bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase II study of second-line treatment with liposomal irinotecan, and S-1 versus liposomal irinotecan and 5-fluorouracil in gemcitabine-refractory metastatic pancreatic cancer patients.
Authors: Pijnappel Esther , Vos-Geelen Judith de , Macarulla Mercade Teresa , Melisi Davide , Pfeiffer Per , Prager Gerald W. , Van Laarhoven Hanneke W.M. , Wilmink Johanna
Published: May 2020

TPS4664

Background: Pancreatic ductal adenocarcinoma (PDAC) is the deadliest form of cancer with a 5-year survival of less than 5% for patients with metastatic disease. Despite improvements over the past years, with the introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel, the majority has disease progression within 6 months after start of first line treatment. The NAPOLI trial was the first phase III study showing that patients with metastatic pancreatic cancer that progressed after treatment with gemcitabine-based chemotherapy benefitted from second line treatment. Patients received liposomal irinotecan (nal-IRI) either as a single agent or in combination with 5-fluorouracil/leucovorin (5-FU/LV), or 5-FU/LV alone. Patients treated with both nal-IRI and 5-FU/LV experienced a median overall survival (mOS) of 6.1 months versus 4.2 months for the 5-FU/LV group. Recently, two Japanese studies (GEST and JASPAC 01) reported on the use of S-1 in patients with PDAC. In patients with locally advanced or metastatic PDAC, S-1 was non-inferior compared to gemcitabine in terms of mOS (8.8 months for gemcitabine versus 9.7 months for S-1). In the adjuvant setting, S-1 showed superior mOS compared to gemcitabine, 46.5 and 25.5 months respectively, HR for mortality of S-1 compared with gemcitabine was 0.57 (95% CI 0.44–0.72). In view of these results, the objective of this NAPAN study is to compare the progression free survival (PFS) of nal-IRI plus S-1, with nal-IRI plus 5-FU/LV in a Western study population for second line treatment of PDAC. Methods: This is a multi-center, open label, randomized phase II trial. Patients ≥ 18 years of age with histologically or cytologically confirmed PDAC, previously treated with gemcitabine (-based) therapy, or progression within 6 months of adjuvant gemcitabine-based treatment are eligible. After a safety run-in of the nal-IRI plus S-1 regimen, patients will be randomized between nal-IRI plus S-1 and nal-IRI plus 5-FU/LV. Primary endpoint of the run-in phase is to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of nal-IRI when co-administered with fixed dose S-1. The primary endpoint of the phase II part is to determine the efficacy of the treatment arms in terms of PFS. Secondary endpoints include OS, response rate according to RECIST 1.1, adverse events according to CTC version 5.0 and Quality of life. Until now 2 of the planned 120 patients have been enrolled. Clinical trial information: NCT03986294 .
A phase II study of siG12D-LODER in combination with chemotherapy in patients with locally advanced pancreatic cancer (PROTACT).
Authors: Varghese Anna M. , Ang Celina , Dimaio Christopher J. , Javle Milind M. , Gutierrez Martin , Yarom Nirit , Stemmer Salomon M. , Golan Talia , Geva Ravit , Semenisty Valeriya , Khamaysi Iyad , Ligresti Rosario , Rotkopf Shay , Gabai-Malka Racheli , Galun Eithan , Shemi Amotz , Schattner Mark , O'Reilly Eileen Mary
Published: May 2020

TPS4672

Background: KRAS alterations are the most frequent driver alterations identified in pancreas cancer; however, KRAS has remained an elusive therapeutic target. siG12D-LODER is a novel, miniature bio-degradable polymeric matrix encompassing a novel small interfering RNA targeting KRAS G12D and all additional G12X mutations (G12C, G12V...). The siG12D-LODER is inserted directly into the pancreas tumor via endoscopic intervention. A Phase 1/2a dose escalation and expansion study of patients receiving a one-time dose of siG12D-LODER with ongoing chemotherapy demonstrated that the combination was well-tolerated and safe and exhibited promising potential efficacy with 10/12 patients achieving disease control and median overall survival 15.1 months (Golan, Oncotarget 2015). Methods: This phase 2 study was initially designed as a randomized, two arm, open label study of gemcitabine and nab-paclitaxel with or without siG12D-LODER for patients with locally advanced pancreas cancer with planned 40 patients in each arm and primary endpoint of progression-free survival. Eighteen patients were enrolled in the chemotherapy alone arm and 18 in the chemotherapy and siG12D-LODER arm. After an interim analysis, the study design has been amended and is now a single arm study in which patients (N=39) with both borderline resectable and locally advanced pancreas cancer will receive investigator’s choice of chemotherapy (the combination of gemcitabine/nab-paclitaxel or modified FOLFIRINOX) and all patients will receive up to three doses of the siG12D-LODER administered once every 12 weeks. Primary endpoint is overall response rate after final siG12D-LODER insertion. Secondary endpoints include duration of response, progression-free survival, overall survival, time to response, percentage of patients proceeding to surgical resection, and percentage of patients receiving radiation therapy. Exploratory analyses include evaluation of KRAS mutation status and monitoring of circulating free DNA and circulating tumor cells. The amended protocol is now open for accrual and four patients having been enrolled to date. Trial accrual is anticipated to be completed by December 2020. Clinical trial information: NCT01676259 .
Study EV-103: New randomized cohort testing enfortumab vedotin as monotherapy or in combination with pembrolizumab in locally advanced or metastatic urothelial cancer.
Authors: Mar Nataliya , Friedlander Terence W. , Hoimes Christopher J. , Flaig Thomas W. , Bilen Mehmet Asim , Balar Arjun Vasant , Henry Elizabeth , Srinivas Sandy , Rosenberg Jonathan E. , Petrylak Daniel Peter , Burgess Earle Frederick , Merchan Jaime R. , Tagawa Scott T. , Carret Anne-Sophie , Steinberg Joyce Leta , Chaney Marya F. , Milowsky Matthew I.
Published: May 2020

