bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 2 study of investigational TORC1/2 inhibitor TAK-228 with fulvestrant in women with ER+/HER2–advanced or metastatic breast cancer (mBC) that has progressed during or after aromatase inhibitor (AI) therapy.
Authors: Garcia Saenz Jose Angel , Ramos Vazquez Manuel , Martin Miguel , Ruiz Amparo , Morales Serafin , Bermejo Begona , Ruiz Isabel , Cubedo Ricardo , Merino Luis De la Cruz , Anton Antonio , Carrasco Eva Maria , Kneissl Michelle , Zohren Fabian , Martinez Noelia 
Published: September 2018

TPS1118 Background: Antiestrogen therapy, including AI, is standard for ER+ tumors in the adjuvant and metastatic setting; however, resistance is common. These tumors may respond to alternative second-line anti-estrogen therapies such as fulvestrant but response durations are often short. Preclinical and clinical studies suggest that simultaneous inhibition of ER and PI3K/mTOR could prevent/delay the emergence of hormone-independent cancer cells, thereby improving patient (pt) outcomes. This study will test whether fulvestrant plus TAK-228, a dual TORC1/2 inhibitor, can overcome endocrine therapy resistance in ER+ mBC. This is an open-label, randomized, phase 2 study of continuous once-daily TAK-228 (4 mg) or once-weekly TAK-228 (30 mg) plus fulvestrant (per label), vs fulvestrant alone, in pts with ER+/HER2– advanced or mBC that has progressed during/after AI therapy (EudraCT 2015-003612-20). Methods: 153 pts will be randomized 1:1:1 and stratified (presence or absence of visceral metastasis, prior hormonal therapy sensitivity, and prior exposure to CDK 4/6 inhibitors). Pts will receive study drug(s) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Pts with histological confirmation of ER+/HER2– advanced or mBC with measureable disease, ECOG 0–1, PD during/after prior AI therapy (progression ≤12 mos after discontinuation of adjuvant therapy or ≤1 mo after discontinuation in the metastatic setting) and adequate organ function, but not prior therapy with mTOR, PI3K, dual PI3K-mTOR or AKT inhibitors, or fulvestrant, > 1 prior line of chemotherapy for mBC or recurrent or progressive disease on > 2 endocrine therapies for mBC are eligible. This study aims to determine the efficacy (primary endpoint: PFS; secondary endpoints: OS, TTP, ORR), safety and tolerability of TAK-228 plus fulvestrant vs fulvestrant alone. The primary hypothesis (TAK-228 plus fulvestrant can improve median PFS to 8 mos [hazard ratio, HR 0.5] vs fulvestrant-alone median PFS of 4 mos) is to be tested at the 0.10 significance level (2-sided; dropout rate 10%). To date, 24 pts have been enrolled. Clinical trial information: EudraCT 2015-003612-20.
ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC).
Authors: Tripathy Debu , Tolaney Sara M. , Seidman Andrew David , Anders Carey K. , Ibrahim Nuhad K. , Rugo Hope S. , Twelves Chris , Dieras Veronique , Müller Volkmar , Hannah Alison , Tagliaferri Mary , Cortés Javier 
Published: September 2018

TPS1120 Background: EP is a next generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival (OS) at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). A Phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of OS (HR 0.087; p = 0.08); a subset of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86]; p < 0.01) (Perez Lancet Oncol 2015). The current Phase 3 trial (ATTAIN) was designed for this subpopulation of pts having high unmet medical need. Methods: Pts with MBC with locally treated stable BM will be randomized 1:1 to EP vs TPC in an open-label, randomized Phase 3 study. Eligibility includes ECOG PS 0 or 1; adequate organ function who received prior ATC (in neo/adjuvant or locally advanced/MBC setting); pts must have had ≥1 prior cytotoxic regimen for MBC (triple negative BC); ≥2 prior cytotoxic regimens and either 1 prior hormone therapy (HR+ BC) or 1 prior HER2 targeted therapy (HER2+ BC). Pts must have undergone definitive local therapy of BM (whole brain radiation [RT]; stereotactic RT or surgical resection as single-agent or combination); signs/symptoms of BM must be stable with steroids unchanged or decreasing for ≥7 days prior to randomization. Primary endpoint is OS. Key secondary endpoints: ORR and PFS by RECIST v1.1 and RANO-BM, clinical benefit rate (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 IV cytotoxic agents. Pts are stratified by region, PS and receptor status. 350 pts will be randomized to obtain number of events required at 90% power to detect a statistically significant improvement in OS (hypothesizing HR = 0.67); 1 interim analysis at 50% of deaths (130 events) will be performed. PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for potential predictive markers of efficacy. Enrollment will begin early 2017. Clinical trial information: NCT02915744.
A randomised phase 2 study of 3 weekly cabazitaxel vs weekly paclitaxel chemotherapy in the first-line treatment of HER2 negative metastatic breast cancer.
Authors: Bahl Amit , Braybrooke Jeremy 
Published: September 2018

