and 83% accruing within 5 years. Phase III trials took longer to accrue (univariate p<0.001) but were not less likely to meet accrual goal (p=0.30). Provision of study drug was an important predictor of success in both analyses performed (borderline significant in success/failure analysis); having at least one agent provided by the study was significantly associated with better accrual. Factors not found to affect accrual included: Time from concept approval by CALGB to study activation, research-only biopsies, and estimated rarity of disease being studied. Conclusion: Provision of drug as a predictor of accrual success has not been previously reported, and will need to be confirmed. This factor is likely a surrogate for physician and patient eagerness to have access to a drug not otherwise available.
PAM50 HER2-enriched (HER2E) phenotype as a predictor of early-response to neoadjuvant lapatinib plus trastuzumab in stage I to IIIA HER2-positive breast cancer.
Authors: Vidal Maria , De La Pena Lorena , Oliveira Mafalda , Cortes Javier , Llombart Antonio , Prat Aleix ,   SOLTI Breast Cancer Research Group
Published: March 2020

TPS665 Background: Combinations of two different anti-HER2 therapies without chemotherapy have generated great expectations. However, it is unclear which group of patients benefits the most from this strategy. Within HER2-positive breast cancer, the PAM50 assay identifies a HER2-Enriched HER2-E intrinsic subtype characterized by high activation of the EGFR/HER2 pathway. Trial Design: This non-randomized, open label multi-centre translational research study will evaluate the ability of the HER2-E subtype to predict pathological complete response (pCR) to dual HER2 blockade with lapatinib and trastuzumab for a total of 18 weeks. Patients with hormone receptor (HR)-positive disease will also receive endocrine therapy. Eligibility Criteria: Operable primary Stage I-IIIa HER2+ breast cancer. Specific Aims: The primary objective is to evaluate the ability of the PAM50 assay to predict pCR in the breast at the time of surgery.Secondary objectives are to (1) assess the correlation of HER2-E with pCR in the breast and axilla, (2) assess the correlation of HER2-E with Residual Cancer Burden (RCB) (3) evaluate the gene expression changes from Day 0 to Day 14 and the correlations with Ki67-IHC at Day 14, (4), identify additional gene expression signatures predictive of pCR, and (5) evaluate safety and tolerability. Methods: The statistical plan is based on the assumption that breast pCR rate will be 35.0% for HER2-E tumors and 8.0% for non-HER2E. The study will have a 95% power with a significance level of 5% (two-sided) and an assumed drop-out rate of 15%. Biomarker Analyses: Baseline, 14-day treated and post-treatment (surgical) formalin–fixed, paraffin–embedded tissues will be obtained. The expression of 547 genes will be explored with the nCounter platform. Subtype will be identified using the PAM50 predictor (Parker et al. J Clin Oncol 2009). Ki-67-IHC will also be evaluated on pre-treatment and Day-14 samples. Target Accrual: 150 patients with a maximum of 75 HR-positive patients across Spain and Portugal. Patient enrollment will begin in May 2013.
CA184-104: Randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) with paclitaxel/carboplatin (PC) versus placebo with PC in patients (pts) with stage IV/recurrent non-small cell lung cancer (NSCLC) of squamous histology.
Authors: Reck Martin , Gonzalez-Mella Pablo , Ahn Myung-Ju , Ghazal Hassan H. , Schneider Claus-Peter , Jassem Jacek , Lu Haolan , McDowell Diane Opatt , Postmus Pieter E. 
Published: March 2020