TPS5092

Background: Cisplatin-based chemotherapy is the standard for first-line (1L) patients (pts) with locally advanced/metastatic urothelial cancer (LA/mUC). PD-1/PD-L1 inhibitors have promising durability of responses but 1L use is restricted to pts ineligible for cisplatin-containing therapy and whose tumors express PD-L1 (CPS ≥10) or pts ineligible for platinum-containing chemotherapy regardless of PD-L1 status. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in UC. EV recently received FDA accelerated approval based on tumor response rates for adults with LA/mUC who have previously received a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy. In the ongoing phase 1b/2 study EV-103/KEYNOTE-869 (NCT03288545), the safety and antitumor activity of EV are investigated as monotherapy (mono) (for the first time in the 1L setting) and in combination with PD-1 inhibitor pembrolizumab (P) +/- chemotherapy in UC. An initial analysis of EV (1.25 mg/kg) + P (200 mg) (both drugs in investigational use here) in this study showed a 73.3% confirmed ORR in 45 1L cisplatin-ineligible LA/mUC pts (dose-escalation + expansion Cohort A) (Rosenberg ASCO 2020). Methods: A new Cohort K randomized 1:1 to 1.25 mg/kg EV mono or 1.25 mg/kg EV + 200 mg P provides additional information on EV + P and the contribution of activity from EV in cisplatin-ineligible pts with LA/mUC in the 1L setting. This cohort will enroll 150 adults (≥18 years) with LA/mUC and measurable disease per RECIST v1.1, and exclude pts with prior systemic treatment for LA/mUC, active CNS metastases, ongoing sensory or motor neuropathy (Grade ≥2), or uncontrolled diabetes. Cisplatin-ineligibility in this study is based on ≥1 of the following: ECOG of 2, creatinine clearance of ≥30 and < 60 mL/min, or hearing loss/dysfunction. In each 3-week cycle of this study, EV is administered on days 1 and 8, and P on day 1. The primary endpoint is ORR per RECIST v1.1 by BICR. Secondary endpoints include ORR per RECIST v1.1 by investigator assessment, DOR, DCR, PFS per RECIST v1.1 by BICR and investigator assessment, OS, safety, and tolerability. Sample size is not based on power calculation for formal hypothesis testing but is selected based on ORR estimate precision based on 95% CIs. Efficacy is summarized by treatment arm with no formal statistical comparisons between arms. The study opened in Oct 2017. Cohort K opened in Jan 2020. Clinical trial information: NCT03288545 .
Phase III study of pembrolizumab (pembro) plus chemoradiotherapy (CRT) versus CRT alone for patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-992.
Authors: Balar Arjun Vasant , James Nicholas D. , Shariat Shahrokh F. , Shore Neal D. , Van Der Heijden Michiel Simon , Weickhardt Andrew James , Fang Xiao , Godwin James Luke , Kapadia Ekta , Michalski Jeff M.
Published: May 2020