TPS1122 Background: Breast cancer (BC) represents 25% of all cancers in women. Whilst the majority have early stage disease approximately 30% will develop metastatic breast cancer (MBC). In HER2 negative MBC, palliative chemotherapy is one of the main treatment options. It remains to be seen whether the use of adjuvant taxane chemotherapy leads to an increase in taxane resistance at the onset of MBC, although for patients with a relatively short disease free interval this may be the case. Cabazitaxel (CBZ) is a novel taxoid selected for development from preclinical evidence in cell lines resistant to docetaxel and paclitaxel including activity in a HER-2 positive BC tumour xenograft, with innate resistance to docetaxel. Clinically CBZ is licensed for metastatic castration-resistant prostate cancer following progression during or after docetaxel chemotherapy. A phase 3 RCT in this patient group showed a 3 month overall survival benefit for patients receiving CBZ and prednisolone compared with mitoxantrone and prednisolone. Methods: CONCEPT is an open label randomised phase 2 trial of first line chemotherapy in patients with HER-2 negative MBC where paclitaxel would be considered the standard treatment. Patients are randomised to cabazitaxel 25 mg/m2 every 21 days for 6 cycles or paclitaxel 80 mg/m2 weekly for 18 weeks. Eligibility includes patients who are PS 0 or 1 who may have received prior docetaxel in the adjuvant setting or be taxane-naïve. The primary endpoint is progression free survival (PFS), defined as the time between the date of randomisation and progression (according to RECIST version 1.1) or death from any cause. Secondary end-points include safety, overall survival and assessment of quality of life factors by FACT-B and EQ-5D-5L. For the current phase 2 study 90 patients will be recruited, with a 1:1 randomisation, proceeding to phase 3 of 160 patients, if the interim analysis does not show futility. To date 38 patients have been recruited from 10 centres. The IDMC met in Oct 2016 and recommended the study continue recruitment.
LCCC 1525: Combination immunotherapy with cyclophosphamide plus pembrolizumab in patients with advanced triple negative breast cancer (TNBC).
Authors: Vincent Benjamin Garrett , Moore Dominic T. , Moore Susan G. , Kaltman Rebecca Davidson , Puhalla Shannon , Gudena Vinay K. , Carey Lisa A. , Dees Elizabeth Claire , Muss Hyman B. , Reeder-Hayes Katherine Elizabeth , Jolly Trevor Augustus , Serody Jonathan Stuart , Anders Carey K. 
Published: September 2018

TPS1125 Background: Immunotherapy is a promising strategy to treat advanced TNBC, an aggressive subtype of BC lacking expression of estrogen and progesterone receptors and HER2. TNBC response to antibodies targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1) are modest (< 20%); high expression of PD-L1 is associated with enhanced response. The presence of intratumoral regulatory T cells (Tregs), potent suppressors of the immune response, dampens response to checkpoint inhibitors. The capacity of cyclophosphamide (Cy), a cytotoxic with known activity in BC, to deplete Tregs is well-established. Preclinical mouse models of TNBC illustrate Treg depletion with improved outcome when Cy is administered prior to PD-1 inhibition. We are testing the hypothesis that a single dose of Cy given prior to pembrolizumab (pembro) will improve progression free survival (PFS) beyond historical control in advanced TNBC. Methods: This phase II, single-arm, multicenter study will evaluate pembro 200 mg IV every 3 weeks following a single priming dose of Cy 300 mg/m2 IV in patients (pts) with advanced TNBC who have received ≥1 prior therapy in the metastatic setting. The primary objective is to estimate PFS for Cy + pembro in advanced TNBC pts. A co-primary objective is to describe reduction in circulating Tregs. Secondary objectives include overall response rate (ORR, RECIST 1.1), duration of response (DOR), disease control rate (DCR) and overall survival (OS). Determination of ORR based on immune response criteria (irRECIST) and association of immunogenomic features with PFS are exploratory. Statistical considerations: A sample size of 36 pts has an 80% power to detect change in median PFS from 1.9 (null) to 2.9 (alternative hypothesis) months at a 0.05 significance level. Assuming 10% dropout rate, we will enroll 40 pts. We will also be able to detect a 67% reduction in Tregs with 80% power and one-sided alpha = 0.05. Correlative studies: Archival primary and/or metastatic tissues are required of all pts to evaluate molecular subtype, gene signature expression, T and B cell receptor repertoires, and PD-1 and PD-L1 expression; correlations with outcome will be performed. Clinical trial information: NCT02768701.
Phase Ib study of heat shock protein 90 inhibitor, onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173).
Authors: Wesolowski Robert , Lustberg Maryam B. , Reinbolt Raquel E. , VanDeusen Jeffrey Bryan , Sardesai Sagar D. , Williams Nicole Olivia , Noonan Anne M. , Dewani Shabana Jaynul , Poi Ming , Wilson Debbie , Grever Michael R. , Stephens Julie , Puhalla Shannon , Mathew Aju , Carson William Edgar , Ramaswamy Bhuvaneswari 
Published: September 2018