TPS8117 Background: Improved outcomes for squamous, advanced NSCLC—beyond standard platinum doublets—have not been demonstrated. Data suggestive of response to immune therapies in squamous NSCLC support investigation in this subtype. Ipi, a fully human monoclonal antibody which binds CTLA-4, augments antitumor immune responses. Ipi improved overall survival (OS) in advanced melanoma, with side effects managed using product-specific treatment guidelines. A randomized phase II study of phased Ipi/PC (Ipi started after 2 cycles of PC) in pts with stage IV NSCLC showed significant improvement in progression-free survival (PFS), as measured by mWHO or immune-related response criteria (irRC), with a trend toward prolonged OS, over chemotherapy alone; irRC were derived from WHO criteria to better capture response patterns observed with Ipi. Improvement in PFS and OS appeared greater in tumors of squamous histology. Ipi did not exacerbate PC toxicity, and immune-related adverse events were managed using protocol-specific guidelines. This global (~253 sites among 34 countries) phase III trial (ClinicalTrials.gov identifier NCT01285609) is investigating whether phased Ipi/PC will prolong OS in first-line pts with squamous NSCLC. Methods: Stage IV/recurrent squamous NSCLC with ECOG 0-1 will be included; pts with CNS metastases or history of autoimmune disease will be excluded. Pts are randomized to 2 cycles of PC (175 mg/m2 and AUC=6, respectively; IV), followed by 4 cycles of study drug (Ipi in Arm A, placebo in Arm B; IV) with 4 additional cycles of PC (total 6 cycles). Pts without progressive disease (PD) after induction receive maintenance therapy with blinded study drug Q12W until PD per mWHO. The study will enroll an estimated 920 pts, randomized 1:1 between arms. The primary endpoint is OS; secondary endpoints include OS among pts who receive blinded therapy, PFS, and best overall response rate. Safety is an exploratory objective of the trial. Clinical trial information: NCT01285609.
Phase III randomized, open label study (ARCHER 1050) of first-line dacomitinib (D) versus gefitinib (G) for advanced (adv) non-small cell lung cancer (NSCLC) in patients (pts) with epidermal growth factor receptor (EGFR) activating mutation(s).
Authors: Mok Tony , Nakagawa Kazuhiko , Rosell Rafael , Wu Yi Long , Trygstad Carl , Capizzi Robert L. , Lee Min Young , Tsuji Fumito , DeBenedetto Robert , Goldberg Zelanna , Wang Tao , Liang Jane Q. , Letrent Stephen P. , O'Connell Joseph P. , Antic Vladan 
Published: March 2020

TPS8123 Background: D is an orally available, potent and selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family tyrosine kinases that has shown activity in preclinical studies on EGFR mutant cell lines, including those resistant to G. In a phase II trial of NSCLC pts who received 1st-line D, 75.6% of 45 pts with confirmed EGFR exon 19 or 21 sensitizing mutations (m) experienced a partial response (PR). The median progression-free survival (PFS) was 18.2 mo, and the PFS rate at 1 yr was 76.5% (preliminary data; Mok et al APLCC 2012). Methods: Based on the phase II data, a phase III randomized, open label trial (ARCHER 1050; NCT01774721) was designed to compare the efficacy of 1st line D with G in pts with adv EGFR m-positive NSCLC. Eligible pts (N=440) have pathologically confirmed stage IIIB/IV NSCLC with at least one activating EGFR m, either exon 19 deletion or exon 21 L858R m. Concurrent m in exon 20 T790M is permitted. Pts must have radiologically measurable disease, ECOG PS 0–1 and no prior systemic therapy. Pts will be randomized (1:1) to receive D 45 mg or G 250 mg orally once daily. The primary endpoint is PFS by Independent Radiologic Review. Secondary endpoints include PFS by investigator assessment, overall survival (OS), OS at 30 mo, best overall response, duration of response, and safety and tolerability. Pt-reported outcomes (HRQoL and disease/treatment-related symptoms) were also assessed. Randomization will be stratified by race (Japanese vs mainland Chinese vs other East Asian vs nonEEast Asian), and EGFR m status (exon 19 deletion vs exon 21 L858R m). A minimum of 268 PFS events is required for 90% power to detect a PFS improvement of ≥50% in D vs G recipients using the intent-to-treat (ITT) analysis population (HR ≤0.667). A significant (0.025 significance level) 1-sided stratified log-rank test for PFS at the final PFS analysis will be indicative of a positive study outcome. An interim analysis is planned to assess safety and whether early discontinuation of the trial is required for futility. Clinical trial information: NCT01774721.
A randomized, open-label phase II study of single-agent vintafolide versus vintafolide plus docetaxel versus docetaxel alone in second-line NSCLC patients with all target lesions expressing folate-receptor (TARGET).
Authors: Edelman Martin J. , Ma Hong , Perez Wendy , Adjei Alex A. , Hanna Nasser 
Published: March 2020

