bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II trial of venetoclax + fulvestrant versus fulvestrant in estrogen receptor+, HER2– locally advanced or metastatic breast cancer following recurrence or progression during or after a CDK4/6 inhibitor: VERONICA.
Authors: Lindeman Geoffrey J , Bardia Aditya , Bowen Rebecca , Flechais Aulde , Lei Guiyuan , Hogea Alexandra , Mobasher Mehrdad , Rafii Saeed 
Published: May 2019

TPS1108 Background: CDK4/6 inhibitors (CDK4/6is) administered with endocrine therapy have demonstrated improvements in progression-free survival (PFS) for estrogen receptor (ER)+ advanced breast cancer (BC), but resistance occurs, and new options are needed in the post-CDK4/6i setting. BCL2 is an estrogen-responsive anti-apoptotic molecule overexpressed in 75% of BCs. The BCL2 inhibitor venetoclax (Ven) has shown improved outcomes and tolerability in hematological malignancies such as chronic lymphocytic leukemia, and has been investigated in BC. A phase 1b study of Ven + tamoxifen demonstrated safety and an efficacy signal in ER+, BCL2+ metastatic BC (mBC). Preclinical data for Ven + fulvestrant (Ful) have also shown synergy. Based on these proof-of-principle data, the current study evaluates safety and efficacy of Ven + Ful vs Ful in women with ER+, HER2– locally advanced (LA)/mBC progressing after first- or second-line of prior therapy for metastatic disease, including ≥8 wks of a CDK4/6i. Methods: VERONICA is a global, randomized, phase 2, multicenter, open-label study. Eligible patients (pts) are aged ≥18 yrs with confirmed ER+, HER2–, inoperable LA/mBC, ≥1 measurable lesion, tissue evaluable for BCL2, and ECOG performance status 0–1. Prior Ful or Ven, or prior chemotherapy for LA/mBC are prohibited. Stratified by BCL2 expression (low vs high) and number of prior lines of mBC therapy (1 vs 2), pts are randomized 1:1 to Ven 800 mg PO daily + Ful 500 mg IM (cycle 1 days 1 and 15, and day 1 of each subsequent 28-day cycle) vs Ful 500 mg IM alone. Treatment continues until disease progression or intolerable toxicity. Primary endpoint is clinical benefit rate defined as complete/partial response + stable disease for ≥24 wks from randomization. Secondary efficacy endpoints include PFS, objective response rate, duration of response, and overall survival. Safety, pharmacokinetic, biomarker (e.g. BCL2 and PI3K expression) and patient-reported outcome analyses will also be conducted. Currently, 21 of the planned 100 pts have been enrolled; enrollment is ongoing. Clinical trial information: NCT03584009.
A phase II trial of olaparib and durvalumab in metastatic BRCA wild type triple-negative breast cancer.
Authors: Mitri Zahi Ibrahim , Vuky Jacqueline , Kemmer Kathleen A. , Savin Michael A. , Parmar Swapnil , Kolodzie Annette Kolodzie , Johnson Brett , Williams-Belizaire Rochelle , Gray Joe W. , Mills Gordon B. 
Published: May 2019

TPS1111 Background: There is an urgent need to develop novel non chemotherapy treatments for metastatic triple negative breast cancer (mTNBC) patients who otherwise have a poor prognosis. Immune checkpoint blockade (ICB) and PARP inhibitors (PARPi) have independently shown promise for the treatment of mTNBC, and the combination has shown early benefit in the MEDIOLA and TOPACIO trials. This trial looks to 1) evaluate the efficacy of the combination of the PARPi olaparib and the PD-L1 inhibitor durvalumab, and 2) perform extensive multi-omics including protein based image analytics (multiplex IHC, cyclic immunofluorescence) on serial biopsies to identify predictive biomarkers and resistance mechanisms. Methods: Trial Design: This is a single-arm phase II study to assess the efficacy of the combination of olaparib and durvalumab in BRCA-wildtype mTNBC. mTNBC participants will undergo a pre-treatment biopsy, then will start a 4 week induction treatment with olaparib (300 mg PO BID). At the end of 4 weeks of single agent therapy, participants will undergo a repeat on-treatment biopsy, following which durvalumab (1500 mg IV every 4 weeks) will be added to olaparib. Participants will also be offered an optional biopsy on progression. Endpoints: The primary endpoint of this study is overall response rate (ORR) to olaparib and durvalumab therapy. Secondary efficacy endpoints include clinical benefit rate, duration of response, progression-free, and overall survival. The incidence and severity of on-treatment adverse events will be collected per CTCAE 5.0. Statistical Methods: 28 participants are planned for enrollment to this study. A 2-stage analysis will be performed using a Simon 2-stage Minimax design. The null (ICB alone) and alternative (ICB + PARPi) hypotheses are: H0: π = 0.15 and Ha: π = 0.35. For the primary endpoint, a total sample size of 28 participants will achieve 80% power to detect the ORR difference of 0.20 with one-sided type I error =0.05. The trial will be terminated in stage I if 2 or less out of the first 15 participants respond. If the trial goes on to the stage II, a total of 28 participants will be studied. If the total number responding is less than or equal to 7, the combination is rejected. Current Enrollment: The study was activated on 1/7/2019. To date, 3 out of 15 patients have been accrued to stage I of the study Clinical trial information: NCT03801369.
Dora: A randomized phase II multicenter maintenance study of olaparib alone or olaparib in combination with durvalumab in platinum responsive advanced triple-negative breast cancer (aTNBC).
Authors: Sammons Sarah , Tan Tira Jing Ying , Traina Tiffany A. , Kim Sung-Bae , Im Young-Hyuck , Bachelder Carol , Marcom Paul Kelly , Dent Rebecca Alexandra 
Published: May 2019

