bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 3 KEYNOTE-426 trial: Pembrolizumab (pembro) plus axitinib versus sunitinib alone in treatment-naive advanced/metastatic renal cell carcinoma (mRCC).
Authors: Rini Brian I. , Powles Thomas , Chen Mei , Puhlmann Markus , Atkins Michael B. 
Published: September 2018

TPS4597 Background: Antiangiogenic agents, including sunitinib and axitinib, have shown clinically significant efficacy in patients (pts) with mRCC. Results from a phase 1b study in 52 pts suggest first-line pembro, an anti–programmed death 1 antibody, in combination with axitinib, has substantial antitumor activity in mRCC (objective response rate [ORR], 71%) and manageable toxicity. The phase 3, multicenter, open-label, randomized KEYNOTE-426 study (NCT02853331) is designed to evaluate the efficacy and safety of pembro plus axitinib versus sunitinib alone in pts with treatment-naive mRCC. Methods: Key eligibility criteria include age ≥18 years, histologically confirmed mRCC with clear cell component (with or without sarcomatoid features), measurable disease (RECIST v1.1, investigator review), no prior systemic therapy for advanced disease, Karnofsky performance status ≥70%, and provision of a tumor sample for biomarker analyses. Before randomization, pts will be stratified by International Metastatic RCC Database Consortium risk category and geographic region. 840 pts will be randomly assigned 1:1 to receive pembro 200 mg every 3 wk + axitinib 5 mg twice daily or sunitinib 50 mg once daily for 4 wk followed by 2 wk off. Treatment will continue until progressive disease, unacceptable adverse events (AEs), or withdrawal of consent. Pts in the pembro arm may receive up to 35 doses of pembro, after which axitinib-only treatment may continue. Imaging will be performed at wk 12, then every 6 wk for the first year, and every 12 wk thereafter. Bone scans will be performed at baseline, and if positive, repeated at wk 18, 30, 42, and 54, and every 24 wk thereafter. AEs will be monitored throughout and graded per National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Primary end points are to compare progression-free survival (RECIST v1.1, central review) and overall survival between treatment arms. Secondary end points include the comparison of ORR, duration of response, disease control rate, safety, and patient-reported outcomes between arms. Enrollment is ongoing. Clinical trial information: NCT02853331.
A randomized, phase II efficacy assessment of multiple MET kinase inhibitors in metastatic papillary renal carcinoma (PRCC): SWOG S1500.
Authors: Pal Sumanta K. , Tangen Catherine M. , Thompson Ian Murchie , Shuch Brian M. , Haas Naomi B. , George Daniel J. , Stein Mark N. , Wright John Joseph , Plets Melissa , Lara Primo 
Published: September 2018

TPS4599 Background: PRCC constitutes approximately 15% of RCC cases, and no standard of care exists for metastatic disease. Approved VEGF- and mTOR-directed therapies for clear cell RCC in metastatic PRCC (mPRCC) have generally been ineffective. Trials assessing sunitinib and everolimus in non-clear cell RCC show a numerical advantage in progression-free survival (PFS) with sunitinib therapy. Prospective studies evaluating sunitinib in mPRCC show a broad range of efficacy, with PFS ranging from 1.6-6.6 months. Another possible approach to treating mPRCC is to target the MET protooncogene, which is frequently altered across both type I and type II disease. SWOG 1500 is a randomized, phase II study which will compare sunitinib to three MET-directed therapies in pts with mPRCC. Methods: Eligible pts will have PRCC (type I, type II or NOS), Zubrod performance status 0-1, and measurable metastatic disease. Pts may have received up to 1 prior systemic therapy, with the exception of prior VEGF-directed treatments. Treated brain metastases are allowed. Tissue must be available for central pathologic review of papillary subtype. Pts will receive either oral sunitinib, cabozantinib, crizotinib or savolitinib in a 1:1:1:1 randomization, with stratification by (1) prior therapy (0 vs 1) and (2) PRCC subtype (type I vs type II vs NOS). The primary endpoint of the study is to compare PFS with sunitinib to PFS with MET-directed therapies. Secondary endpoints in the study include comparison of response rate, overall survival and safety profile. Translational aims of the study include correlation of clinical outcome with MET mutation, copy number and other markers of MET signaling. Radiographic assessment will be performed every 12 wks. Interim analyses are planned for each arm. A total of 275 pts will be enrolled, with 26 pts registered as of Jan 30, 2017. Clinical trial information: NCT02761057.
A randomized phase II study of chemoradiation and pembrolizumab for locally advanced cervical cancer.
Authors: Duska Linda R. , Showalter Timothy Norman , Petroni Gina R. , Bullock Timothy 
Published: September 2018