TPS5093

Background: Pembro has shown clinical activity across many stages of bladder cancer (BC), including metastatic BC, MIBC, and NMIBC. Current NCCN and AUA/ASCO/ASTRO/SUO guidelines recommend CRT as a bladder-preserving treatment option for selected pts with MIBC. This phase 3 study was designed to investigate the safety and efficacy of pembro + CRT in pts with MIBC who opt for bladder preservation. Ongoing phase 2 studies (NCT02662062; NCT02621151) have shown that pembro + CRT may be a promising therapeutic option in MIBC. Methods: KEYNOTE-992 (NCT04241185) is a phase 3, global, multicenter, double-blind, placebo-controlled, randomized trial to evaluate the efficacy and safety of pembro + CRT versus placebo + CRT in pts with previously untreated MIBC. Adults (≥18 years) opting for bladder preservation with histologically confirmed cT2-T4a, nonmetastatic (N0M0) MIBC after maximal TURBT are eligible. An estimated 636 pts will be randomly assigned 1:1 to receive CRT + either pembro 400 mg IV every 6 weeks (Q6W) or placebo. Treatment will continue with pembro or placebo Q6W for up to 9 doses. CRT regimens will be decided by the investigator before randomization. Accepted radiotherapy regimens are conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Accepted concurrent radiosensitizing chemotherapy regimens are cisplatin monotherapy (35 mg/m2 IV weekly), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) + mitomycin C (12 mg/m2 on day 1), or gemcitabine monotherapy (27 mg/m2 IV twice weekly). Randomization will be stratified by ECOG PS (PS 0/1 vs 2), PD-L1 combined positive score ( < 10 vs ≥10), T stage (T2 vs T3/4), and geographic region (US vs Europe vs rest of world). Pts must provide tissue for biomarker analysis. Efficacy will be assessed by cystoscopy (± biopsy), CT or MRI (with blinded independent central review), and urine cytology at 10 weeks after CRT, then Q12W up to the end of year 2, and then Q24W thereafter. The primary end point is bladder-intact event-free survival, defined as time from randomization to residual/recurrent MIBC, nodal or distant metastasis, radical cystectomy, or death from any cause. Key secondary end points are OS, metastasis-free survival, time to occurrence of NMIBC, and safety. Clinical trial information: NCT04241185 .
Phase III study of the hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Choueiri Toni K. , Albiges Laurence , Fan Li , Perini Rodolfo F. , Zojwalla Naseem J. , Powles Thomas , Rini Brian I.
Published: May 2020

TPS5094

Background: In RCC, the Von Hippel-Lindau ( VHL) tumor suppressor gene is inactivated in most cases, resulting in the accumulation and overactivation of HIF-2α. HIF-2α is a key oncogenic driver in RCC and is involved in the activation of genes associated with angiogenesis, tumor progression, and metastasis, such as vascular endothelial growth factor A ( VEGFA), cyclin D1, and CXCR4. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α, and it has shown antitumor activity in a phase 1/2 study in patients with previously treated advanced ccRCC. Methods: The current study (NCT04195750) is a phase 3, open-label, multicenter, randomized, active-controlled trial to compare the efficacy and safety of MK-6482 with everolimus in patients with previously treated advanced ccRCC. Adults aged ≥18 years will be eligible if they have unresectable, locally advanced, or metastatic ccRCC; have measurable disease per RECIST v1.1; and received ≤3 prior systemic regimens, which must include a PD-1/PD-L1 inhibitor (≥2 doses) and a VEGF-targeted therapy, for locally advanced or metastatic RCC. Approximately 736 patients will be randomly assigned 1:1 to receive MK-6482 120 mg orally once daily or everolimus 10 mg orally once daily. At randomization, patients will be stratified by International Metastatic RCC Database prognostic scores (0 vs 1-2 vs 3-6) and by the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 vs 2-3). Responses will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review at week 9 from the date of randomization, then every 8 weeks through week 49, and then every 12 weeks thereafter. Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event. Dual primary endpoints are progression-free survival per RECIST v1.1 and overall survival. Key secondary endpoints include objective response rate, duration of response, patient-reported outcomes, and safety. Clinical trial information: NCT04195750 .
PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 alterations.
Authors: Daneshmand Siamak , Grivas Petros , Sridhar Srikala S. , Gupta Shilpa , Bellmunt Joaquim , Sonpavde Guru , Fleming Mark T. , Lerner Seth P. , Loriot Yohann , Wang Hao , Takkele Hiywot , Andresen Corina , Rearden Jessica , Berman Craig , Pal Sumanta K.
Published: May 2020

TPS5095

Background: Radical surgery ± cisplatin‐based (neo)adjuvant chemotherapy (NAC) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients are unable to receive NAC due to cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a FGFR1–3 selective oral tyrosine kinase inhibitor, has shown promising clinical activity and tolerability in patients with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in patients with high-risk invasive urothelial carcinoma and susceptible FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 patients. Adults with high-risk invasive UTUC or UBC with susceptible FGFR3 genetic alterations (i.e. activating mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for or refusing cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin-based NAC are eligible. Those who received non cisplatin-based NAC are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Patients receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include quality of life, pharmacokinetics, cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. The study was initiated in late 2019 and is expected to end in 2024. Clinical trial information: NCT04197986 .
Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO): A single-arm, open-label window-of-opportunity trial of neoadjuvant abemaciclib in platinum-ineligible muscle invasive bladder cancer patients.
Authors: Nauseef Jones , Vlachostergios Panagiotis J. , Molina Ana M. , Nanus David M. , Sternberg Cora N. , McClure Timothy D , Scherr Douglas , Martin M. Laura , Inghirami Giorgio , Elemento Olivier , Tagawa Scott T. , Faltas Bishoy Morris
Published: May 2020

