bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase Ib/II study of niraparib combination therapies for the treatment of metastatic castration-resistant prostate cancer (NCT03431350).
Authors: Subudhi Sumit Kumar , Aparicio Ana , Zurita Amado J. , Doger Bernard , Kelly William Kevin , Peer Avivit , Rathkopf Dana E. , Karsh Lawrence Ivan , Tryon Jeffrey J. , Kothari Nishi , Zhao Xin , Zhu Eugene , Ricci Deborah S. , Tran Namphuong , De Bono Johann S.
Published: May 2019

TPS5087

Background: Assessing multiple therapies in a single clinical trial can facilitate the rapid identification of new agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib (Nirap) is a highly selective PARP inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. PARP inhibition may be especially lethal in tumor cells with genetic DNA damage response deficits (DRD). Based on promising preclinical and clinical data, this study is designed as a master protocol with nirap as a backbone therapy. Combination 1 assesses the safety and efficacy of nirap plus JNJ-63723283 (JNJ-283), an anti-PD-1 monoclonal antibody. Combination 2 assesses nirap plus abiraterone acetate and prednisone (AA-P). Methods: This multicenter, global, open-label study is currently open at 18 sites in 5 countries of the planned XX sites, and is enrolling patients with mCRPC who have progressed on ≥1 androgen-receptor targeted therapy for mCRPC. Enrollment at time of abstract submission was 25 for combination 1. When combined with AA-P, the RP2D has been determined to be nirap 200 mg. The recommended phase-2 dose (RP2D) of nirap plus JNJ-283 was determined in Part 1 based on the incidence of specified adverse events and PK data to be 480 mg every 4 weeks. For Part 2 of the study, patients are assigned to receive oral niraparib daily plus JNJ-283 infusions once every four weeks until disease progression, unacceptable toxicity, death, study termination. Part 2 is described in the table. Clinical trial information: NCT03431350. [Table: see text]
Prostate cancer with oligometastatic relapse: Combining stereotactic ablative radiotherapy and durvalumab, a randomized phase II trial (POSTCARD - GETUG-P13).
Authors: Supiot Stéphane , Libois Vincent , Guimas Valentine , Rio Emmanuel , Rolland Frederic , Bompas Emmanuelle , Vansteene Damien , Tigreat Marine , Lisbona Albert , Colliaux Jeremy , Campion Loic , Blanc-Lapierre Audrey
Published: May 2019

TPS5088

Background: Following Stereotactic Body RadioTherapy (SBRT) targeting prostate cancer (PCa) oligometastasis, a tumor response assessed by PSA decrease is observed in a majority of case. To increase this tumor response, immune targeting agents can be combined with SBRT. We hypothesize that the anti-PDL1 agent Durvalumab will enhance immune response following SBRT targeting oligometastatic lesions. In this multicenter randomized phase II trial, we therefore propose to assess the comparative efficacy of SBRT with or without Durvalumab (MEDI4736) in oligometastatic recurrent hormone sensitive prostate cancer patients. Methods: Patients with PCa were eligible if they had a biochemical recurrence following treatment with curative intent, with a maximum of 5 bone or lymph node metastases, seen only on FCH-PET CT or Ga-PSMA PET CT, not seen on conventional imaging assessments (bone scan or thorax, abdomen and pelvis CT scan). Main exclusion criteria are serum testosterone level < 8.5 nmol/ml, PSA doubling time less than 6 months, lung, brain, liver or other visceral metastases, any prior immune therapy. Patients were randomly assigned (2:1) to either SBRT + Durvalumab, or SBRT alone, with a stratification by investigation center, and number of metastases (1 vs 2-5). Durvalumab (1500 mg/cycle) will be started one month prior to SBRT to be able to evaluate PSA and immune response to the drug. It will be combined with SBRT (3x 9 or 3 x 11 Gy) and then given adjuvantly until progression with a maximum of 12 months. Ninety-six patients will be recruited in 15 centers over a recruitment period of 2.5 years. The primary endpoint is two-year Progression-free survival. Secondary objectives include quality of life, androgen deprivation therapy free survival, prostate cancer specific survival, overall survival, time to first symptomatic event, acute and late toxicity. Patients in both groups will be observed for PSA progression every 3 months after random assignment, with confirming imaging at PSA progression. Clinical trial information: NCT03795207.
IMPACT: Immunotherapy in patients with metastatic cancers and CDK12 mutations.
Authors: Reimers Melissa Andrea , Abida Wassim , Chou Jonathan , George Daniel J. , Heath Elisabeth I. , McKay Rana R. , Pachynski Russell Kent , Zhang Jingsong , Choi Jae Eun , Feng Felix Y , Neshewat Gina , Cieslik Marcin , Daignault-Newton Stephanie , Small Eric Jay , Chinnaiyan Arul , Alva Ajjai Shivaram
Published: May 2019

