bluuebunny/crossref_metadata_2025 huggingface dataset:
JAVELIN BRCA/ATM: A phase 2 trial of avelumab (anti–PD-L1) plus talazoparib (PARP inhibitor) in patients with advanced solid tumors with a BRCA1/2 or ATM defect.
Authors: Hyman David Michael , Zelnak Amelia B. , Bauer Todd Michael , Ulahannan Susanna Varkey , Ford James M. , Cesari Rossano , Hoyle Margaret , Chappey Colombe , Stewart Ross , Conte Umberto , Yap Timothy A
Published: May 2019

TPS2660

Background: Defects in DNA damage response genes, including BRCA1/2 and ATM, confer sensitivity to PARP inhibitors. Talazoparib is a potent, oral PARP inhibitor with a dual mechanism of action (PARP enzyme inhibition and PARP trapping). Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody with a wild-type Fc region that has shown clinical activity in multiple tumor types. Preclinical and early clinical data suggest that combining a PARP inhibitor with an immune checkpoint inhibitor may provide improved activity. Methods: JAVELIN BRCA/ATM (NCT03565991) is an ongoing, open-label, multicenter, phase 2 trial assessing the combination of avelumab and talazoparib. Enrollment of ≈200 patients with a histologically confirmed locally advanced or metastatic solid tumor that has progressed on > 1 line of standard-of-care treatment for locally advanced or metastatic disease and has a germline or somatic defect in BRCA1 or 2 (cohort 1) or ATM (cohort 2) genes is planned. Patients with concomitant defects in > 1 gene ( BRCA1, BRCA2, or ATM) will be enrolled in cohort 1. Exclusion criteria include prior treatment with an immune checkpoint or PARP inhibitor, prior treatment with any other anticancer or radiation therapy within 2 weeks prior to enrollment, a known history of an immune-mediated or autoimmune condition, and known symptomatic brain metastases requiring steroids. The primary endpoint is confirmed objective response by blinded independent central review according to RECIST v1.1 and according to the Prostate Cancer Working Group 3 (PCWG3) for patients with metastatic castration-resistant prostate cancer (mCRPC). Secondary endpoints include safety; investigator-assessed confirmed objective response, time to tumor response, duration of response, and progression-free survival (per RECIST v1.1 and per PCWG3 for patients with mCRPC); overall survival; pharmacokinetic parameters; and potential predictive biomarkers. The study is currently enrolling patients at centers in the United States and Europe. Clinical trial information: NCT03565991.
Feasibility study of microbial ecosystem therapeutics (MET-4) to evaluate effects of fecal microbiome in patients on immunotherapy (MET4-IO).
Authors: Tan Tira Jing Ying , Butler Marcus O. , Hansen Aaron Richard , Hogg David , Sacher Adrian G. , Bedard Philippe L. , Ross Kendra , Chow Helen , Al-Kindy Aida , Boross-Harmer Sarah , Xu Wei , Coburn Bryan , Siu Lillian L. , Spreafico Anna
Published: May 2019