TPS1113 Background: PARP inhibition (PARPi) with olaparib is approved in HER2-negative germline BRCA mutant (g BRCAm) metastatic breast cancer. Maintenance PARPi in relapsed platinum-sensitive ovarian cancer improves median PFS regardless of gBRCA mutation status. Preclinical work has shown that platinum response strongly correlates with olaparib response in breast cancer models; hence, maintenance therapy trials are underway in aTNBC. PARPi modulates immune responses and enhances immunogenicity in many preclinical models. We hypothesize that olaparib either alone or in combination with the PD-L1 inhibitor durvalumab will have clinical efficacy as maintenance therapy in aTNBC subjects who have responded to platinum-based chemotherapy. Methods: DORA is a randomized, international, multicenter, phase II study designed to explore the efficacy of olaparib or olaparib in combination with durvalumab as maintenance therapy in platinum-sensitive aTNBC. 60 subjects will be enrolled following a minimum of 3 cycles of treatment with platinum-based (cisplatin or carboplatin) chemotherapy as a single agent or combination therapy in the first or second-line setting. Subjects deriving clinical benefit (CR / PR / SD) from platinum-based therapy will be eligible and randomized in a 1:1 ratio. Patients in arm 1 will receive olaparib orally 300mg BID continuously and in arm 2 will receive olaparib orally 300mg BID continuously in combination with durvalumab 1500mg IV every 4 weeks. Assessment of tumor response will be done every 8 weeks. Primary endpoint: progression-free survival. Secondary endpoints: overall survival, clinical benefit rate, safety. Correlative analyses: pre-treatment archival/fresh biopsy samples are mandated. Post-treatment tissue biopsy is requested. Serial ctDNA will be collected at baseline, staging, and progression to correlate with response and track emerging genomic alterations in a platinum sensitive cohort under the pressure of PARP inhibition. Whole exome DNA sequencing, IHC for PDL-1 and TILs will be performed on tissue samples. ClincalTrials.gov Identifier: NCT03167619. (Moore K, et al "SOLO-1: Phase III trial of maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients with advanced ovarian cancer and a BRCA1/2 mutation" ESMO 2018; Abstract LBA7-PR). Clinical trial information: NCT03167619.
Novel anti-EGFRvIII bispecific T cell engager (BiTE) antibody construct in glioblastoma (GBM): Trial in progress of AMG 596 in patients with recurrent or newly diagnosed disease.
Authors: Rosenthal Mark , Balana Carmen , Van Linde Myra Ellen , Sayehli Cyrus , Fiedler Walter M. , Wermke Martin , Massard Christophe , Ang Agnes , Kast Johannes , Stienen Sabine , Cloughesy Timothy Francis 
Published: May 2019