TPS5091

Background: Tumors with biallelic CDK12 loss have been identified as a distinct subtype in metastatic castration resistant prostate cancer (mCRPC) and other cancer types. The CDK12 biallelic loss mCRPC genomic signature, distinct from homologous recombination deficient (HRD) and ETS fusion signatures, is characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens, and increased tumor T cell infiltration. Early clinical experience with anti-PD-1 immunotherapy in CDK12 loss mCRPC patients (pts) is notable for deep and sustained PSA as well as radiographic responses. We hypothesize that CDK12 biallelic loss is a potential biomarker of immune checkpoint immunotherapy (ICI) efficacy in mCRPC and other cancers. Methods: IMPACT (NCT03570619) is a multi-center, open label, phase 2 study of pts with metastatic cancers that harbor CDK12 biallelic loss. mCRPC pts will be enrolled in cohort A (n = 25) in a Mini-Max Simon Two-Stage design, and all other pts in single-stage cohort B (n = 15). All pts will receive induction therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks (up to 52 weeks in total). Eligible pts must have identified biallelic CDK12 loss on any CLIA/CAP approved next generation sequencing assay and a histologic diagnosis of metastatic prostate adenocarcinoma or other metastatic carcinoma. No prior ICI is allowed. The primary endpoint is the overall response rate (ORR) in cohort A per PCWG3 criteria. An ORR of 30% is targeted in cohort A. Secondary endpoints include safety, secondary efficacy measures, quality of life, and survival measures. Exploratory objectives include tumor whole exome analysis and changes in immune profiles with therapy. Comprehensive and serial monitoring of peripheral blood immune cell populations will be performed via T cell clonal diversity assessment and multi-parametric flow cytometry. Changes in myeloid and lymphoid populations will be assessed from whole blood. Polarization and effector function of T cells and activation of antigen presenting cells will be further characterized from isolated peripheral blood mononuclear cells. Study accrual is ongoing. Clinical trial information: NCT03570619.
BEATcc (ENGOT-Cx10/GEICO 68-C/GOG3030/JGOG1084): A randomized, open label, phase III study of cisplatin and paclitaxel chemotherapy with bevacizumab (CTx plus B) with or without atezolizumab (Atz) as first-line treatment for metastatic, persistent, or recurrent (m/r) carcinoma of the cervix (CCx).
Authors: Oaknin Ana , Gladieff Laurence , Colombo Nicoletta , Villacampa Guillermo , Mirza Mansoor Raza , De Giorgi Ugo , Randall Leslie M. , Takekuma Munetaka , González-Martín Antonio
Published: May 2019

TPS5594

Background: The combination of CTx plus B is first line treatment for most patients (pts) with m/r CCx not amenable for local therapy based on GOG240 results. GOG240 regimen showed an improvement in overall survival (OS) compared to CTx alone: 16.8 vs. 13.3 months (HR 0.77, 95% CI 0.62–0.95, p = 0.007). However, further improvement in first line therapy outcomes is an unmet need. Immune-checkpoint inhibitors are breakthrough therapies in several tumor types, and their development in CCx is supported by a strong scientific rationale. Human papillomavirus infection (HPV) causes more than 90% of CCx cases. PD-L1 is a HPV biomarker and is found frequently up-regulated in CCx. Nivolumab and pembrolizumab (Pb) (anti-PD-1 antibodies) have shown response rates of 26.3% and 14.3%, respectively, in pretreated m/r CCx. This has led to the recent FDA approval of Pb in pretreated PD-L1+ m/r CCx. The BEATcc trial (NCT03556839) evaluates the addition of the anti-PD-L1 agent Atz to GOG240 regimen as first line treatment for m/r CCx, following the synergistic rationale between anti-VEGF agents and PD-1/PD-L1 blockade. Methods: Eligible pts: m/r CC with adequate organ function. Pts will be randomized 1:1 to either Arm A (control): C 50 mg/m2 + Tx 175mg/m2 + B 15 mg/kg (CTx plus B) i.v. D1 Q3W or Arm B (experimental): CTx plus B + Atz 1200 mg i.v. D1 Q3W. Stratification factors: prior chemo-radiation, histology and Chemotherapy backbone (CTx vs carboplatin-Tx). Treatment is planned until disease progression, unacceptable toxicity or withdrawal of consent. Pts with a complete response after ≥6 cycles or those with unacceptable CTx toxicity may be allowed to continue only on biologics therapy. An Independent Data Monitoring Committee will analyze the safety of the first 12 pts in the experimental arm completing 2 treatment cycles. The primary endpoint is OS. The study started enrolling in October 2018 and will enroll approximately 404 pts across Europe, Japan, and the US. Clinical trial information: NCT03556839.
Phase 2 trial of tisotumab vedotin in platinum-resistant ovarian cancer (innovaTV 208).
Authors: Mahdi Haider , Schuster Steven Robert , O'Malley David M. , McNamara Donna M. , Rangwala Reshma A. , Liang Shang-Ying , Jain Shweta , Nicacio Leonardo , Chon Hye Sook
Published: May 2019

TPS5602

Background: Ovarian cancer (OC) is the most lethal gynecologic cancer, accounting for ≈185,000 deaths worldwide in 2018. Most patients (pts) initially respond to platinum-based chemotherapy (chemo), but more than 50% of pts recur. Pts who recur in ≤6 months have platinum-resistant OC (PROC), which is associated with poor prognosis. Standard therapy for PROC includes chemo ± bevacizumab (bev). However, many pts receive single-agent chemo, which demonstrates limited response and survival (≈12% ORR, 3-4 mo PFS, ≈12 mo OS). Therefore, there is an urgent need for novel therapeutic strategies. Tissue factor (TF) is a novel oncogenic target expressed in OC. Tisotumab vedotin (TV) is a first-in-class antibody drug conjugate comprising a TF-targeted fully human monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. TV has shown encouraging antitumor activity and a manageable safety profile in PROC in the multicohort phase 1/2 innovaTV 201 study. innovaTV 208 is a multicenter, open-label, phase 2 trial with a safety run-in phase for a dose-dense regimen (DDR) evaluating the efficacy and safety of TV in pts with PROC. Methods: innovaTV 208 will enroll ≈142 adult pts with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer; measurable disease by RECIST v1.1; and ECOG score 0-1. Eligible pts must have received bev-containing treatment for OC. Pts with platinum-refractory disease, increased risk of bleeding, active ocular surface disease, or grade > 1 peripheral neuropathy will be excluded. A safety run-in phase for the DDR will be performed in up to 12 pts who received ≤5 prior treatment regimens for PROC. In the DDR, TV will be given at previously decided lower doses IV 3Q4W for the same dose intensity as the standard 1Q3W dose; the primary endpoint is incidence of DLTs. In phase 2, pts who received ≤1 prior cytotoxic chemo regimen for PROC will be randomized to receive TV administered as IV 1Q3W or as IV 3Q4W, if shown to be tolerable. The primary endpoint for phase 2 is confirmed ORR by RECIST v1.1. Secondary endpoints include DOR, time to response, DCR, CA-125 response rate by GCIG criteria, PFS, OS, pharmacokinetics, and safety. Clinical trial information: NCT03657043.
A phase 3 trial evaluating efficacy and safety of lenvatinib in combination with pembrolizumab in patients with advanced endometrial cancer.
Authors: Makker Vicky , Casado Herraez Antonio , Aghajanian Carol , Fujiwara Keiichi , Pignata Sandro , Penson Richard T. , Dutcus Corina E. , Guo Matthew , Dutta Lea , Orlowski Robert , Smith Alan , Miller David S.
Published: May 2019