TPS2664

Background: Differences in microbiome diversity and composition in immune checkpoint inhibitor (ICI)-responders vs non-responders have been demonstrated. Transplantation of responder feces in mouse models recapitulated the ICI-responsive phenotype. MET-4 is an oral alternative to fecal transplant consisting a well-defined mixture of intestinal bacteria isolated from healthy donor stool sample. We hypothesize that co-administration of MET-4 with ICI is safe and results in alterations of the gut microbiota. Methods: Three cohorts (n = 65) of subjects with any advanced solid tumor type treated with monotherapy anti- PD1/PD-L1 antibody outside of a therapeutic clinical trial will be enrolled. Group A: safety cohort of 5 subjects already on ICI will receive MET-4 in addition to standard of care (SOC) ICI. If < 2 subjects report adverse events of CTCAE grade ≥3 within 4 weeks at least possibly related to MET-4, this dose will be declared safe and groups B/C may start enrolling. Group B (n = 40): subjects with advanced solid tumors starting on ICI, randomized 3:1 to MET-4 plus SOC vs. SOC. Group C (n = 20): subjects with advanced solid tumors already on ICI with first unconfirmed disease progression randomized 1:1 to MET-4 plus ICI continuation vs. continuing ICI. Serial stool samples will be collected for taxonomic composition, diversity, metagenomics content and MET-4 species abundance. We anticipate the following analyses: 16S rRNA sequencing, shotgun metagenomics sequencing, qPCR, Nanostring nucleic acid detection and metabolomics profiling. Serial blood sampling for flow cytometry/CyTOF. Immune microenvironment of tumor specimen will be examined using immunohistochemistry. Other major inclusion criteria: willingness to provide correlative samples, RECIST v1.1 measurable disease and ECOG 0-2. Subjects unable to swallow oral medications are excluded. For the primary objective of cumulative relative abundance and changes of ICI-responsiveness associated species between baseline and day 12 MET-4, assuming a change of 0.5 standard deviation (SD) of microbial alpha diversity, our study will have ≥84% power to identify a significant difference given a significance level at 0.05 in group B. Assuming a change of 0.9 SD of microbial alpha diversity, we will have ≥83% power to identify a significant difference in group C. Response rates and progression free survival will be assessed per RECIST v1.1 and compared with historical data. Clinical trial information: NCT03686202.
Phase 1 trial of TLR9 agonist lefitolimod in combination with CTLA-4 checkpoint inhibitor ipilimumab in advanced tumors.
Authors: Reilley Matthew , Tsimberidou Apostolia Maria , Piha-Paul Sarina Anne , Yap Timothy A , Fu Siqing , Naing Aung , Rodon Jordi , Nguyen Ly Minh , Ager Casey , Meng Martin , Jayaprakash Priyamvada , Schmidt Manuel , Baumann Matthias , Meric-Bernstam Funda , Curran Michael A. , Hong David S.
Published: May 2019

TPS2669

Background: Drugs targeting pathogen associated molecular patterns are an attractive strategy to stimulate the immune system. Toll-like receptors (TLR) have generated significant interest as an effective means of stimulating the immune system that result in the killing of tumor cells. TLR-9 agonists can function to promote an early immune response and are an appealing partner for combination with checkpoint blockade to improve immune activation. Lefitolimod (MGN1703) is a covalently closed dumbbell-shaped DNA molecule that functions as a TLR-9 agonist. We developed a clinical trial combining lefitolimod with ipilimumab (anti-CTLA4) in patients with advanced malignancies. In the dose-escalation phase 19 patients were enrolled and no DLTs were encountered. Safety data and maximum planned dose level of lefitolimod at 120mg weekly and ipilimumab 3mg/kg every 3 weeks was previously presented. Adverse events related to the combination included fatigue, appetite loss, rash, and anemia. Methods: This trial (NCT02668770) was designed to evaluate the safety profile and maximum tolerated dose of lefitolimod with ipilimumab. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. Lefitolimod is administered via subcutaneous (SC) injection weekly while ipilimumab is given at 3mg/kg intravenous on day 8 of each 3 week cycle. Lefitolimod starting dose was 15mg SC weekly with 3 dose level escalations up to 120mg SC weekly. Patients receive treatment for 4 cycles (total 12 weeks) with the combination, and those with stable disease or response were eligible to remain on lefitolimod therapy for up to 1 year. Eligible patients have a metastatic or unresectable solid tumor refractory to standard therapies, ECOG ≤ 2, and normal organ and bone marrow function. Patients are allowed to have received prior checkpoint blockade agents. Enrollment in expansion cohorts in ongoing. To better understand relevant immunologic changes associated with treatment, paired pre- and post-treatment biopsies of target lesions and peripheral blood collection during treatment is required for target expansion cohort patient populations. In addition to evaluating target patient populations at the combination dose established during escalation, an expansion cohort for patients with cutaneous metastases involves combination treatment with intratumoral delivery of lefitolimod. Clinical trial information: NCT02668770.
A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation.
Authors: Papadopoulos Kyriakos P. , Ou Sai-Hong Ignatius , Johnson Melissa Lynne , Christensen James , Velastegui Karen , Potvin Diane , Faltaos Demiana , Chao Richard C.
Published: May 2019