TPS2071 Background: GBM is the most aggressive primary brain tumor in adults and is extremely difficult to treat. Patients with GBM tend to progress rapidly within weeks or months. Median overall survival is only 12–15 months despite aggressive treatment, and less than 5% of patients survive 5 years. GBM also severely impacts quality of life and cognitive function. Approximately 50% of GBM tumors test positive for amplification or mutation of the epidermal growth factor receptor (EGFR), the most common of which is the EGFRvIII gain-of-function mutation. AMG 596 is a bispecific T cell engager (BiTE®) antibody construct designed to crosslink and engage CD3-positive T cells to EGFRvIII-positive tumor cells, inducing tumor cell lysis and T cell proliferation. A clinical trial is being conducted for this novel immunotherapy agent in patients with EGFRvIII-positive GBM. Methods: NCT03296696 is a phase 1, first-in-human, open-label, sequential dose-escalation and dose-expansion study evaluating the safety, tolerability, and pharmacokinetics and pharmacodynamics (PK/PD) of AMG 596 in patients with EGFRvIII-positive GBM. AMG 596 is administered via continuous intravenous infusion. The study is expected to enroll approximately 82 patients total and comprises two groups (Group 1: patients with recurrent GBM; Group 2: patients with newly diagnosed GBM in the maintenance treatment phase after standard of care). Key inclusion criteria include: male or female; ≥ 18 years of age; with pathologically documented and diagnosed grade IV GBM; Eastern Cooperative Oncology Group performance status ≤ 1; life expectancy ≥ 3 months per study investigator; and acceptable renal, hematological, and hepatic function. The primary endpoint evaluates the safety and tolerability of AMG 596 via collection of treatment-emergent adverse events. Additional endpoints include objective response rate per modified Response Assessment in Neuro-Oncology Criteria and PK/PD analyses of AMG 596 in serum. The study began enrolling patients in April 2018 and enrollment is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com. Clinical trial information: NCT03296696.
Phase I study of PD-L1 inhibition with avelumab and laser interstitial thermal therapy in patients with recurrent glioblastoma.
Authors: Hormigo Adilia , Mandeli John , Hadjipanayis Constantinos , Gnjatic Sacha , Kim-Schulze Seunghee , Ghatan Saadi 
Published: May 2019

TPS2074 Background: Glioblastoma (GBM) the most frequent malignant brain tumor in the adult has a dismal prognosis and limited treatment options. Current advances have highlighted how tumors and specifically GBM evade the immune system by exploiting the mechanisms of tolerance and inducing local and systemic immunosuppression. Another hurdle in the treatment of GBM is the blood-brain barrier (BBB). Recent work suggests that MRI-guided laser interstitial thermal therapy (LITT) can increase the permeability of the BBB and may have an abscopal effect. Therefore, utilizing MRI-guided LITT, a potential immunogenic cell death-inducing procedure that disrupts the BBB and makes Avelumab a PD-L1 monoclonal antibody being more accessible to GBM tumors, seem a valid approach for immunomodulation and successful implementation of a combined regimen to treat brain cancer. Methods: This is a prospective non-randomized open label to characterize the tolerability and safety profile of Avelumab in combination with LITT in patients with recurrent glioblastoma who were treated with radiation therapy with concurrent Temozolomide chemotherapy at diagnosis, and whose tumor at recurrence measures less then 3 cm3. Avelumab is administered within a week after real-time MRI-guided LITT therapy and every 2 weeks thereafter. On part A patients are treated with intravenous Avelumab alone and on part B patients receive Avelumab in combination with MRI-guided LITT. Part A completed enrollment without DLT. Enrollment on part B began in October 2018. A Simon minimax two-stage design is being used for efficacy. Toxicity will be scored using the NCI-CTCAE 4.03 criteria. Blood samples and tumor tissue will be collected for correlative studies. Quantification of the changes in inflammatory and immunosuppressive profiles across time points for patients receiving treatment with Avelumab will be obtained. This information will instruct future immunotherapy approaches to treat GBM and the rational for those combinations. Clinical trial information: NCT03341806.
A phase I clinical trial using armored GPC3 CAR T cells for children with relapsed/refractory liver tumors.
Authors: Steffin David Henry Michael , Batra Sai A , Rathi Purva , Guo Linjie , Li Wenpeng , Courtney Amy N , Metelitsa Leonid S , Heczey Andras 
Published: May 2019