TPS5096

Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichment of molecular alterations in cell cycle genes in MIBC, including copy number losses of CDKN2A in 41% of pts. Abemaciclib is a unique CDK4/6 inhibitor with single agent activity and a target kinome distinct from other CDK4/6 inhibitors. We have demonstrated that CRISPR knockout of CDKN2A increases susceptibility to abemaciclib in bladder cancer cell lines. Beyond tumor-intrinsic effects, abemaciclib also modulates the tumor microenvironment (TME) via upregulating human endogenous retroviral elements and increasing T cell infiltration. Methods: Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO) is a single arm, window-of-opportunity trial of neoadjuvant abemaciclib which will evaluate tumor cell and TME changes in response to abemaciclib. Enrolled pts must be ineligible for platinum-based neoadjuvant therapy for resectable MIBC. Pts receive abemaciclib (200 mg BID PO) for 4 weeks prior to RC. Tumor tissue collected via transurethral resection of bladder tumor (TURBT) and residual tumor at RC undergo single cell RNA sequencing and whole-exome sequencing. Patient-derived organoids and xenografts are generated for a co-clinical trial of abemaciclib alone or in combination. The primary endpoint is the measurement of changes in cell cycle dynamics. Secondary objectives are assessment of toxicity via NCI CTCAE v 5.0 and pathologic downstaging of MIBC. We will perform targeted sequencing of a panel of cell cycle genes in serial plasma and urine cell free DNA to evaluate changes in the variant allele fractions of somatic alterations. The novel design of this trial allows dynamic in vivo assessment of tumor changes and creates a new paradigm for studying tumor evolution in real time. Clinical trials information: NCT03837821. Clinical trial information: NCT03837821 .
A phase III, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914).
Authors: Bex Axel , Russo Paul , Tomita Yoshihiko , Grünwald Viktor , Ramirez Luz-Margarita , McHenry Brent M. , Motzer Robert J.
Published: May 2020

TPS5099

Background: Surgery is standard treatment for nonmetastatic renal cell carcinoma (RCC). Unfortunately, patients (pts) with stage II or III RCC have high risk of relapse with 5-year disease-free survival rates of ~51%–56%; prevention of recurrence is an unmet need. In CheckMate 214, first-line nivolumab plus ipilimumab (NIVO+IPI) demonstrated significant overall survival improvements in pts with advanced/metastatic RCC, with a manageable safety profile. Moreover, while not yet confirmed in randomized controlled trials, evidence suggests that anti-PD-(L)1 monotherapy may provide sufficient clinical activity in some pts with advanced RCC. These findings indicate a potential for improved clinical outcomes in the early-stage adjuvant RCC setting. As such, the phase 3, double-blind CheckMate 914 study will evaluate NIVO and NIVO+IPI vs placebo in pts with high risk of relapse after nephrectomy (NCT03138512). Methods: Key inclusion criteria: radical or partial nephrectomy with negative surgical margins > 4 weeks and ≤12 weeks before randomization; predominantly clear cell histology; pathologic TNM staging T2a (grade [G] 3 or 4), T2b (any G), T3 (any G), or T4 (any G) N0M0, or any T (any G) N1M0; Eastern Cooperative Oncology Group performance status ≤1; no clinical/radiological evidence of macroscopic residual disease or distant metastases post-nephrectomy; and tumor tissue obtained ≤3 months pre-enrollment. Key exclusion criteria: conditions requiring corticosteroid or immunosuppressive systemic treatment, autoimmune disease, prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways, and prior systemic treatment for RCC. In part A, pts are randomized 1:1 to receive NIVO+IPI or placebo infusions; in part B, pts are randomized 1:1:2 to receive NIVO+IPI, placebo infusions, or NIVO with IPI placebo. All treatments are given for 24 weeks or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Stratification factors: TNM staging and type of nephrectomy procedure. Primary endpoint: disease-free survival per blinded independent central review (part A: NIVO+IPI vs placebo; part B: NIVO vs placebo). Secondary endpoints: overall survival (part A: NIVO+IPI vs placebo; part B: NIVO vs placebo and NIVO+IPI vs NIVO), disease-free survival (part B: NIVO+IPI vs NIVO), and safety. Enrollment in the study is ongoing. Total target enrollment across parts A and B is 1600 pts. Clinical trial information: NCT03138512 .
PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).
Authors: Haas Naomi B. , Puligandla Maneka , Allaf Mohamad E. , McDermott David F. , Drake Charles G. , Signoretti Sabina , Cella David , Gupta Rajan T. , Shuch Brian M. , Lara Primo , Kapoor Anil , Heng Daniel Yick Chin , Leibovich Bradley C. , Michaelson M Dror , Choueiri Toni K. , Jewett Michael A.S. , Maskens Deb , Harshman Lauren C , Master Viraj A. , Carducci Michael Anthony
Published: May 2020