TPS5601 Background: The standard of care for patients with LACC is concurrent chemoradiation therapy (CRT) with weekly cisplatin. Five-year disease overall survival after contemporary CRT for LACC is only 66%. Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ helper and CD8+ cytotoxic T cells are found in cervical tumors, indicating the inherent immunogenicity of these tumors. The failure of the immune system to eradicate HPV DNA integration is thought to be associated with the cancer cells’ acquisition of mechanisms to avoid cytotoxic T cells, including, but not limited to, the expression of checkpoint inhibitory molecules such as PD-L1 and the recruitment of FoxP3+ immunosuppressive regulatory T cells. Low ratios of CD8+ T cells: regulatory T cells are associated with poor survival for cervical cancer patients, suggesting that strategies to enhance immune response would be effective. Additionally, in cervical cancer, PD-1 is expressed by the majority of infiltrating CD8+ T cells, suggesting that blocking of PD-1 could have therapeutic potential, inducing tumor-specific immunity in cervical cancer patients. We hypothesized that CRT may increase tumor responsiveness to anti-PD-1 therapy by enhancing antigen availability and disrupting immune-regulatory networks. However, it is unclear how treatment with cisplatin and/or ionizing radiation could influence the quality and quantity of the immune response. Methods: A randomized Phase II open-label multi-center study was designed in which 88 eligible subjects with LACC will be treated with standard CRT plus the PD-1 monoclonal antibody pembrolizumab. The primary objectives in the study are to estimate the safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. Secondary objectives will evaluate the metabolic response and rates of distant metastases following treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also affords the opportunity to characterize the effect of treatment on immune response pathways by estimating the effects of treatment on specific immune markers. Clinical trial information: NCT02635360.
TRUST: Trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33 / AGO‐OVAR OP7).
Authors: Mahner Sven , Heitz Florian , Burges Alexander , Reuss Alexander , Kraemer Bernhard , Schmalfeldt Barbara , Sehouli Jalid , Lampe Bjoern , Schnelzer Andreas , Wimberger Pauline , Fotopoulou Christina , Guyon Frederic , Lecuru Fabrice , Querleu Denis , Greggi Stefano , Colombo Nicoletta , Aletti Giovanni Damiano , Harter Philipp , Du Bois Andreas 
Published: September 2018