TPS5607

Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor α, RET, and KIT. Pembrolizumab (PEMBRO) is a monoclonal antibody targeting programmed cell death receptor 1 (PD-1). Preliminary analyses of a phase 1b/2 study of LEN + PEMBRO showed promising antitumor activity and a manageable safety profile in advanced endometrial cancer (EC). Methods: A multicenter, randomized, open-label, phase 3 study (KEYNOTE-775/E7080-G000-309; clinicaltrials.gov NCT03517449) will evaluate efficacy and safety of LEN + PEMBRO vs treatment of physician’s choice (TPC) in patients with advanced EC. Patients must be aged ≥ 18 years, have advanced EC that progressed after 1 prior platinum-based therapy, have measurable disease per RECIST v1.1, and an Eastern Cooperative Oncology Group performance status ≤ 1. Patients must have mismatch repair (MMR) status confirmed by central laboratory via immunohistochemistry on archived or fresh tumor biopsy. ~780 patients (~120 MMR-deficient; ~660 MMR-proficient) will be randomized to receive LEN 20 mg orally once daily and PEMBRO 200 mg intravenously (IV) every 3 weeks (Q3W) or TPC. Patients will be randomized first according to MMR status; MMR-proficient patients will be further stratified by ECOG PS, geographic region, and prior history of pelvic radiation. TPC is either doxorubicin 60 mg/m2 by IV Q3W or paclitaxel 80 mg/m2 by 1-hour IV infusion weekly (3 weeks on/1 week off). The dual primary endpoints are progression-free survival (PFS; per RECIST v1.1 by blinded independent central review) and overall survival (OS). The PFS analysis will occur at the planned interim analysis (~363 OS events in MMR-proficient patients; ~524 PFS events), and the study will have 99% power to detect a hazard ratio (HR) of 0.55 with a 1-sided 0.0005 significance level. A final OS analysis will occur at 518 OS events, when the study will have 90% power to detect a HR of 0.75 with a 1-sided 0.0245 significance level. Secondary endpoints include objective response rate, health-related quality of life, safety and tolerability, and pharmacokinetics. Clinical trial information: NCT03517449.
ADAPTcycle: Adjuvant dynamic marker-adjusted personalized therapy comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk HR+/HER2- early breast cancer.
Authors: Harbeck Nadia , Gluz Oleg , Christgen Matthias , Graeser Monika , Hilpert Felix , Krauss Katja , Kreipe Hans Heinrich , Nitz Ulrike , Kates Ronald E. , Schinkoethe Timo , Wuerstlein Rachel , Kuemmel Sherko
Published: May 2019

TPS596

Background: WSG (West German Study Group)-ADAPTcycle is a prospective, multi-center, interventional, two-arm, open-label, controlled (neo)adjuvant, non-blinded, randomized phase III trial (EudraCT 2018-003749-40). It investigates whether HR+/HER2- intermediate-risk patients (pts) (about 20 % of HR+/HER2- early breast cancer, EBC) identified during screening (OncotypeDX and 3-week endocrine therapy (ET)) derive additional benefit from 2-years of the CDK4/6 inhibitor ribociclib plus ET compared to chemotherapy (CT) (followed by adjuvant ET). Co-primary endpoints are disease-free and distant disease-free survival. Methods: Starting Q1 2019 (enrollment 36 months, 80 sites), 5600 pts will be screened and 1670 randomized in a 3:2 ratio (1002 to ribociclib + ET; 668 to standard CT followed by ET). Pre-/postmenopausal pts with histologically confirmed invasive HR+/HER2- EBC at clinically enhanced risk (cT2-4 or Ki67 > 20 % or G3 or cN+) are eligible if they fulfill the ADAPT intermediate-risk group criteria: Recurrence Score (RS) ≤ 25 and poor endocrine response or RS > 25 and good endocrine response in p/cN0-1 pts or RS ≤ 25 with good endocrine response in c/pN2-3 pts. Endocrine responsiveness is determined by Ki67 response (drop to ≤ 10 %) after 3-week ET. Treatment duration is 2 years for the ribociclib + ET (premenopausal: AI + GnRH) arm and 16-24 weeks for the CT arm; treatment can be given in the neoadjuvant or adjuvant setting. 5-year follow-up consists of standard adjuvant ET. Patient reported outcomes (ePROs) are collected using CANKADO; ECG monitoring is performed using a novel CANKADO-based methodology. For translational analyses, tumor tissue will be collected at baseline (prior to ET), after 3-weeks ET (+/- 1w). Additional samples are required if residual tumor is diagnosed in case of neoadjuvant treatment and at time of recurrence. Exploratory tissue biomarker research will be conducted to assess alterations of molecular markers (e. g., ESR1, PIK3CA, CCND1, CDKN2A, RB1). Circulating DNA and tumor cells from blood samples will be used to assess mutations, gene expression, etc. Clinical trial information: 2018-003749-40.
ABC trial (A011502): A randomized phase III double-blinded placebo controlled trial of aspirin as adjuvant therapy breast cancer.
Authors: Chen Wendy Y. , Winer Eric P. , Ballman Karla V. , Partridge Ann H. , Carey Lisa A. , Carvan Margaret , Matyka Carol , Visvanathan Kala , Symington Banu , Holmes Michelle D.
Published: May 2019