TPS5101

Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 2020, 396 patients have been enrolled. Clinical trial information: NCT03055013 .
Phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adagloxad simolenin (OBI-822) and OBI-821 treatment in patients with early-stage triple-negative breast cancer (TNBC) at high risk for recurrence.
Authors: Rugo Hope S. , Chow Louis W. C. , Cortes Javier , Fasching Peter A. , Hsu Pei , Huang Chiun-Sheng , Kim Sung-Bae , Lu Yen-Shen , Melisko Michelle E. , Nanda Rita , Sharma Priyanka , Schwab Richard B. , Xu Binghe
Published: May 2020

TPS599

Background: Adagloxad simolenin (AS) is a therapeutic vaccine comprising the tumor-associated antigen Globo H linked to the carrier protein keyhole limpet hemocyanin (KLH). The KLH provides antigenic immune recognition and T-cell responses. AS is co-administered with a saponin-based adjuvant OBI-821 to induce a humoral response. A phase 2 trial showed that AS/OBI-821 exhibited a trend for superior progression-free survival vs placebo in patients whose breast cancers have higher Globo H expression. Methods: Patients with TNBC (ER/PR < 5%, and HER2-negative) with nonmetastatic disease and either 1) residual invasive disease of ≥1 cm in the breast or ≥1 positive axillary node following neoadjuvant chemotherapy or 2) ≥4 axillary lymph nodes with invasive carcinoma treated with adjuvant chemotherapy are included. Patients are prescreened for Globo H expression using a validated IHC assay (H-score of ≥15). Patients will receive either AS (30 μg) with OBI-821 (100 μg) or volume-matched placebo (1:1), administered as SC injections. Up to 21 SC injections of study treatment (or placebo), will be administered over 100 weeks, given on the following schedule: weekly for 4 doses; every 2 weeks for 4 doses; every 4 weeks for 4 doses; and then every 8 weeks for 9 doses. Patients may terminate treatment due to disease recurrence or unacceptable toxicity, withdrawal of consent, protocol violation, loss to follow-up or death. The primary objective is to determine the effect of AS/OBI-821 treatment on invasive disease-free survival in patients with TNBC at high risk for recurrence. Secondary objectives are to determine the impact of AS/OBI-821 treatment on overall survival, quality of life (QoL), breast cancer-free interval, distant disease-free survival, safety, and tolerability. Imaging and clinical examination will be performed regularly for 5 years. QoL will be assessed using the EORTC Core Quality of Life Questionnaire (QLQ)-C30 plus the EORTC Breast Cancer-specific QLQ-BR23 questionnaire and the European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire. Adverse events will be graded/recorded as per National Cancer Institute CTCAE v5.0. An estimated 668 subjects will be enrolled, treated for up to 2 years and followed until occurrence of 187 events (invasive disease recurrence or death) or 3 years from last subject randomized. Survival follow-up is for 5 years from randomization of last subject. Clinical trial information: NTC03562637 .
ENGOT-cx11/KEYNOTE-A18: A phase III, randomized, double-blind study of pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer.
Authors: Lorusso Domenica , Colombo Nicoletta , Coleman Robert L. , Randall Leslie M. , Duska Linda R. , Xiang Yang , Hasegawa Kosei , Rodrigues Angelica Nogueira , Cibula David , Mirza Mansoor Raza , You Benoit , Oaknin Ana , Christiaens Melissa , Taskiran Cagatay , Braicu Elena Ioana , Korach Jacob , Marth Christian , Keefe Stephen Michael , Puglisi Martina , Pignata Sandro
Published: May 2020

TPS6096

Background: High-risk locally advanced cervical cancer has a poor prognosis, and more than half of patients recur in 2 y. External beam radiotherapy (EBRT) with concurrent chemotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer. The immunostimulatory activity of the PD-1 inhibitor pembrolizumab (pembro) may be enhanced by concurrent chemoradiotherapy (CRT). After the KEYNOTE-158 study, in which pembro showed durable antitumor activity, pembro monotherapy was approved for patients with PD-L1–positive recurrent or metastatic cervical cancer who progressed during or after chemotherapy. ENGOT-cx11/KEYNOTE-A18 (NCT04221945) is a phase III, randomized, placebo-controlled study evaluating pembro with concurrent CRT for the treatment of locally advanced cervical cancer. Methods: Approximately 980 patients with high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA), locally advanced, histologically confirmed cervical cancer who have not received systemic therapy, immunotherapy, definitive surgery, or radiation will be randomized 1:1 to receive either 5 cycles of pembro 200 mg every 3 wk (Q3W) + CRT followed by 15 cycles of pembro 400 mg Q6W or 5 cycles of placebo Q3W + CRT followed by 15 cycles of placebo Q6W. The CRT regimen includes 5 cycles (with optional 6th dose) of cisplatin 40 mg/m2 Q1W + EBRT followed by brachytherapy. Randomization is stratified by planned EBRT type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cancer stage at screening (stage IB2-IIB vs III-IVA), and planned total radiotherapy dose. Treatment will continue until the patient has received 20 cycles of pembro (5 cycles 200 mg Q3W, 15 cycles 400 mg Q6W) vs placebo (~2 y) or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are PFS per RECIST v1.1 by blinded independent central review and OS. Secondary endpoints are PFS at 2 y, OS at 3 y, complete response at 12 wk, ORR, PFS and OS in PD-L1–positive patients, EORTC QLQ-C30 and QLQ-CX24, and safety. Enrollment is ongoing. Clinical trial information: NCT04221945.
Basket study of the oral progesterone antagonist onapristone ER in women with progesterone receptor positive (PR+) recurrent granulosa cell tumor (GCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC).
Authors: Grisham Rachel N. , Li Karen , Iasonos Alexia , Girshman Jeffrey , Cadoo Karen Anne , Kyi Chrisann , Makker Vicky , Cohen Seth M. , O'Cearbhaill Roisin Eilish , Sabbatini Paul , Schram Alison M. , Troso-Sandoval Tiffany A. , Chitiyo Viola N. , Kennedy Maureen , Ngangom Elena N. , Jang Dasom N. , Tew William P. , Chiang Sarah , Aghajanian Carol
Published: May 2020