TPS3161

Background: RAS proteins are part of the family of small GTPases which regulate intracellular signaling pathways responsible for cell growth, migration, survival and differentiation. Oncogenic point mutations in RAS in codons 12, 13, and 61 occur in up to one-third of all human cancers and result in constitutive activation of RAS signaling, playing a key role in uncontrolled cellular growth and malignant transformation. Mutant KRASG12C in particular comprises approximately 14% of lung adenocarcinoma and 4% of colon adenocarcinoma, and less commonly in certain other types of cancer. For decades, KRAS was considered undruggable due to its high affinity for GTP/GDP and the lack of a clear binding pocket. Recent discoveries have enabled the development of compounds, including MRTX849, that covalently bind to KRASG12C at the cysteine at residue 12, lock the protein in its inactive GDP-bound conformation, and inhibit KRAS-dependent signal transduction. MRTX849 is a potent, orally-available, mutation-selective small molecule covalent inhibitor of KRASG12C. MRTX849 inhibits KRASG12C signaling in cell lines harboring this mutation, and results in tumor regression in a broad spectrum of KRASG12C animal models. Methods: This multi-center, Phase 1/2, multiple expansion cohort trial evaluates the safety, pharmacokinetics (PK), metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumor malignancies with a KRAS (p.G12C) mutation. The study starts with an evaluation of dose and regimen of MRTX849 using a combination of the accelerated titration and modified toxicity probability interval designs, with MRTX849 initially administered once daily in a continuous regimen expressed in 3-week cycles. As potentially viable regimens are identified, Phase 1b expansion cohorts will be opened to provide greater safety and PK data for determination of the recommended Phase 2 dose (RP2D) and regimen. In Phase 2, separate cohorts of patients by histological diagnosis, including non-small cell lung cancer, colorectal, and other solid tumors, will be enrolled and evaluated for clinical activity using a predictive probability design. The study is open for enrollment, and recruitment is ongoing. Clinical trial information: NCT03785249.
A phase I dose-escalation and immune biomarker study of intravenous FF-10832, liposomal gemcitabine, in patients with advanced solid tumors.
Authors: Borazanci Erkut Hasan , Falchook Gerald Steven , Abbas Atif , Wheeler Catherine A. , Maier Gary , Johansen Mary , Sedivy Paula , Subach Ruth Ann , Sen Shiraj , Jones Suzanne Fields , Ioroi Tadaaki , Matsumoto Takeshi , Suzuki Takeaki , Madden Timothy , Hamilton Erika Paige
Published: May 2019

TPS3163

Background: FF-10832 (832) is a liposomal formulation of gemcitabine (GEM) that demonstrates a prolonged half-life and preferential uptake in tumor vs normal tissues and marrow in pre-clinical models. Macrophage uptake has been shown in the tumor microenvironment (TME), with subsequent GEM release in tumor cells. This relative selectivity and anti-tumor immunological changes observed in the TME may lead to decreased toxicity and increased efficacy compared to GEM. Ferumoxytol (FMX) may be a surrogate for nanoparticle penetration into tissue and is being examined as a potential correlate for activity. Methods: This ongoing Phase 1, 3+3 dose-escalation study of 832 will determine the safety profile, maximum tolerated dose, dose-limiting toxicities (DLT) and recommended Phase 2 dose, and will be followed by expansion. Enrollment of up to 60 patients (pts) with advanced solid tumors is planned. Pre-treatment (tx) FMX MRI scans are performed, followed by 832 administration on Days 1 &15 of each 28-day cycle until disease progression or unacceptable toxicity. In addition to standard biomarker and imaging evaluations, change in macrophage polarity, myeloid-derived suppressor cell (MDSC) and regulatory T cell populations are being investigatedin peripheral blood and tumor tissue. Clinical trial information: NCT03440450.
CA224-060: A randomized, open label, phase II trial of relatlimab (anti-LAG-3) and nivolumab with chemotherapy versus nivolumab with chemotherapy as first-line treatment in patients with gastric or gastroesophageal junction adenocarcinoma.
Authors: Feeney Kynan , Kelly Ronan , Lipton Lara Rachel , Chao Joseph , Acosta-Rivera Mirelis , Earle Dennis , Lei Ming , Kollia Georgia , Tebbutt Niall C.
Published: May 2019