TPS599

Background: In-vitro and in-vivo evidence suggest that aspirin may have an anti-tumor effect. Multiple epidemiologic studies have reported improved breast cancer survival among regular aspirin users compared to non-users. Pooled data from randomized trials of aspirin for cardiovascular disease have also reported a decreased risk of metastatic cancer among aspirin users. However, the exact benefits and risks for breast cancer survivors need to be confirmed in a randomized controlled trial. Even if the clinical effect were modest, the global impact would be substantial since aspirin is inexpensive and widely available. Methods: The primary objective is to compare the effect of 300 mg daily aspirin versus placebo upon invasive disease-free survival (iDFS) in high risk HER2 negative breast cancer patients. Secondary objectives include effects on overall survival, cardiovascular disease, toxicity, and adherence. A biospecimen repository will be created for correlative analyses including tumor collection at baseline and blood and urine samples and questionnaires assessing lifestyle factors associated with inflammation (pain, sleep, stress, and depression) at baseline and 2 years. Study design: Subjects will be randomized (1:1) to aspirin 300 mg vs placebo daily for 5 years in a double-blinded fashion. Stratification factors include hormone receptor (HR) status (positive vs negative), body mass index ( < or ≥ 30 kg/m2), and stage (II vs III). Subjects will be followed every 6 six months while on study drug, then annually for 10 years. Accrual goal is 2936 patients to reach 381 iDFS events. We have 80% power to detect HR 0.75 assuming 5-year iDFS on placebo of 77%. Eligibility: Eligible subjects include patients aged 18-70 diagnosed with a primary invasive HER2 negative breast cancer. If HR positive, tumors need to be node positive and diagnosed within the past 10 years. If HR negative, tumors can be node positive or T2-4N0 within 18 months of diagnosis. Subjects who are currently anticoagulated or those with a prior history of GI bleeding, atrial fibrillation, or myocardial infarction are excluded. Subjects who regularly use aspirin (defined as ≥ 5 days per week) need to stop 30 days prior to enrollment. Updated accrual numbers will be given at the time of presentation. Clinical trial information: NCT02927249.
NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).
Authors: Mamounas Eleftherios P. , Bandos Hanna , White Julia R. , Julian Thomas B. , Khan Atif J. , Shaitelman Simona Flora , Torres Mylin Ann , Vicini Frank , Ganz Patricia A. , McCloskey Susan Ann , Paik Soonmyung , Gupta Nilendu , Li X. Allen , DiCostanzo Dominic J. , Curran Walter John , Wolmark Norman
Published: May 2019

TPS600

Background: This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PPAx nodes that are pathologically negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC PPAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts may receive appropriate adjuvant systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1,636 pts are to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 2-7-19 is 1,164 (71.1%). Contacts: Protocol: CTSU member website https://www.ctsu.org . Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org . Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. Support: U10 CA-2166; -180868, -180822; 189867; Elekta NCT01872975 Clinical trial information: NCT01872975.
KEYNOTE-756: Randomized, double-blind, phase 3 study of pembrolizumab vs placebo combined with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2−) breast cancer.
Authors: Cardoso Fatima , Bardia Aditya , Andre Fabrice , Cescon David W. , McArthur Heather L. , Telli Melinda L. , Loi Sherene , Cortes Javier , Schmid Peter , Harbeck Nadia , Denkert Carsten , Jackisch Christian , Jia Liyi , Hirshfield Kim M. , Karantza Vassiliki
Published: May 2019

TPS601

Background: Although ER+/HER2− breast cancer (BC) has better overall prognosis than other subtypes, a high-risk subpopulation is characterized by high-grade tumors, decreased sensitivity to endocrine therapy (ET), higher responsiveness to chemotherapy (CT), and worse prognosis. Based on prior studies, increased pathological complete response (pCR) rates after neoadjuvant CT may have a substantial impact for patients with high-risk, early-stage HR+/HER2− BC. KEYNOTE-756 (ClinicalTrials.gov, NCT03725059) is a global, randomized, double-blind, phase 3 study of pembrolizumab (vs placebo) + CT as neoadjuvant treatment followed by pembrolizumab (vs placebo) + ET as adjuvant treatment for patients with high-risk, early-stage ER+/HER2− BC. Methods: Patients with T1c-2 cN1-2 (tumor size ≥2 cm) or T3-4 cN0-2 grade 3, invasive, ductal ER+/HER2− BC will be stratified by lymph node involvement (positive vs negative), tumor PD-L1 status (positive [CPS≥1] vs negative [CPS < 1]), ER positivity (ER+ ≥10% vs ER+ < 10%), and anthracycline dosing schedule (every 3 weeks [Q3W] vs Q2W), then randomized 1:1 to neoadjuvant treatment with pembrolizumab 200 mg Q3W or placebo combined with paclitaxel (80 mg/m2 Q1W) for 4 cycles followed by doxorubicin (60 mg/m2) or epirubicin (100 mg/m2), each with cyclophosphamide (600 mg/m2) Q2/3W for 4 cycles. After definitive surgery (± radiation therapy, as indicated), patients will receive adjuvant treatment of pembrolizumab (200 mg Q3W) or placebo for 9 more administrations combined with ET, which can be given for up to 10 years. There will be no crossover between treatment arms when moving from neoadjuvant to adjuvant treatment. Dual primary endpoints are pCR rate (ypT0/Tis ypN0) and event-free survival (EFS). Secondary endpoints include ypT0/Tis and ypT0 ypN0 pCR rates in all patients and all 3 pCR definitions in those with PD-L1+ tumors, EFS in patients with PD-L1+ tumors, overall survival, safety, and health-related quality of life. Interim analyses are planned. Enrollment is currently ongoing. Clinical trial information: NCT03725059.
Cctg MA.39 tailor RT: A randomized trial of regional radiotherapy in biomarker low-risk node-positive breast cancer (NCT03488693).
Authors: Parulekar Wendy R. , Berrang Tanya , Kong Iwa , Rakovitch Eileen , Theberge Valerie , Gelmon Karen A. , Chia Stephen K. L. , Bellon Jennifer Ruth , Jagsi Reshma , Ho Alice Y. , White Julia R. , Zellars Richard C. , Bane Anita , Boileau Jean-Francois , Lemieux Julie , Montenegro Alexander , Chen Bingshu E. , Whelan Timothy Joseph
Published: May 2019