TPS6098

Background: Onapristone extended release (ER) is a type I full progesterone antagonist that inhibits progesterone mediated PR activation and stabilizes PR association with corepressors. Onapristone has shown activity across multiple preclinical models of hormonally driven cancer. A phase I dose escalation study of onapristone ER in PR+ breast, endometrial and ovarian cancer patients found all doses tested to be well tolerated, with 50mg PO BID determined to be the recommended phase 2 dose (RP2D). GCT (98% of cases PR+), LGSOC (58% of cases PR+) and EEC (67% of cases PR+) are hormonally driven cancers which generally have poor responses to chemotherapy and limited treatment options in the recurrent setting. Methods: This is an open-label, investigator-initiated basket study of onapristone ER in patients with PR+ recurrent GCT, LGSOC, or EEC currently enrolling patients at Memorial Sloan Kettering Cancer Center in NY, USA (NCT03909152). The primary objective is to evaluate the efficacy, in terms of response rate by RECIST 1.1 criteria, within 36 weeks of treatment. Eligible patients must have received at least 1 prior line of chemotherapy, have measurable disease by RECIST 1.1 criteria, and have tumor tissue collected within 3 years prior to enrollment with PR expression ≥ 1% by IHC. Patients are allowed to have unlimited additional prior lines of chemotherapy, biologic therapy, immunotherapy or hormonal therapy. Enrolled patients are treated with onapristone ER 50mg PO BID until time of progression or intolerable toxicity. The 3 disease cohorts are currently enrolling to Stage I in parallel with expansion from stage I to stage II planned when the prespecified response criteria are met for each cohort as described in the table below. Clinical trial information: NCT03909152. [Table: see text]
MIRASOL (GOG 3045/ENGOT OV-55): A randomized, open-label, phase III study of mirvetuximab soravtansine versus investigator’s choice of chemotherapy in advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate-alpha (FRα) expression.
Authors: Moore Kathleen N. , Van Gorp Toon , Wang Jiuzhou , Esteves Brooke , Zweidler-McKay Patrick A
Published: May 2020

TPS6103

Background: Elevated FRα expression is a characteristic of several solid tumors, including epithelial ovarian cancer (EOC), thereby providing an attractive candidate for targeted therapeutic approaches. Mirvetuximab soravtansine is an antibody-drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has shown consistent and meaningful single agent clinical activity, along with favorable tolerability, in patients with high FRα expressing tumors. Methods: MIRASOL is a randomized phase III 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 high FRα positivity by immunohistochemistry (high expression; ≥ 75% of cells with PS2+ staining intensity) and ≤ 3 prior lines of therapy are required for inclusion. MIRASOL is designed to randomize 430 patients, 1:1 to Arm 1 (intravenous mirvetuximab soravtansine at a dose of 6 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 investigator) and secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. MIRASOL opened for enrollment in December 2019. Clinical trial information: NCT04209855.
DUETTE: A randomized phase II study to assess a second maintenance treatment with olaparib (ola) or ola+ceralasertib (cer), in patients (pts) with platinum-sensitive relapsed (PSR) epithelial ovarian cancer who have previously received PARP inhibitor maintenance treatment (NCT04239014).
Authors: Oza Amit M. , Pierce Andrew , Lau Alan , Kurian Nisha , Parr Graeme , Lao-Sirieix Si-Houy , Ah-See Mei Lin W. , Dean Emma , Loembé Bienvenu
Published: May 2020