TPS2647 Background: CAR T therapies have been successful against hematologic malignancies, but have benefited only a handful of patients with solid cancers. Glypican 3 (GPC3) is an attractive immunotherapeutic target due to its preferential expression on multiple pediatric and adult solid cancers and lack of expression on non-malignant tissues. GPC3-CAR T cells were tested preclinically and inclusion of the 4-1BB costimulatory endodomain with IL-15 and IL-21 co-expression enabled CAR T cells to expand and persist the most in vitro and in vivo and led to robust antitumor activity in vivo. We are now testing GPC3-CAR T cells with IL15 and IL-21 for the first time in children with relapsed/refractory liver tumors. Methods: In this Phase 1 trial (GAP, NCT02932956), we are evaluating patients in 3 cohorts: 1) GPC3-CAR alone; 2) GPC3-CAR and IL-15; 3) GPC3-CAR with IL-15 and IL-21. We will 1) define the safety and establish the Recommended Phase 2 Dose (RP2D) of GPC3-CAR T cells co-expressing IL-15 and IL-21; 2) determine persistence and anti-tumor activity of GPC3-CAR T cells; 3) examine changes in gene and protein expression in the tumor microenvironment associated with potential immune escape mechanisms. Inclusion criteria are the following: age ≤18; histology proven, GPC3-positive tumor; life expectancy>12 weeks; Child-Pugh-Turcotte score<7; serum AST<5 times ULN; total bilirubin<3 times ULN for age; INR ≤1.7; absolute neutrophil count>500/μl; platelet count>20,000/μl; Hgb≥9.0 g/dl. Toxicity will be monitored using the Common Terminology Criteria of Adverse Events v4. The RP2D will be determined by the standard 3+3 dose escalation method using 5 dose levels. Persistence will be quantified using RT-PCR and flow cytometry. Antitumor activity will be defined by 3D imaging using RECIST 1.1 criteria and the immune-related response criteria. Immune-escape will be examined using single cell RNA sequencing and imaging of paraffin-embedded tissues using codetection by indexing to evaluate candidate proteins. Data will be analyzed via descriptive statistics. Cohort 1 of this study is now open for enrollment. Clinical trial information: NCT02932956.
A phase II study of autologous tumor infiltrating lymphocytes (TIL, LN-144/LN-145) in patients with solid tumors.
Authors: Chesney Jason Alan , Lutzky Jose , Thomas Sajeve Samuel , Nieva Jorge J. , Munoz Couselo Eva , Martin-Liberal Juan , Rodriguez-Moreno Juan Francisco , Cacovean Alex , Li Huiling , Fardis Maria , Gettinger Scott N. 
Published: May 2019

TPS2648 Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has demonstrated durable complete responses in immunogenic tumors with high mutational burden in metastatic melanoma patients who had not received prior immune checkpoint inhibitors (ICI); CR rate 24%. Pembrolizumab is an approved agent for the treatment of metastatic melanoma and head & neck cancers, among others. Further, ICI have been reported to potentially enhance the efficacy of TIL therapy. One aim of this study is to improve the efficacy response for early line patients by combining TIL with anti-PD-1 in ICI-naïve patients with metastatic melanoma (Cohort 1) and head & neck cancers (Cohorts 2). In Cohort 3, TIL therapy alone is offered to NSCLC patients who have received prior systemic therapy, including ICI. Methods: IOV-COM-202 is a prospective, Phase 2 multicenter, open-label study in which 36 patients (12 per cohort) are to be enrolled in one of three cohorts; Cohorts 1 and 2: TIL therapy in combination with pembrolizumab, or Cohort 3: TIL therapy alone. Patients will have tumors resected at local centers and shipped to a central GMP facility to undergo a 22-day manufacturing process that yields cryopreserved infusion product (LN-144/LN-145) that is shipped back to treating center. All patients receive TIL therapy consisting of 1 week of preconditioning cyclophosphamide/fludarabine, followed by a single infusion of LN-144/LN-145 (Day 0) and up to 6 doses of IL-2 (600,000 IU/kg). Patients in Cohorts 1 and 2 also receive pembrolizumab on Day -1 and then Q3W for up to 2 years or until disease progression or acceptable toxicity. Co-primary endpoints for each cohort are objective response rate (ORR) per RECIST 1.1, and safety (grade ≥ 3 TEAE). Eligibility criteria: Cohorts 1 (melanoma) and 2 (head & neck): patients must not have received prior ICI (eg, anti-PD-1, anti-CTLA-4) and may have received up to 3 lines of prior systemic therapy, Cohort 3 (NSCLC): patients must have received 1-3 prior lines of systemic therapy including ICI. After tumor resection for TIL manufacturing, patients must have additional measurable disease for assessment per RECIST 1.1. Adequate bone marrow/organ function and ECOG PS of 0 or 1 is required. Clinical trial information: NCT03645928.
Adoptive transfer of tumor-infiltrating lymphocytes in patients with sarcomas, ovarian, and pancreatic cancers.
Authors: Amaria Rodabe Navroze , Bernatchez Chantale , Forget Marie-Andree , Haymaker Cara L. , Conley Anthony Paul , Livingston J. Andrew , Varadhachary Gauri Rajani , Javle Milind M. , Maitra Anirban , Tzeng Ching-Wei David , Hinchcliff Emily , Bayer Virginia , Gasior Yvonne , Hilton Tyler , Celestino Joseph , Rangel Kelly M , Yuan Ying , Lu Karen H. , Hwu Patrick , Jazaeri Amir A. 
Published: May 2019