TPS602

Background: Biomarker low risk, ER positive (+), HER2 negative (-) breast cancer with low burden nodal involvement may be associated with good outcomes (Woodward 2016, Mamounas 2017). There is conflicting data regarding the efficacy of regional radiotherapy after breast conserving surgery (BCS) or mastectomy in these patients (Kyndi 2008, Whelan 2015, Poortmans 2015, Liu 2015). Our hypothesis is that the risk of recurrence in patients with biomarker low risk, ER+, Her2- breast cancer and involvement of 1-3 lymph nodes where regional RT is omitted will not be inferior to the risk of recurrence in patients treated with regional RT. Methods: MA39 is a Canadian Cancer Trials Group led, NCTN sponsored, randomized phase III study comparing breast cancer recurrence free interval (BCRFI) in patients with ER+, Her2-, LN 1-3+ breast cancer that is low risk as defined by Oncotype Dx Recurrence Score < 18. Secondary objectives include a comparison of DFS, breast cancer mortality, OS, locoregional and distant recurrence free intervals, toxicity, arm volume and mobility measurements, patient reported outcomes and cost effectiveness. Key eligibility criteria include: age ≥ 40 years; BCS or mastectomy with axillary dissection and 1-3 positive axillary nodes; BCS and SLNB alone and 1-2 positive axillary nodes; mastectomy and SLNB alone and only 1 positive axillary node; planned endocrine therapy ≥ 5 years; adjuvant chemotherapy allowed. Statistical design: The primary analysis will be a test of non-inferiority (NI) in the intention to treat population. If the upper bound of a one-sided 95% interval for the hazard ratio for BCRFI is < 1.4, NI will be declared. Using a one-sided α of 0.05 and a power of 87%, it is anticipated that 278 events are required. With an expected 5 years of accrual and 4.5 years of follow-up, 2140 patients are needed for the final sample size. Conduct to Date: Study activation May 30 2018. Participation as of February 2019: Registrations 64 Randomizations 26. CIRB approval for continuation of MA.39 was received on January 11 2019. Clinical trial information: NCT03488693.
The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA).
Authors: Kanbayashi Chizuko , Thompson Alastair Mark , Hwang Eun-Sil Shelley , Partridge Ann H. , Rea Daniel William , Wesseling Jelle , Shien Tadahiko , Mizutani Tomonori , Shibata Taro , Iwata Hiroji
Published: May 2019

TPS603

Background: Retrospective data suggest breast cancer-specific survival rates with versus without surgery in patients with low-grade ductal carcinoma in situ (DCIS) are similar. Some DCIS patients have a low likelihood of progression to invasive cancer, but predicting who is at risk has not been established. Thus, treatment with a well-balanced risk / benefit ratio has not been achieved. Four active surveillance clinical trials for low risk DCIS have commenced in the United Kingdom (LORIS), Europe (LORD), United States (COMET), and Japan (LORETTA). We aim to examine the effectiveness & safety of active surveillance compared with surgical based treatment approaches for low-risk DCIS patients. Methods: Non surgical approaches are of the two types; active surveillance (AS) alone and AS + endocrine therapy (ET). In the randomized trials LORIS and LORD, the study arms are AS only, but while ET is an option in COMET, ET is mandatory in the single arm trial LORETTA. COMET and LORETTA have broader inclusion criteria as compared to LORIS and LORD. In COMET, comedo necrosis is eligible. In LORETTA, findings other than calcification on mammography (MMG) are also eligible (e.g. low echo area on breast ultrasound). Leaders of the four trials hold regular meetings to foster international DCIS trials collaboration to share information. LORIS Clinical trial information: ISRCTN27544579, LORD Clinical trial information: NCT02492607, COMET Clinical trial information: NCT02926911, LORETTA Clinical trial information: UMIN000028298 [JCOG1505]. Clinical trial information: UMIN000028298, NCT02492607, NCT02926911, ISRCTN27544579. [Table: see text]
Tabelecleucel in combination with pembrolizumab (Pembro) in platinum-pretreated, recurrent/metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (EBV+NPC).
Authors: Siu Lillian L. , Bauml Joshua , Adkins Douglas , Colevas A. Dimitrios , Perez Cesar Augusto , Choe Jennifer Hsing , Zhang Yang , Shi Wen , Navarro Willis H. , Haigentz Missak , Rabinowits Guilherme , Pfister David G.
Published: May 2019