TPS8125 Background: Folate receptor (FR) is frequently overexpressed in NSCLC and is a potential biomarker for therapy selection. Vintafolide (EC145) is designed to target FR expressing cells and consists of folate linked to desacetylvinblastinehydrazide. The FR targeted imaging agent, 99mTc-etarfolatide (EC20), consists of folate coupled to technetium and identifies lesions that overexpress FR which may respond to vintafolide treatment. A phase II study of single-agent vintafolide in heavily pre-treated lung adenocarcinoma patients (pts) showed promising activity in clinical benefit response (50% vs. 14.3%) and overall survival (OS, 47.2 wks vs. 14.9 wks), in pts whose target lesions all expressed FR [FR (100%)] vs pts whose target lesions were not all FR positive (Edelman et al, JTO 2012:7:1618-21). This trial assesses the benefit of vintafolide as second-line therapy in NSCLC FR (100%) pts. Methods: This is a randomized, open-label phase II study of vintafolide vs. vintafolide + docetaxel vs. docetaxel in second line NSCLC FR (100%) pts ( NCT01577654 ). Key eligibility criteria include: cytologic or histologic diagnosis of NSCLC, 1 prior systemic therapy for advanced disease, and PS 0-1. At baseline, pts undergo 99mTc-etarfolatide imaging to detect FR-positive lesions. FR (100%) pts are randomized 1:1:1 to vintafolide, vintafolide + docetaxel, or docetaxel. Vintafolide (2.5 mg) is administered on d 1, 4, 8, and 11 of a 3-wk cycle. Docetaxel (75 mg/m2) is given on d 1 of a 3-wk cycle. Treatment continues until disease progression or unacceptable toxicity. Pts receiving vintafolide + docetaxel who discontinue docetaxel due to toxicity may continue vintafolide alone. Disease status is evaluated by RECIST v1.1 criteria every 6 wks and adverse events are monitored throughout. The primary objective of this study compares PFS between the docetaxel control arm and each experimental arm with the goal of demonstrating a hazard ratio of ≤0.67 favoring the experimental arms. Secondary objectives include response rate, disease control rate, OS, and safety/tolerability. Enrollment to the study is ongoing. Clinical trial information: NCT01577654.
GALAXY-2 trial: A randomized phase III study of ganetespib in combination with docetaxel versus docetaxel alone in patients with advanced non-small cell lung adenocarcinoma.
Authors: Fennell Dean Anthony , Goss Glenwood D. , Socinski Mark A. , Nakagawa Kazuhiko , Schiller Joan H. , Bonomi Philip , Hirsh Vera , Kelly Karen , Spicer James F. , Rosell Rafael , Zaric Bojan , Ciuleanu Tudor-Eliade , Vukovic Vojislav M. , Teofilovici Florentina , El-Hariry Iman , Guo Wei , Ramalingam Suresh S. 
Published: March 2020

TPS8126 Background: Hsp90 is a molecular chaperone recognized as a key facilitator of cancer cell growth and survival. Ganetespib is a resorcinolic Hsp90 inhibitor that has shown single-agent activity in patients with lung, breast, and other cancers after progression on standard treatments. Ganetespib in combination with docetaxel induces synergistic efficacy in human non-small-cell lung carcinoma (NSCLC) tumor xenografts. Ganetespib is well tolerated and has not shown severe liver or common ocular toxicities reported for other Hsp90 inhibitors. Transient diarrhea is the most common adverse event, and is manageable with appropriate supportive care. A large randomized study of ganetespib in combination with docetaxel in advanced NSCLC patients (GALAXY-1 Trial) is ongoing. Preliminary results indicate good tolerability of the combination, and improvement in efficacy, including OS. Methods: GALAXY-2 is a randomized (1:1), international, open-label phase III study enrolling patients who received and progressed on one prior systemic therapy for advanced NSCLC of adenocarcinoma histology. Patients (N=500) are prospectively stratified for ECOG PS, total LDH, and best response to first-line therapy. The primary endpoint is OS. Key secondary endpoints include: OS in 3 subpopulations (mKRAS and elevated LDH and LDH5); PFS, ORR, DCR, DOT, and DOR. Patients in the control arm are treated with docetaxel 75 mg/m2 on Day 1 of a 3-week cycle. In the combination arm, ganetespib 150 mg/m2 is given on Day 1 with 75 mg/m2 docetaxel, and ganetespib 150 mg/m2 alone is given on Day 15 of each 3-week cycle. Two interim analyses for OS will be performed. Tumor tissue and blood samples will be collected for planned translational studies.