TPS4143

Background: Blockade of the immune checkpoint receptor programmed death-1 (PD-1) has shown clinical benefit in multiple tumor types. Nivolumab (anti–PD-1) has demonstrated a survival advantage versus (vs) placebo in patients (pts) with advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) (Kang YK et al. Lancet 2017;390:2461–71). Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates effector T-cell function and is a marker of T-cell exhaustion. Preliminary data in melanoma suggest that combining nivolumab with relatlimab (anti–LAG-3) could improve efficacy without substantially increasing toxicity vs nivolumab especially, but not exclusively, in LAG-3-expressing pts (Ascierto PA et al. Ann Oncol 2017;28(S5):LBA18). Furthermore, LAG-3 expression was as high as 33% in an analysis of solid tumors including GC (Edwards R et al. J Immunother Cancer 2017;5(S3):P510). Study CA224-060 will assess the clinical efficacy and safety of relatlimab and nivolumab with chemotherapy for first-line treatment of GC or GEJC. Methods: This is a randomized, open-label, multicenter, phase 2 study of relatlimab and nivolumab with oxaliplatin-based chemotherapy vs nivolumab with oxaliplatin-based chemotherapy. Approximately 250 adult pts with untreated, locally advanced, unresectable or metastatic GC or GEJC will be enrolled. To be randomized, pts must have tumor tissue for analysis of biomarkers, LAG-3 status, and PD-L1 combined positive score. Key exclusion criteria include HER2-positive status, untreated CNS metastases, or significant cardiovascular disease. The primary endpoint is objective response rate (ORR) using RECIST v.1.1 by blinded independent central review in LAG-3-expressing pts. Other endpoints include investigator-assessed ORR, ORR in LAG-3-negative pts, duration of response, overall survival, progression-free survival, and safety and tolerability. Efficacy signals in biomarker subgroups will be explored. Currently, 26 sites are activated with 15 randomized pts. Clinical trial information: NCT03662659.
NET-02: A multi-center, randomised, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: McNamara Mairead Geraldine , Swain Jayne , Craig Zoe , Wadsley Jonathan , Reed Nicholas , Faluyi Olusola Olusesan , Lamarca Angela , Hubner Richard , Mansoor Wasat , Sarker Debashis , Howard Helen C , Cairns David A. , Meyer Tim , Valle Juan W.
Published: May 2019

TPS4158

Background: The prognosis for pts with PD-EP-NEC is poor. First-line treatment for advanced disease is etoposide/platinum-based chemotherapy, analogous to that of high grade lung NEC, with no standard second-line treatment, and is an area of unmet need. Methods: This is a multi-centre, randomised, phase II trial of nal-IRI; 80mg/m2 intravenously (IV) over 90 mins, prior to 5-FU; 2400 mg/m2 infusion over 46 hrs and folinic acid, Q14 days, or docetaxel; 75mg/m2 IV over 60 mins, Q21 days, as second-line therapy in pts with progressive PD-EP-NEC (Ki-67 > 20%), with the overall aim of selecting a treatment for continuation to a phase III trial. The standard arm is that used in high-grade lung NEC, of which docetaxel is a second-line therapy option (NCCN guidelines) and combination regimens such as Irinotecan/5-FU are a second-line therapy option currently used without trial evidence for this subset of pts. Pts must have had prior treatment with first-line platinum-based chemotherapy, have documented disease progression and have an ECOG performance status of ≤2. This study plans to recruit 102 pts from 16 UK centres (over 37 mths). Primary endpoint is 6-mth progression-free survival (PFS) rate; trial is designed to have an 80% chance of demonstrating that the one-sided 95% confidence interval of the 6 mth PFS rate excludes 15%, if the true rate is at least 30%, where 30% is the required level of efficacy, and a rate of < 15% would give grounds for rejection. If both treatment arms exceed the required level of efficacy to warrant further evaluation in a phase III trial, treatment with the higher PFS rate at 6 mths will be selected. Secondary endpoints include overall survival, objective response rate, toxicity, quality of life, serum neuron-specific enolase. Exploratory endpoints include quantification of circulating tumour cells (CTCs), circulating tumour deoxyribonucleic acid (ctDNA) and molecular profiling of CTCs, ctDNA and tumour tissue, and generation of CTC-derived xenografts. This trial is open and has enrolled 6 pts at time of submission. Clinical trial information: 10996604.
Phase II multi-institutional study of nivolumab (Nivo), cabiralizumab (Cabira), and stereotactic body radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer (LAUPC).
Authors: Cohen Deirdre Jill , Medina Benjamin , Du Kevin Lee , Coveler Andrew L. , Manji Gulam Abbas , Oberstein Paul Eliezer , Perna Serena K , Miller George
Published: May 2019