TPS1127 Background: Heat shock protein 90 (HSP90) is a molecular chaperone which is necessary for proper folding and stabilization of proteins. Client proteins of HSP90 include many oncogenic proteins known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathway and androgen receptor. High expression of HSP90 in breast cancer has been associated with poor outcome. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Methods: Patients with inoperable or metastatic, triple negative or < 10% hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel is administered alone. The primary objective of the study is to determine recommended phase II dose and assess the toxicity profile of the combination. The secondary objectives include pharmacokinetic of each agent. Overall response rate, response duration and progression-free survival will also be assessed. The study is currently enrolling patients to dose level 2. Clinical trial information: NCT02474173. [Table: see text]
Clinical trials of VAL-083 in patients with chemo-resistant glioblastoma.
Authors: Bacha Jeffrey A. , Steino Anne , Schwartz Richard Stephen , Langlands John , Kanekal Sarath , Lopez Lorena , O'Brien Barbara Jane , Chen Zhongping , Penas-Prado Marta , Brown Dennis 
Published: September 2018

TPS2082 Background: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine and inducing interstrand DNA cross-links, double-strand breaks and cell death in GBM cell lines and GBM cancer stem cells, independent of MGMT status in vitro. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. Our recent phase I/II clinical trial in recurrent GBM patients failing both TMZ and bevacizumab, suggested that VAL-083 offers clinically meaningful survival benefits for patients with recurrent GBM and pinpointed a new dosing regimen (40 mg/m2/d on days 1,2,3 of a 21-day cycle) which was well-tolerated and was selected for study in subsequent GBM trials. Methods: These trials include i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves overall survival at 9 months, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962). ii) A pivotal Phase 3 study in recurrent GBM after failing both TMZ and bevacizumab. The control arm will consist of a limited number of salvage chemotherapies currently used in bevacizumab-failed GBM. If successful, this study will serve as the basis for a New Drug Application (NDA) submission for VAL-083. iii) A single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM. Clinical trial information: NCT02717962.
Cognitive support program for patients with brain metastases.
Authors: Richard Nadine M. , Bernstein Lori J. , Shultz David , Laperriere Normand , Kongkham Paul N. , Berlin Alejandro , Conrad Tatiana Deirdre , Millar Barbara-Ann , Bernstein Mark , Zadeh Gelareh , Edelstein Kim 
Published: September 2018

TPS2086 Background: Brain metastases occur in ~30% of cancer patients. While treatment options continue to evolve, prognosis remains poor in both morbidity and survival, and quality of life (QOL) is increasingly emphasized. Most patients will experience cognitive dysfunction. Deficits in executive and self-regulatory functions, memory, and communication interfere with patients’ functional independence, participation in valued activities, relationships and QOL; they also affect families and caregivers. There are currently no established interventions for oncology and supportive care teams to address cognitive dysfunction and its impact on patient and family QOL. This study targets this gap in knowledge and clinical practice through development and piloting of a novel cognitive support program (CSP) for brain metastasis patients and their primary caregivers. Methods: Building on relevant neuroscience and behavioral research in other cognitively-impaired populations, we designed the CSP as a brief, structured, client-centered program. Using a prospective longitudinal design, 24 cognitively-impaired patients are being recruited from an outpatient multidisciplinary brain metastasis clinic. Each patient, together with their primary caregiver, attends 3 weekly individual sessions to learn strategies for memory, communication and executive functions. At-home practice between sessions applies the strategies in daily activities. Feasibility will be assessed through retention and adherence. Preliminary efficacy will be assessed by reliable change on cognitive, functional and QOL measures completed by patients pre-, post-, and 3 months following the CSP intervention. Caregivers will complete ratings of patient functioning and their own QOL at the same intervals. Analyses of variance will examine CSP intervention effects, with regression analyses to explore moderating effects of participant demographics, baseline levels of cognitive impairment, disease and treatment factors (e.g., volume and location of brain lesions, CNS-directed treatments received). Results of this pilot trial will lay the groundwork for a future randomized trial and further development of cognitive supports for brain metastasis patients and their families.
A phase 1, open-label, dose-escalation study of olaratumab as a single agent and in combination with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide in pediatric patients with relapsed or refractory solid tumors.
Authors: Mascarenhas Leo , Tai Datchen Fritz , Bishop Michael William , DuBois Steven G. , Laetsch Theodore Willis , Levy Donna Elise , Pillay Sada 
Published: September 2018