TPS6104

Background: Ovarian cancer is the leading cause of death from gynecological cancers in the USA, and the fifth most common cause of cancer death in women. Ola is a PARPi approved for first-line maintenance treatment of BRCA-mutated advanced ovarian cancer in women who achieve a complete or partial response to platinum-based chemotherapy. Ola is also efficacious in combination with bevacizumab in the same population, independent of BRCA mutation status. Cer is a potent, oral, selective inhibitor of ATR. ATR is a critical DDR kinase that is activated in response to replication stress and stalled replication forks. There is no second maintenance standard of care for patients with PSR ovarian cancer who have previously received a PARPi in the maintenance setting. Pre-clinical models have shown that several mechanisms of PARPi resistance may be overcome by ATR inhibition, such as BRCA reversion, replication fork protection and DDR rewiring. DUETTE will select pts with tumor response or stable disease after second or third-line platinum-based treatment, with the expectation to enrich for non-BRCA reversion PARPi resistance mechanisms. The study will address the role of a second maintenance treatment following prior 1L or 2L maintenance, an emerging population of unmet need, and includes translational studies that aim to further our knowledge of clinical PARPi resistance mechanisms and predictors of treatment response. Methods: DUETTE is a global, multi-center, phase II study. 192 pts with PSR epithelial ovarian cancer who have previously received PARPi maintenance treatment, will be retreated with platinum and those who have not progressed after ≥ 4 cycles will be randomized (1:1:1) to 3 treatment arms: Arm 1, open-label: cer 160 mg once daily (qd) days 1 to 7 plus ola 300 mg twice daily (bd); Arm 2, blinded: ola monotherapy 300 mg bd and Arm 3, blinded: ola-placebo. Treatment is administered in 28-day cycles. All pts will be stratified by BRCA status (mutation or wildtype) and response to most recent line of platinum-based chemotherapy (CR/PR or SD). The primary endpoint is to assess the efficacy of maintenance ola monotherapy and cer+ola combination therapy compared with placebo by PFS using blinded, independent central review. Secondary endpoints are overall survival, PFS2, ORR, DoR, safety and tolerability. Enrolment is planned to start in April 2020.
Multicentre randomized phase II trial of olaparib as maintenance therapy in platinum-sensitive advanced endometrial carcinoma: The GINECO-UTOLA study.
Authors: Joly Florence , Brachet Pierre Emmanuel , Abadie Lacourtoisie Sophie , Asselain Bernard , Floquet Anne , Collard Olivier , Rodrigues Manuel , Leroy Karen , Jeanne Corinne , Leary Alexandra , Betrian Sarah , You Benoit , Fernandez Diez Yolanda , Hardy-Bessard Anne-Claire , Chevalier Annick , Kalbacher Elsa , Cornila Corina , Foa Cyril , Follana Philippe , Alexandre Jerome
Published: May 2020

TPS6109

Background: Advanced endometrial cancer (EC) patients relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Data from the TGCA suggest opportunities to targeting DNA repair in women with EC. Particularly type 4 (High copy number or serous like, with frequent TP53 mutations) and type 2 (microsatellite instability hypermutated) EC can be associated with defects in double strand break DNA repair by homologous recombination (HR) and could potentially be targeted by olaparib. We propose a placebo-controlled, multicenter, two-arm, phase II trial comparing olaparib versus placebo in maintenance therapy after chemotherapy in patients with advanced/metastatic EC. Methods: The primary objective of this trial is to evaluate the efficacy of maintenance olaparib in comparison to placebo after platinum based chemotherapy, defined by PFS according to Recist. Key eligibility criteria include: advanced/metastatic histologically confirmed EC (excepted carcino-sarcoma, small cells& neuroendocrine); prior surgery, adjuvant chemotherapy, radiation and hormonal therapy are permitted; objective or stable response after first-line chemotherapy is mandatory. 147 patients are randomized (2:1) after chemotherapy to receive Olaparib 300mg twice daily or placebo in maintenance after at least 4 cycles of platinum based chemotherapy. Olaparib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Stratification is on IHC P53 and MMR status. Primary hypothesis is a 66.7% relative increase in the median PFS rate in the olaparib arm (from 4.5 to 7.5 months), corresponding to a 0.60 Hazard Ratio. Secondary endpoints include PFS according to P53, MMR and NGS HRD status, PFS2, disease specific survival, time to subsequent therapy, overall survival, objective response, disease control rate, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24, EORTC-FA, EQ5D) and safety. Trial is recruiting in France (in February n= 40 randomization). Conclusion: this will be the first study that evaluate the efficacy of olaparib in maintenace after chemotherapy in advanced/metastastic EC, stratified on molecular profil. Clinical trial information: NCT03745950.
CCTG HN.10: A phase II single-arm trial of elective volume adjusted de-escalation radiotherapy (EVADER) in patients with low-risk HPV-related oropharyngeal squamous cell carcinoma (NCT03822897).
Authors: Bratman Scott Victor , Berthelet Eric , Butler James B. , de Almeida John R , Karam Irene , Metser Ur , Olson Robert Anton , Pochini Craig , Waldron John , Yu Eugene , McNiven Andrea , Cheung Winson Y. , Gaudet Marc , Hunter Sarah , Chen Bingshu E. , Parulekar Wendy R.
Published: May 2020