TPS2650 Background: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has a long history of efficacy in metastatic melanoma, and is being increasingly considered across other solid tumors. Preclinical data generated at MD Anderson Cancer Center has demonstrated the ability to grow TIL from a variety of tumor types including various types of sarcomas, ovarian and pancreas cancers. We are testing the efficacy of TIL across multiple tumor types using two different manufacturing protocols. Methods: We are conducting two ongoing investigator initiated basket TIL therapy trials. The first (NCT03449108) includes cohorts with poorly differentiated soft tissue and bone sarcomas, osteosarcoma, and platinum resistant ovarian cancer. The TIL product used in this trial is an investigational cell product (LN-145, Iovance Biotherapeutics, Inc.). The second trial (NCT03610490) includes cohorts of osteosarcoma, platinum resistant ovarian cancer, and pancreatic cancer (who have progressed on, or received maximal benefit from, front-line therapy). For this trial, TIL are manufactured at MD Anderson Cancer Center using a protocol that includes the use of urelumab (an agonistic anti-CD137 antibody) combined with T cell receptor activation during TIL expansion. In both trials eligible subjects undergo tumor harvest using a surgical excisional biopsy of the tumor for TIL manufacturing, receive a modified cyclophosphamide and fludarabaine lymphodepletion regimen and up to six doses of IL-2 (600,000 IU/kg) following TIL infusion. No intervening therapy is allowed between tumor harvest and initiation of lymphodepletion. The primary endpoint for each cohort is ORR as assessed by investigators using RECIST 1.1 criteria. The Simon’s two stage design is used to monitor the efficacy of each cohort independently. In the first stage, 10 patients will be treated per cohort. If there is no confirmed response in these 10 evaluable patients, the cohort will be terminated. If the cohort moves forward to Stage II, an additional 8 patients will be treated leading to a total of 18 patients. Three or more responders out of 18 treated patients for the cohort will be considered clinically relevant to justify further investigation. Enrollment is ongoing in all cohorts in both trials. An accrual update will be provided at the annual meeting. Clinical trial information: NCT03449108, NCT03610490.
SWOG 1609 (DART): A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors.
Authors: Patel Sandip Pravin , Othus Megan , Chae Young Kwang , Giles Frank , Hayward Jourdain , McLeod Christine , Chen Helen X. , Sharon Elad , Mayerson Edward , Ryan Christopher W. , Plets Melissa , Blanke Charles David , Kurzrock Razelle 
Published: May 2019

TPS2658 Background: Immune checkpoint blockade, in particular anti-CTLA-4 and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in advanced rare solid tumors. We sought to investigate the activity of ipilimumab and nivolumab in previously unstudied rare solid tumors, with planned biomarker evaluation pending including whole exome sequencing, RNAseq, and multiplex immune profiling via the NCI CIMACs. Methods: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1mg/kg iv q6weeks) plus nivolumab (240mg iv q2weeks) across 37 cohorts of rare tumors. Eligible patients had incurable rare cancer, defined histologically with an incidence of less than 6 in 100,000 per year, and did not have an approved or standard therapy available that had been shown to prolong overall survival. Patients were required to be 18 years of age or older, have a Zubrod performance status of 0-2, with absolute neutrophil count ≥ 1,000/mcL, platelets ≥ 75,000/mcL, hemoglobin ≥ 8 g/dL, creatinine clearance ≥ 50 mL/min, total bilirubin ≤ 2.0 x institutional upper limit of normal (IULN), AST and ALT ≤ 3.0 x IULN, TSH or free T4 serum ≤ IULN, and normal adrenocorticotropic hormone (ACTH) ≤ IULN. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (complete (CR) and partial responses (PR)); secondary endpoints included progression-free (PFS) and, overall survival (OS), stable disease (SD) ≥ 6 months, and toxicity. The primary objective of this Phase II trial was to evaluate the overall response rate (ORR, confirmed complete and partial responses [CR and PR]) by RECIST v1.1. Our objective was to distinguish between a true ORR 15% (null hypothesis) versus 30% (alternative hypothesis). A Simon’s two-stage design was used, which required an analysis on the first 6 eligible patients who received therapy. If 1 or more of the 6 patients had a response (confirmed CR or PR), an additional 10 patients were to be accrued. The study was activated on 1/13/17 with the first patient treated on 3/1/17. The trial is currently open at 862 sites across the NCTN (with 352 sites having enrolled patients) and 554 patients enrolled to date. Clinical trial information: NCT02834013.