TPS6092

Background: Approximately 25% of patients (pts) with NPC develop RM disease, which has a poor prognosis (median overall survival [mOS]: 12–16 mo), despite standard treatments with radiation and/or chemotherapy. NPC is an EBV-associated cancer in which programmed cell death ligand 1 (PD-L1) expression is upregulated upon EBV activation. Pembro showed antitumor activity in a phase 1b study of pts with RM-NPC (objective response rate [ORR]: 26%; mOS: 16.5 mo) (Hsu, J Clin Oncol 2017;35:4050-56). Targeting RM EBV+ NPC with tab-cel immunotherapy (off-the-shelf, allogeneic EBV-specific T cells) in pts has also shown promise, with 2-yr OS rates of 84% (Prockop, ASCO 2016;34:3012). The favorable safety profile of tab-cel offers the opportunity for combination immunotherapy with pembro for increased efficacy. Methods: This multicenter, open-label, single-arm phase 1b/2 study evaluates safety and efficacy of tab-cel in combination with pembro. Study participants are ≥12 yrs of age with incurable, locally recurrent or metastatic EBV+ NPC previously treated with platinum-containing therapy. Pts are checkpoint-inhibitor naïve (phase 1b/2) or refractory to anti-PD-1 or anti-PD-L1 therapy (phase 1b). Tab-cel is selected from a bank based on matching ≥2 HLA alleles, including ≥1 restricting HLA allele, between pts and donors. Tab-cel will be administered intravenously (IV) on days 1, 8, and 15 of a 21-day cycle. Initial tab-cel dose is 2x106 cells/kg and the de-escalated tab-cel dose (if needed) is 1x106 cells/kg. Pembro is administered at 200 mg IV Q3W in adults and 2 mg/kg IV Q3W in pts aged 12 to 17 yrs. Primary outcomes of phase 1b are to characterize dose-limiting toxicities, identify the maximum tolerated dose (MTD) or in the absence of MTD, the recommended phase 2 dose, and assess safety. Primary outcomes for phase 2 are ORR and safety. Secondary endpoints include progression-free survival, OS, and duration of response. Enrollment is ongoing for 12-24 participants in the phase 1b portion of the study with a 6+6 design. Phase 2 is expected to enroll 36 pts. Clinical trial information: NCT03769467.
A global phase III multicenter, randomized, double-arm, open label trial of ASP-1929 photoimmunotherapy versus physician’s choice standard of care for the treatment of patients with locoregional, recurrent head and neck squamous cell carcinoma (rHNSCC).
Authors: Biel Merrill A. , Gillenwater Ann M. , Cognetti David M. , Johnson Jennifer Maria , Argiris Athanassios , Tahara Makoto
Published: May 2019

TPS6094

Background: rHNSCC commonly affects local or regional sites and is associated with considerable morbidity and mortality. Outcomes of these patients remain poor with limited curative treatment options and low response rates. New modalities that are targeted, minimally invasive, and provide improved tumor response and control while having limited systemic side effects are needed. Photoimmunotherapy (PIT) is a new cancer-targeted platform technology. It is a combination drug and device treatment that utilizes monoclonal antibodies conjugated to a dye (IRDye 700DX) that is photoactivated using nonthermal red light to induce rapid and selective tumor cell death. The objective of this phase 3 study is to evaluate the efficacy and safety of ASP-1929 (EGFR-directed antibody cetuximab-IR700 conjugate) PIT treatment as a monotherapy in patients with locoregional rHNSCC. Methods: A global, multicenter phase 3, randomized, double-arm, open-label, controlled trial of ASP-1929 PIT vs physician’s choice standard of care (SOC) for the treatment of locoregional, rHNSCC in patients who have failed or progressed on or after at least two lines of therapy, of which at least one line must be systemic therapy, is currently underway. Primary endpoints of the study are PFS and OS and the key secondary endpoint is ORR. Key inclusion criteria include: disease not amenable to curative therapy; tumor(s) accessible for PIT light treatment and measurable by CT or MRI; male or female ≥ 18 yrs old with life expectancy > 6 months; ECOG score of 0 to 1. Key exclusion criteria include: history of ≥ Grade 3 cetuximab infusion reaction; distant metastatic disease; tumors invading a major blood vessel unless embolized. The study will include ~275 subjects in a 2:1 randomization (ASP-1929 PIT: Physician’s choice SOC). The physician’s choice SOC arm includes cetuximab, methotrexate, or docetaxel. Tumor(s) are illuminated with 690 nm PIT light treatment 24 hrs following completion of ASP-1929 infusion (640 mg/m²). Clinical trial sites will be in the USA, EU and Asia. Clinical trial information: NCT03769506.
A phase 3 (COSMIC-311), randomized, double-blind, placebo-controlled study of cabozantinib in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy.
Authors: Brose Marcia S. , Robinson Bruce , Bermingham Candy , Puvvada Soham , Borgman Anne E. , Krzyzanowska Monika K. , Capdevila Jaume , Sherman Steven I.
Published: May 2019