TPS4163

Background: Treatment of LAUPC most commonly involves chemotherapy +/- RT. Patients(pts) who can be downstaged and undergo R0 resection have significant improvement in overall survival, but conventional chemoRT converts < 10% of patients with LAUPC. If the effects of RT can be augmented then higher R0 resection rates may be achieved and improve survival. In pre-clinical models, RT leads to increased expression of M-CSF from pancreatic tumor cells and marked immune suppression within the tumor microenvironment via expansion of tumor associated macrophages (TAMs). Concurrent blockade of M-CSF with RT reduces TAM infiltration, prevents the generation of tumor promoting T cell populations, and increases the therapeutic effect of RT. RT also induces up-regulation of PD-L1 in TAMs, another mode of immune suppression that can account for RT resistance in LAUPC. (Seifert et al. 2016). These data suggest the efficacy of RT in LAUPC is limited by its promotion of innate and adaptive immune suppression. CSF1R blockade with Cabira combined with PD-1 blockade with Nivo may enhance the efficacy of SBRT by reprogramming the TAM compartment in tumors, thereby preventing an immune suppressive phenotype and augmenting T-cell mediated anti-tumor response. Methods: Single arm phase II study designed to evaluate safety, tolerability, and surgical resection rate in LAUPC pts treated with concurrent Nivo, Cabira, and SBRT. Exploratory endpoints include immune changes within blood and tissue following treatment and correlation with clinical endpoints. Key eligibility: completion of 2- 6 months standard induction chemotherapy, normal organ and marrow function, pre- and on-treatment biopsy, and PS ≤ 1. Following initial biopsy and placement of fiducials, Cabira 4mg/kg and Nivo 240mg are given D1 of every 14 day cycle. SBRT 6.6 Gy x 5 consecutive fractions starts D8. After 2 cycles, repeat biopsy and imaging is performed. Treatment with Cabira and Nivo continues every 2 weeks and imaging is done every 8 weeks, at which time pt is assessed for surgical resection. If pt is downstaged, treatment is discontinued and pt proceeds to surgery. Preliminary 6 pt safety cohort is monitored for unacceptable toxicities. If < 3 unacceptable toxicities in the first 6 subjects enrolled, then plan for expansion phase with 14 more pts. As of abstract submission, 3 pts have been enrolled. Clinical trial information: NCT03599362.
An open label phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination in patients with advanced solid/metastatic tumors.
Authors: De Bono Johann S. , Cojocaru Elena , Plummer Elizabeth Ruth , Knurowski Tomasz , Clegg Karen , Ashby Fay , Pegg Neil , West William , Brooks Anthony Nigel
Published: May 2019

TPS5089

Background: CCS1477 is a potent, selective and orally bioavailable inhibitor of the bromodomain of p300 and CBP, two homologous and critical co-activators of the androgen receptor (AR) and its variant forms, including mutated, amplified and spliced AR, as well as c-Myc. CCS1477 represents a new therapeutic option for prostate cancer patients who have progressed after failure of anti-androgen therapy and in combination with anti-androgens such as enzalutamide or abiraterone. Methods: This is a Ph I/IIa study to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose and schedule(s) of CCS1477 and investigate clinical activity of CCS1477 monotherapy and CCS1477 in combination with abiraterone or enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). The trial aims to enrol approximately 150 patients and is currently recruiting in the UK with plans to open additional sites in the USA (NCT03568656). Key inclusion criteria (for the mCRPC) require previous treatment with abiraterone and/or enzalutamide, taxane as well as evidence of disease progression (PCWG-3 guidelines). Single dose and steady state pharmacokinetics will be determined along with changes in plasma PSA, LDH and ALKP and in circulating tumour cell number. Anti-tumour activity will be determined by standard imaging according to PCWG-3 guidelines. Paired tumour biopsies for biomarker assessment are being collected. Cohort 1 of the monotherapy dose-escalation (rolling 6 design; 3-6 patients/cohort) has completed. Enrolment to cohort 2 began in January 2019. Dose finding in combination (CCS1477 + abiraterone; CCS1477 + enzalutamide) will be open once monotherapy dose escalation completes. Following definition of a recommended phase 2 dose and schedule for monotherapy and in combination, three expansion arms in patients with mCRPC will be opened in parallel (25 patients/arm); CCS1477 monotherapy; CCS1477 + abiraterone; CCS1477 + enzalutamide. A further expansion in patients with advanced solid tumours with a mutation in p300 or CBP will also be opened. Clinical trial information: NCT03568656.
Nivolumab and ipilimumab treatment in prostate cancer with an immunogenic signature (NEPTUNES).
Authors: Wong Yien Ning Sophia , Sankey Peter , Josephs Debra Hannah , Jones Robert J , Crabb Simon J. , Beare Sandy , Duggan Marian , White Laura , Charlaftis Nikolaos , Wheeler Graham , Linares Josep , Quezada Sergio A. , Ensell Leah , Flanagan Cliona , Kularatne Bihani Yoshana , Chung Moon , Pritchard Colin C. , Freeman Alex , Marafioti Teresa , Linch Mark David
Published: May 2019