TPS5602 Background: Primary cytoreductive surgery (PDS) followed by chemotherapy has been considered as standard management for advanced ovarian cancer patients (pts) over decades. An alternative approach of interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT) was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS). Owing to important limitations of these studies, especially regarding surgical quality, optimal timing of surgical therapy in advanced ovarian cancer is still unclear. Methods: TRUST is an international open, randomized, controlled multicenter trial investigating overall survival (OS; primary endpoint) after PDS vs NACT and subsequent IDS in pts with FIGO stage IIIB‐IVB ovarian, tubal, and peritoneal carcinoma. Secondary objectives are safety of complete tumor resection, progression‐free survival and quality of life (QoL) as well as surgical morbidity. In order to guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (e.g. ≥50% complete resection rate in upfront surgery for FIGO IIIB-IV pts, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST Quality committee delegates. A 1:1 randomization to PDS or NACT followed by IDS stratified by center and age‐ECOG combination (ECOG 0 and age ≤65 years vs ECOG > 0 or age > 65 years) is performed. Pts in the PDS arm will undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas pts in the IDS arm will be treated with 3 cycles of NACT after histologic confirmation of the disease, followed by IDS and subsequently 3 cycles of platinum-based chemotherapy. Intention of surgery for both groups will be complete tumor resection as per guideline recommendations. Health related QoL will be assessed using the EORTC QLQ‐C30, QLQ‐OV28, and EQ‐5D‐3L questionnaires. For sample size planning, we considered a prolongation of median OS from 45 months in the IDS arm to 60 months in the PDS arm (HR 0.75) as clinically relevant. 380 events are needed to obtain a power of 80% in two‐sided log-rank test with significance level of 0.05. The primary analysis will be done in the ITT‐population of 686 randomized pts. By Feb 3 2017, 46 pts were randomized. Clinical trial information: NCT02828618.
FORWARD I (GOG 3011): A randomized phase 3 study to evaluate the safety and efficacy of mirvetuximab soravtansine (IMGN853) versus chemotherapy in adults with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian cancer (EOC), primary peritoneal cancer, or primary fallopian tube cancer.
Authors: Moore Kathleen N. , Vergote Ignace , Oaknin Ana , Colombo Nicoletta , Banerjee Susana N. , Oza Amit M. , Pautier Patricia , Kelly Catherine Margaret , Malek Karim S. , Ruiz-Soto Rodrigo , Birrer Michael J. 
Published: September 2018

TPS5607 Background: Elevated FRα expression is characteristic of a number of solid tumors, including EOC, thereby providing an attractive candidate for targeted therapeutic approaches. Mirvetuximab soravtansine is an antibody-drug conjugate (ADC), comprising a FRα-binding antibody linked to the tubulin-disrupting maytansinoid DM4, that has shown single agent clinical activity and a favorable safety profile in an ongoing, first-in-human phase 1 trial (NCT01609556). Methods: FORWARD I is a randomized phase 3 study designed to evaluate the efficacy of mirvetuximab soravtansine compared with that of standard-of-care chemotherapy in adult patients with platinum-resistant EOC, primary peritoneal cancer, or fallopian tube cancer. Confirmation of FRα positivity by immunohistochemistry (medium or high expression; ≥ 50% of cells with at least moderate staining intensity) and ≤ 3 prior lines of therapy are required for inclusion. A maximum of 333 patients are expected to be recruited. Patients will be randomized 2:1 to Arm 1 (intravenous mirvetuximab soravtansine at a dose of 6.0 mg/kg, calculated using adjusted ideal body weight, on Day 1 of a 21-day cycle) or Arm 2 (investigators’ choice chemotherapy: paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary efficacy endpoint is progression-free survival (PFS; by blinded independent central review) and secondary endpoints include objective response rate, quality of life, overall survival, safety and tolerability, and duration of response. The first patient was enrolled in January 2017. Clinical trial information: NCT02631876.
Phase II open-label randomized multi-centre study of neoadjuvant olaparib in patients (pts) with platinum sensitive (PS) relapsed high grade serous ovarian cancer (OC): The NEO trial.
Authors: Kanjanapan Yada , Lheureux Stephanie , May Taymaa , Wilson Michelle K. , Bernardini Marcus , Shaw Patricia Ann , Vergote Ignace , Brenton James D. , Provencher Diane M. , McNeish Iain A. , Ghatage Prafull , Ledermann Jonathan A. , Colombo Nicoletta , Gourley Charlie , Weberpals Johanne , Ramsahai Janelle , Ricker Nicole , Accardi Sarah , Wang Lisa , Oza Amit M. 
Published: September 2018