TPS6097

Background: Treatment options are limited for patients with RAI-refractory DTC that is resistant to VEGFR-targeted therapy. Cabozantinib inhibits receptor tyrosine kinases including VEGFR2, MET, AXL, and RET, which are implicated in the development of DTC, and has shown clinical activity in early-phase studies of patients with RAI-refractory DTC. This study evaluates the efficacy and safety of cabozantinib in patients with RAI-refractory DTC who have progressed during or after prior VEGFR-targeted therapy. Methods: This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT03690388). The co-primary endpoints are progression-free survival and objective response rate evaluated by blinded independent radiology committee (BIRC) per RECIST v 1.1. Additional endpoints include safety, overall survival, quality of life, and changes in relevant biomarker levels (eg, thyroglobulin). Approximately 300 patients will be randomized in a 2:1 ratio to receive either cabozantinib (60 mg QD orally) or placebo. Randomization is stratified by prior treatment with lenvatinib and age (≤ 65 yrs vs > 65 yrs). Eligible patients must have a pathologic diagnosis of DTC and must have been previously treated with or deemed ineligible for treatment with iodine-131 for DTC. Patients must have received lenvatinib or sorafenib for DTC and progressed during or following treatment with a VEGFR inhibitor. Up to 2 prior VEGFR-targeting TKI agents are allowed. Patients randomized to placebo may be eligible for real time on-study crossover to cabozantinib based on BIRC confirmation of disease progression. Unblinded patients randomized to cabozantinib may continue on study treatment if there is clinical benefit per investigator. Key words: Radioiodine-refractory differentiated thyroid cancer, cabozantinib, VEGFR-targeted therapy, trial-in-progress. Clinical trial information: NCT03690388.
ACCURACY: phase (P) 2 trial of AL101, a pan-Notch inhibitor, in patients (pts) with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) with Notch activating mutations (Notchact mut).
Authors: Ferrarotto Renata , Ho Alan Loh , Wirth Lori J. , Dekel Edith , Walker Russell W. , Vergara-Silva Andrea Leninka
Published: May 2019

TPS6098

Background: Notch signaling plays a key role in tumorigenesis. Notch cleavage by γ-secretase frees the Notch intracellular domain, which promotes the expression of target genes involved in cancer. AL101, a small molecule, is a γ-secretase inhibitor that potently inhibits Notch1-4, resulting in robust antitumor activity in vivo (PMID 26005526), including ACC xenograft models with Notchact mut (Ferrarotto, AACR 2019, Abstr 4885). Three P1 trials tested AL101 as monotherapy or in combination regimens in > 200 solid/hematologic cancer pts. In the P1 trial of AL101 monotherapy, conducted in 94 pts with advanced/metastatic solid tumors refractory to standard therapies (Tx), AL101 was generally well tolerated, with manageable AEs, and the recommended P2 dose was 4 mg IV once weekly (QW; El-Khoueiry, ASCO 2018, Abstr 2515). 4 pts had objective responses, 2 of those had Notchmut (1 of which had ACC). ACC, a rare cancer that most commonly develops in the major salivary glands, but can also arise in minor salivary glands in the trachea, lacrimal gland, and other sites, is refractory to chemotherapy, with a high recurrence rate. Notchact mut are found in a subset of ACC pts (11%–22%), with particularly aggressive disease and poor prognosis. There is no proven active treatment for R/M ACC pts (PMID 27870570). Methods: ACCURACY (NCT03691207) is an open-label, single-arm, multicenter study of AL101 (4 mg IV QW) in pts with R/M ACC (bone-exclusive disease included) with known Notch1-4act mut. Pts with disease progression within 6 months of enrollment or newly diagnosed metastatic pts are allowed; pts who received > 3 prior systemic Tx are excluded. Primary endpoint: ORR by RECIST v1.1 (or modified MDA bone criteria), by independent review committee (IRC). Secondary endpoints: ORR by investigator review (IR), duration of response by IRC and IR, PFS by IRC, OS, and safety. Per the Simon optimal design, 12 pts are enrolled in stage 1; if ≥2 pts respond, 24 additional pts are enrolled in stage 2. If ≥4 pts in stage 2 respond, the trial is deemed positive. This design yields 5% type I error rate and 80% power, if ORR is 25%. 4 of planned 36 pts have been enrolled as of 2/12/19. Clinical trial information: NCT03691207.
A phase 2 study of nivolumab (NIVO) alone or plus ipilimumab (IPI) for patients with locally advanced unresectable (laBCC) or metastatic basal cell carcinoma (mBCC).
Authors: Stein Julie E. , Brothers Patricia , Applebaum Katie , Gaskin Angela , Wang Hao , Taube Janis M. , Lipson Evan J.
Published: May 2019

TPS9595

Background: Basal cell carcinoma (BCC) is the most common human cancer. Although laBCC and mBCC are rare (<10,000 cases per year in the US), tumors are typically locally invasive and often destroy skin and surrounding structures, leading to substantial morbidity. Standard-of-care therapies include hedgehog pathway inhibitors (HhPi) (e.g., vismodegib, sonidegib), but these medications may be poorly tolerated due to side effects (e.g., muscle spasms, alopecia, dysgeusia), and anti-tumor responses often lack durability. Several published reports have described patients with advanced HhPi-refractory BCC who experienced durable, objective tumor regressions after administration of anti-PD-1, which may be better tolerated than HhPi. The purpose of this study is to evaluate the efficacy of NIVO (anti-PD-1) alone and in combination with IPI (anti-CTLA-4) in patients with laBCC or mBCC, either in the first-line setting or after HhPi therapy. Methods: NCT03521830 is an open-label, phase 2 study of NIVO alone (cohort A) and plus IPI (cohort B) for patients with laBCC or mBCC. Subjects enrolled to cohort A (treatment-naïve or after HhPi therapy) will receive NIVO 480mg IV q4 weeks for up to 48 weeks. Subjects with progressive BCC after anti-PD-1 +/- HhPi will enroll to cohort B and receive NIVO 240mg + IPI 1mg/kg IV q3 weeks x 4 doses followed by NIVO 480mg IV q4 weeks x 7 doses. The primary endpoint is objective response rate (ORR) per RECIST v1.1. Secondary endpoints are duration of response, progression-free and overall survival, and disease control rate (i.e., % of patients with stable disease lasting ≥26 weeks or complete or partial response). Exploratory studies will include assessment of changes in immune cell subsets and immune checkpoint expression in pre- and on-treatment tumor biopsies, correlated with clinical outcomes. A Simon’s two stage design is planned for each cohort, testing for 15% null vs. 40% alternative ORR for cohort A, and 5% null vs. 20% alternative ORR for cohort B. The study will enroll up to 19 patients on cohort A and 21 patients on cohort B. Subject accrual began in November 2018. Clinical trial information: NCT03521830.
KEYNOTE-629: Phase 2 study of pembrolizumab for recurrent/metastatic or locally advanced unresectable cutaneous squamous cell carcinoma (cSCC).
Authors: Grob Jean Jacques , Gonzalez Rene , Basset-Seguin Nicole , Schachter Jacob , Vornicova Olga , Bauman Jessica Ruth , Grange Florent , Meyer Nicolas , Piulats Josep M. , Zhang Eric (Pingye) , Gumuscu Burak , Swaby Ramona F. , Hughes Brett Gordon Maxwell
Published: May 2019