TPS5090

Background: Responses to checkpoint inhibitor (CPI) monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC) have been limited. This is in part attributed to low tumour mutational burden (TMB) and low tumour infiltrating lymphocytes (TILs). Previously ~20% patients with prostate cancer have demonstrated high TILs or TMB1. We hypothesize that patients with higher TMB due to mismatch repair deficiency (dMMR) or defective DNA damage response (dDDR) and patients with high TILs are more likely to respond to combination CPI with anti PD-1 and anti CTLA-4 therapy. Methods: NEPTUNES is a single arm phase II trial designed to assess the efficacy of nivolumab and ipilimumab in biomarker selected patients with mCRPC that have progressed following ≥1 line of therapy. The immunogenic signature (ImS) biomarker is defined by ≥1 of the following: 1) dMMR by immunohistochemistry (IHC); 2) dDDR detected by the UW-OncoPlex sequencing assay and; 3) high TILs on multiplexed IHC. The UW-OncoPlex assay detects mutations in >260 genes and provides an estimation of TMB. Assuming an ImS+ rate of 20%, we aim to pre-screen 175 patients in order to enrol 35 patients into the main study. The primary endpoint is composite response rate (CRR), achieved if ≥1 of the following criteria are satisfied: 1) radiological response by RECIST 1.1; 2) PSA response ≥50%; 3) conversion of circulating tumour cells (CTC) count from ≥5 cells at baseline to <5 cells at week 9. The treatment will be deemed ineffective if the CRR is <20%. Nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) is dosed every three weeks for up to 4 times, followed by a 480mg flat dose of nivolumab every 4 weeks for up to one year. Baseline biopsies are mandated and paired biopsy at week 12 is encouraged. The secondary endpoints include safety, overall survival, and radiological and PSA progression free survival. Exploratory biological markers including TMB, mutational profiles, change in TILs and liquid biomarkers will be correlated with the primary clinical endpoint. Since opening in February 2018, 126 patients have been pre-screened with 25 ImS+. To date, 9/25 ImS+ patients have been enrolled into the main study. The trial is ongoing, with patient accrual expected to complete by late 2019. References: 1Linch, M., Goh, G., Hiley, C., Shanmugabavan, Y., McGranahan, N., Rowan, A., . . . Swanton, C. (2017). Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann Oncol, 28(10), 2472-2480. doi:10.1093/annonc/mdx355. Clinical trial information: NCT03061539.
DUO-O: A randomized phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients.
Authors: Harter Philipp , Bidziński Mariusz , Colombo Nicoletta , Floquet Anne , Rubio Pérez Maria Jesús , Kim Jae-Weon , Lheureux Stephanie , Marth Christian , Nyvang Gitte-Bettina , Okamoto Aikou , Reuss Alexander , Scambia Giovanni , Trillsch Fabian , Vardar Mehmet Ali , Van Nieuwenhuysen Els , Lichfield Jasmine , Rugman Paul , Twumasi-Ankrah Philip , Aghajanian Carol
Published: May 2019