TPS5608 Background: Olaparib is a PARP inhibitor with clinical benefit in relapsed OC, especially in pts with germline BRCA1/2 mutation ( gBRCA). Study 19 (NCT00753545) found a progression free survival (PFS) gain from maintenance olaparib, post chemotherapy for PS relapse. Olaparib treatment in gBRCA OC pts relapsing post ≥ 3 prior chemotherapy regimens gave a response rate (RR) of 46% in the PS subgroup (Study 42; NCT01078662). Efficacy of olaparib may extend to OC with homologous recombination DNA repair pathway deficiency (HRD); susceptible to synthetic lethality from PARP inhibition. NEO [NCT02489006] is a window of opportunity study to assess tumor heterogeneity and the pharmacodynamic effects of olaparib given prior to surgery in PS OC, analyse the tumor genomic landscape pre and post olaparib, and assess for predictive biomarkers beyond BRCA mutation. Methods: This phase 2 study enrols pts with high grade serous OC, primary peritoneal or fallopian tube cancer with a progression free interval of ≥6 months and sensitive to their last line of platinum therapy. Pts must be suitable for secondary debulking surgery and agree to pre-operative tumour biopsy. All pts receive olaparib tablets 300mg po bid for 6 ± 2 weeks pre-surgery. Post-operatively, pts are randomised 1:1 to olaparib or 6 cycles of platinum-based chemotherapy followed by maintenance olaparib. The primary endpoint is the degree of PAR and PARP-1 inhibition in the blood and tumor following pre-operative olaparib in PS relapsed OC. Clinical efficacy is assessed by RR (RECIST 1.1), CA125, PFS and PFS2. Translational studies include next generation sequencing HRD panel to assess for somatic and germline mutations including RAD51B/C/D, PPM1D, FANCM, BRIP1, PALB2 and BARD1; evaluation of gene expression change in tumor tissue pre and post olaparib; assessment for resistance mechanisms and impact of heterogeneity. Circulating tumor DNA measured weekly pre-surgery is assessed for its prognostic value, alone and compared with CA125. The study will enrol 50-70 pts with estimated accrual of 3 pts/month across multiple sites, and opened at Princess Margaret Cancer Centre in 7/2016. Clinical trial information: NCT02489006.
A phase II trial of enzalutamide in patients with androgen receptor positive (AR+) ovarian, primary peritoneal or fallopian tube cancer and one, two, or three prior therapies.
Authors: Grisham Rachel N. , Giri Dilip D. , Iasonos Alexia , Zhou Qin , Girshman Jeffrey , McGrath Sean Patrick , O'Cearbhaill Roisin Eilish , Sabbatini Paul , Tew William P. , Hyman David Michael , Hensley Martee Leigh , Zamarin Dmitriy , Konner Jason A. , Snyder Charen Alexandra , Cadoo Karen Anne , Spriggs David R. , Iyer Gopa , Aghajanian Carol 
Published: September 2018