TPS9598

Background: Findings from phase 1 and 2 studies suggest that targeting programmed death 1 (PD-1)/PD-L1 pathway can provide durable antitumor activity in patients with local/regionally advanced or metastatic cSCC and may be a promising treatment option. The open-label, single-arm, phase 2 KEYNOTE-629 trial (NCT03284424) will be conducted to test the clinical activity of the PD-1 inhibitor pembrolizumab in locally advanced, unresectable, and recurrent or metastatic cSCC. Methods: Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for up to 35 infusions (≤24 months) or until protocol-specified treatment discontinuation. Treatment will not be stratified in this study. Eligibility criteria include age ≥18 years; locally advanced cSCC for which the patient is ineligible for resection or radiotherapy (RT) or for which the patient previously underwent RT to the index site or systemic therapy for curative intent; presence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and Eastern Cooperative Oncology Group performance status 0 or 1. Treatment will be discontinued for progressive disease, unacceptable toxicity, intercurrent illness preventing administration, investigator’s decision, patient withdrawal of consent, pregnancy, or cessation for administrative reasons. Response will be assessed by imaging 6 weeks after treatment initiation, every 6 weeks through year 1, and every 9 weeks thereafter or more frequently if clinically indicated. After disease progression or the start of new anticancer therapy, the patient will be followed up every 12 weeks until death, consent withdrawal, or study end, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment end or 90 days if the patient experiences serious adverse events. The primary end point is objective response rate (RECIST v1.1). Secondary end points include response duration, disease control rate, progression-free survival, overall survival, and safety. Recruitment is ongoing in 10 countries and will continue until approximately 50 additional patients with locally advanced, unresectable cSCC are enrolled. Clinical trial information: NCT03284424.
Personalized response-driven adjuvant therapy after combination ipilimumab and nivolumab in high-risk resectable stage III melanoma: PRADO trial.
Authors: Reijers Irene , Rozeman Elisa A. , Menzies Alexander M. , Van De Wiel Bart A. , Eriksson Hanna , Suijkerbuijk Karijn , Van Der Veldt Astrid Aplonia Maria , Kapiteijn Ellen , Hospers Geke , Klop Willem M.C. , Spillane Andrew , Scolyer Richard A. , Svane Inge Marie , Bastholt Lars , Schmidt Henrik , Larkin James M.G. , Van Akkooi Alexander Christopher Jonathan , Long Georgina V. , Blank Christian U.
Published: May 2019

TPS9605

Background: Adjuvant (adj) immune checkpoint inhibition (ICI) improves relapse free survival (RFS) in stage III melanoma patients (pts). However, preclinical and translational data suggest that neo-adjuvant (neoadj) treatment might be favorable due to broader immune activation. The phase 1b OpACIN study comparing neoadj to adj IPI plus NIVO demonstrated a high pathological response rate (pRR) of 78% complicated by 90% gr 3-4 immune-related adverse events (irAEs). The phase 2 OpACIN-neo trial tested safety and efficacy of three different schemes of neoadj IPI+NIVO and identified two cycles of IPI 1mg/kg + NIVO 3mg/kg as well tolerated (20% gr 3-4 irAEs), with a high pRR of 77%. In both trials, none of the pts with a pathologic response have relapsed after a median follow-up of 30 and 8.3 months. In stage IV melanoma, long-term benefit is observed in patients achieving CR with ICI, even after cessation of therapy. This raises the question of whether a therapeutic lymph node dissection (TLND) can be omitted when a deep pathologic response with neoadj IPI+NIVO is achieved. Methods: The aim of this international multi-center investigator-initiated phase 2 PRADO extension study is to confirm the pRR and toxicity of 2 cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg (the preferred OPACIN-neo regimen) and to test response-driven subsequent therapy i.e. omitting surgery and adjuvant ICI based on the pathological response. 100-110 pts with stage IIIB/C melanoma and a measurable lymph node (≥15mm according to RECIST 1.1) will receive two cycles of IPI 1mg/kg + NIVO 3mg/kg after marker placement into the largest lymph node metastasis. After six weeks, pts will undergo resection of the index lymph node. For pCR/near pCR, pts will not undergo TLND; For pPR, pts will undergo TLND; and for pNR, pts will undergo TLND and start adjuvant NIVO or targeted therapy +/- radiotherapy for 52 weeks. Primary endpoints are pRR of marked lymph node and RFS at 24 months. Baseline biopsies, blood samples (week 0, 6, 12) and faeces (week 0, 6) will be collected for translational research analyses. The first patient in this trial was included in October 2018; 22 patients have been enrolled. Clinical trial information: NCT02977052.