TPS6592

Background: Treatment for HPV positive(+) oropharyngeal squamous cell carcinoma (OSCC) is highly effective but associated with significant short and long term treatment related morbidity. We hypothesize that decreasing the regions of elective nodal irradiation (ENI) in the neck will lead to less toxicity and better quality of life/functional outcomes while maintaining high disease control rates in patients with favourable prognosis HPV+ OSCC. Methods: HN.10 is a Canadian Cancer Trials Group phase II trial with a primary objective to evaluate the efficacy of primary definitive radiotherapy (RT) or chemoradiotherapy (CRT) utilizing volume reduced ENI as measured by 2-year event-free survival (EFS) in patients with low-risk HPV+ OPSCC. Secondary objectives include to evaluate overall survival, local control, regional control, locoregional control, out-of-field regional control, distant metastasis free survival, early and late toxicities of treatment, subjective swallowing functions, quality of life, utilization of healthcare resources, work productivity, and prognostic biomarkers. An imaging and biospecimen bank will be compiled as part of trial conduct. Key eligibility criteria include: pathologically proven diagnosis of HPV+ OPSCC; HPV association determined locally by either p16 immunohistochemistry or direct detection of HPV DNA sequences (e.g. by PCR or in situ hybridization) performed on a core needle or surgical biopsy specimen of the primary tumour or involved cervical lymph node; clinical stage T1-3 N0-1 M0 (UICC/AJCC 8th Ed.); fit for radiotherapy +/-chemoradiotherapy. Statistical Design: The primary endpoint is 2-year EFS. Assuming 2-year EFS to be 91% (Ha) for low-risk HPV-related OPSCC with standard treatment, and that the experimental treatment will be considered as ineffective if the 2-year EFS is ≤ 85% (H0), with one-sided alpha of 0.1, a sample size of 100 patients will have 80% power to detect a 6% difference of 2-year EFS. With 3 years of accrual and 2 years of follow-up, the total duration of this study will be 5 years. A total of 304.7 person-years of follow-up is needed for the final analysis. The null hypothesis (H0) will be rejected when the observed survival rate is 88.85% or higher (i.e. if there are 18 or fewer EFS events observed). Conduct to Date: Study activation February 20, 2019. Enrollment as of January 29 2020: 23. Clinical trial information: NCT03822897 .
Open-label, randomized, multicenter, phase IV trial comparing parenteral nutrition using multi-chamber bags (Eurotubes) versus traditional 2/3-chamber bags in subjects with metastatic or locally advanced inoperable cancer requiring parenteral nutrition: The PEKANNUSS trial of the AIO.
Authors: Haag Georg Martin , Hofheinz Ralf-Dieter , Arends Jann , Goetze Thorsten Oliver , Roetzer Ingeborg , Serve Hubert , Pink Daniel , Weissinger Florian , Behringer Dirk M. , Zander Thomas , Luley Kim Barbara , Fischer von Weikersthal Ludwig , Lammert Frank , Dallacker Walter , Kreiss-Sender Janine , Koci Buleza , Mueller Daniel Wilhelm , Pauligk Claudia , Strehler Yara , Al-Batran Salah-Eddin
Published: May 2020

TPS7086

Background: Approximately 50% of all cancer subjects suffer from cancer anorexia-cachexia syndrome accompanied by an inadequate food intake and predicting mortality, poor therapeutic response, diminished functional capacity, and reduced QoL. Especially in the advanced stages, parenteral nutrition (PN) is often required and accompanied by an increased risk of blood stream infections associated with increased mortality and other serious medical conditions such as sepsis. Furthermore, the switch from oral food intake to PN changes the patient’s everyday life leading to reduced autonomy and flexibility (e.g. due to dependency on home nursing services). This study aims at evaluating the incidence of catheter-related infections (CRI) and the frequency of self-administered parenteral nutrition at home (HPN) in patients receiving standard PN via A) traditional two- or three-chamber bags (often requiring addition of vitamins and/or medications by home care service) or B). the multi-chamber bags Eurotubes (minimizing additional supplements and enabling self-administration by patients at home). In addition, one group of patients will receive low glucose HPN via Eurotubes to investigate a possible benefit on clinical outcome. Methods: This is an open-label, randomized, multicenter, investigator-initiated, phase IV trial. Overall, 350 patients with inoperable metastatic or locally advanced solid tumors who have an indication for parenteral nutrition will be enrolled. Patients will be randomized 1:1:1 ratio to Arm A (Standard PN using Eurotubes) or Arm B (Standard PN using 2/3-chamber bags), or to Arm A-1 (low glucose using Eurotubes). Patients will be assessed (physical exam, ECOG, weight, QoL, lab tests, AEs, HPN documentation) every 4 weeks during the 12 months HPN treatment period. Co-primary endpoints are incidence of CRI and patient autonomy (rate of self-administered PN at home). Secondary endpoints comprise weight change, change in albumin and CRP levels, overall survival, QoL, and safety. Recruitment has just started; first patient in was on February 5th, 2020. Clinical trial information: NCT04105777 .