TPS2599 Background: Olaratumab (LY3012207, IMC-3G3), a PDGFRα antagonist, is a targeted human IgG1 monoclonal antibody that specifically binds PDGFRα, blocking PDGF-AA, -BB, and -CC binding and receptor activation. Preclinical studies of olaratumab with or without chemotherapy have demonstrated antitumor activity in human sarcoma xenograft models. Positive survival outcomes were observed in adult patients with advanced soft tissue sarcoma when they were treated with olaratumab + doxorubicin vs doxorubicin alone in a randomized phase 2 trial. Methods: This multicenter clinical trial (NCT02677116) includes patients < 18 years of age with a diagnosis of relapsed or refractory solid tumors not amenable to curative treatment, for whom chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide is deemed appropriate. The primary objective is to determine a recommended dose of olaratumab + ≥1 chemotherapy regimen(s) in pediatric patients based on any dose-limiting toxicity, and olaratumab serum exposure-matching between adult and pediatric patients. Secondary objectives include assessment of antitumor activity of each combination, immunogenicity, and pharmacokinetics. At least 12 pediatric patients will be treated with 1 cycle (21 days) of olaratumab monotherapy (dose level 1 [Part A] and dose level 2 [Part B]) on Days 1 and 8. If the patient does not experience a dose-limiting toxicity in the first cycle of monotherapy, the patient will then receive olaratumab plus either doxorubicin, vincristine/irinotecan, or high-dose ifosfamide per investigator discretion. Dose-limiting toxicity criteria will also be evaluated for the respective combinations in cycle 2. Treatment will continue until disease progression or other discontinuation criteria are met. Dose level 2 will be initiated after acceptable safety results from dose level 1 monotherapy (a minimum of 6 evaluable patients, and the pharmacokinetic profile). As of December 2016, enrollment is currently occurring in dose level 1. Clinical trial information: NCT02677116.
A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of oral COH29, a novel ribonucleotide reductase (RNR) inhibitor in adult patients (pts) with advanced solid tumors.
Authors: Chao Joseph , Synold Timothy W. , Frankel Paul Henry , Mortimer Joanne E. , Chung Vincent M. , Smith D. Lynne , Nallu Rajiv , Pillai Raju K. , Simpson James , Horne David , Kwak Larry W. , Malkas Linda 
Published: September 2018

TPS2600 Background: Human RNR catalyzes the rate-limiting step in the formation of deoxyribonucleotide triphosphates (dNTPs) necessary for DNA repair and replication. Rapidly dividing tumor cells are especially sensitive to RNR inhibition due to elevated dNTP requirements. Overexpression of the RNR RRM2 subunit is also associated with neoplasia, metastasis, and poor prognosis. COH29 is an aromatically substituted thiazole compound that is a novel small molecule inhibitor of RNR activity, and exhibits unique mechanisms and target specificity that overcomes the weaknesses of other small molecule RNR inhibitors. Preclinically, it is more potent than hydroxyurea and gemcitabine, and is not associated with iron chelating-related toxicities such as hypoxia. Cell lines deficient in BRCA1 also exhibit greater sensitivity to COH29 than BRCA1 wildtype cell lines, implicating inhibition of DNA repair mechanisms in line with PARP inhibitors. Methods: In this Phase I, single site, dose escalation, safety study pts will receive oral COH29 twice a day for 21 days of a 28-day cycle. Eligible pts are age ≥ 18 years, ECOG ≤ 2, able to take oral medication, have adequate organ and marrow function, and diagnosed with any solid tumor refractory to standard therapies. Dose escalation will be pursued utilizing a Simon’s accelerated titration design, which allows skipping of dose levels (dose doubling) during the accelerated dose-finding phase. Primary objectives are to determine the maximum tolerated dose of COH29, toxicities per CTCAEv4, and PKs. Secondary objectives include assessment of objective response per RECIST 1.1 every 2 cycles. PD assessment includes measurement of plasma CK18 levels to determine degree of cellular apoptosis, evaluation of dNTP pool levels in peripheral blood mononuclear cells (PBMCs) to evaluate RNR inhibition, as well as measurement of PAR expression in PBMCs to assess PARP inhibition. Quantitation of tumor RRM2 expression using dual-color immunohistochemistry will be explored as a predictive biomarker of anti-tumor response to COH29. Clinical trial information: NCT02112565.