TPS5610 Background: Approximately 75% of women with epithelial ovarian cancer (OC) present with advanced disease. Most of these women will ultimately recur and require life-long treatment for their cancer. Well tolerated therapies for treatment in the recurrent setting are needed. The AR is expressed in greater than 60% of cases of OC and is more prevalent than the estrogen or progesterone receptor. All past clinical studies of AR inhibition in OC have focused on unselected populations of heavily pretreated women; however preclinical data suggests that AR expression decreases in OC cells with increasing lines of therapy. Enzalutamide is a small molecule androgen receptor-antagonist that is FDA approved for treatment of prostate cancer and is currently being investigated as treatment for breast and ovarian cancer. Methods: This is a phase II, single-institution trial of enzalutamide 160mg po QD in patients with AR+ ovarian, fallopian tube or primary peritoneal cancer. Eligible patients must be found to have greater than or equal to 5% AR staining by IHC on FFPE tumor tissue and been treated with only 1,2 or 3 prior cytotoxic therapies. Patients must have RECIST 1.1 defined measurable disease. Enrolled patients are treated with enzalutamide until progression of disease or unacceptable toxicity. The primary endpoint is to estimate the proportion of women who achieve a complete or partial response by RECIST 1.1 criteria or survive progression free for at least 6 months. Secondary objectives include the retrieval of optional tumor biopsies at time of progression to evaluate the effect of enzalutamide on AR expression and to observe the effect of enzalutamide on serum testosterone and estradiol levels. This study will enroll 58 patients at Memorial Sloan Kettering Cancer Center and its regional sites. The study utilizes a safety lead-in phase and a two-stage design. The first patient enrolled in April 2015. The safety lead-in phase has been completed. The prespecified activity goal for the first stage was met; second stage accrual began in October 2016. Thus far, 35 patients have initiated treatment. Clinical trial information: NCT01974765.
A randomized controlled trial comparing primary tumor resection plus systemic therapy with systemic therapy alone in metastatic breast cancer (JCOG1017 PRIM-BC).
Authors: Shien Tadahiko , Mizutani Tomonori , Tanaka Kiyo , Kinoshita Takayuki , Hara Fumikata , Fujisawa Tomomi , Masuda Norikazu , Tamura Kenji , Hojo Takashi , Kanbayashi Chizuko , Niikura Naoki , Shibata Taro , Fukuda Haruhiko , Iwata Hiroji 
Published: September 2018

TPS588 Background: The possibility of improving the survival of stage IV breast cancer patients by primary tumor resection (PTR) has been reported by several retrospective studies; however, these studies essentially suffer from biases such as arbitrary patient selection, diverse timing of surgery or various regimens of systemic therapy. Five prospective randomized trials including our trial have evaluated the efficacy of PTR for them. Two have reported final results, but those results were inconsistent. Therefore, this subject still remains a hotly debated topic at major breast conferences. Methods: Our trial is being conducted to confirm the superiority of PTR plus systemic therapy over systemic therapy alone in stage IV pts who are sensitive to primary systemic therapy (PST) in this study. The inclusion criteria are untreated pts with histologically confirmed invasive breast cancer with one or more measurable distant metastatic lesions diagnosed by radiological examination.All pts receive PST according to the ER and HER2 status of the primary breast cancer after the first registration. After three months, the pts who are sensitive to PST are randomized to the PTR plus systemic therapy arm or the systemic therapy alone arm. After randomization and surgery in the former arm, or after randomization in the latter arm, the same systemic therapies are continued until progression of diseases and next appropriate regimens are started after that. The primary endpoint is the overall survival, and the secondary endpoints are proportion of pts without tumor progression at the metastatic sites, yearly local recurrence-free survival, proportion of local ulcer/local bleeding, yearly primary tumor resection-free survival, adverse events (AEs) of chemotherapy, operative morbidity, and serious AEs. Sample size for randomized pts was determined to attain at least 80% of power to detect a 6 months difference with one-sided alpha of 0.05.The pts accrual was started in May 2011. Enrollment of 410 pts for randomization is planned over a 7-year accrual period. 307 pts have been randomized until Jan 2017. This trial was registered at UMIN-CTR[umin.ac.jp/ctr/] as UMIN000005586. Clinical trial information: UMIN000005586.
PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients.
Authors: Earl Helena Margaret , Vallier Anne-Laure , Qian Wendi , Grybowicz Louise , Thomas Stanly , Mahmud Saba , Harvey Caron , McAdam Karen , Hughes-Davies Luke , Roylance Rebecca , Copson Ellen , Brown Jessica , Provenzano Elena , McMurtry Emma , Tischkowitz Marc , Abraham Jean 
Published: September 2018

TPS591 Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 - Safety: both research arms combined. Stage 2 - Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the-winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 - Efficacy: anticipated pCR ~55-60% for all trial patients and ~60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 17 Sites activated: 12 [expected number of sites 30-50].