TPS5598

Background: Ovarian cancer (OC) is the leading cause of death from gynecologic cancers in US women. Despite high response rates to first-line treatment, ~70% of patients (pts) relapse within 3 years and then remain largely incurable. First-line treatment needs to be improved to achieve long-term remission in pts and improve the cure rate. The Phase III SOLO1 trial showed a meaningful clinical benefit for olap maintenance therapy in newly diagnosed OC pts with a BRCA mutation (Moore et al N Engl J Med 2018). Preliminary data suggest that combining a PD-L1 inhibitor, anti-angiogenic and PARP inhibitor (triplet therapy) may achieve a synergistic antitumor effect. The DUO-O study (NCT03737643) evaluates the efficacy and safety of treatment combinations involving standard-of-care platinum-based chemotherapy (chemo), VEGF inhibitor bev, anti-PD-L1 antibody durva and PARP inhibitor olap, in women with newly diagnosed advanced OC. Methods: Eligible pts for this double-blind, randomized, Phase III study must have newly diagnosed, advanced, high-grade epithelial OC and either have completed primary surgery or plan to have interval debulking surgery. Depending on their tumor BRCA mutation (tBRCAm) status (determined by central test), pts will join one of two independent cohorts. Pts in the non-tBRCAm cohort (n~906) will be randomized (1:1:1) before cycle 2 to: a) chemo + bev + placebo (for 6 cycles) followed by bev (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets); b) chemo + bev + durva (6 cycles) followed by bev + durva (1120 mg q3w [total 15 months]) + placebo (tablets) maintenance treatment; or c) chemo + bev + durva (6 cycles) followed by bev + durva + olap (300 mg bd tablets [24 months]) maintenance treatment. Pts in the open-label tBRCAm cohort (n~150) will receive 6 cycles of chemo + durva followed by durva + olap maintenance therapy, with optional use of bev. The primary endpoint of progression-free survival will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, overall response rate and duration of response. Enrollment began in January 2019. Clinical trial information: NCT03737643.
ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC).
Authors: Hardy-Bessard Anne-Claire , Moore Kathleen N. , Mirza Mansoor Raza , Asselain Bernard , Redondo Andres , Pfisterer Jacobus , Pignata Sandro , Provencher Diane M. , Cibula David , Reyners Anna K.L. , Bodnar Lubomir , Glasspool Rosalind Margaret , Papadimitriou Christos A. , Eitan Rami , Han Sileny , Duska Linda R. , Rimel Bj , Hazard Sebastien , Chen Jian , Pujade-Lauraine Eric
Published: May 2019

TPS5600

Background: Despite surgery and SOC therapy (paclitaxel and carboplatin ± bevacizumab[bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3/4 OC. Niraparib (ZEJULA) is the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the US and Europe for maintenance treatment in pts with recurrent OC regardless of BRCAmut status. Preclinical data suggest synergy with PARPi + anti-PD-1 blockade. Niraparib + pembrolizumab has shown clinical efficacy in pts with platinum-resistant or secondary refractory OC regardless of biomarker status. Dostarlimab is an anti–PD-1 humanized monoclonal with clinical activity as monotherapy in early phase trials. The primary objective of the currently enrolling FIRST trial is to compare PFS (per RECIST v1.1) in pts treated with SOC + dostarlimab + niraparib to SOC. Methods: Eligible pts (up to 912) are FIGO stage 3 (with residual disease, CC0 high risk, or planned neoadjuvant therapy) or stage 4, non-mucinous epithelial OC and ECOG score < 2. After 1 cycle of SOC, pts are stratified by concurrent bev use, BRCAmut/HRR status, and disease burden then randomized as 1:1:2 to 1 of 3 arms (Table). An innovative feature of ENGOT-OV44/FIRST (NCT03602859; EUDRACT 2018-000413-20) is the pre-planned adaptive study design to adapt the control arm to the evolving SOCs in OC, allowing pts in the control arm to receive up to date SOC. These adaptations will occur when practice-changing data are released. Following publication of SOLO1 results, BRCAmut pts will only be randomized to arm 2 or 3 to ensure they receive niraparib. Further adaptations may be incorporated as new data become available, leading to stop randomization in arm 1 or 2 of pts based on their biomarker status. Clinical trial information: NCT03602859. [Table: see text]
NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC).
Authors: Slamon Dennis J. , Fasching Peter A. , Patel Ravindranath , Verma Sunil , Hurvitz Sara A. , Chia Stephen K. L. , Crown John , Martin Miguel , Barrios Carlos H. , Spera Gonzalo , Lopez Céline , Hor Inès , Pelov Diana , Hughes Gareth , Nawinne Moditha , Hortobagyi Gabriel N.
Published: May 2019

TPS597

Background: RIBO is a selective inhibitor of CDK4/6 with demonstrated efficacy and is well tolerated when combined with ET in pre-/peri- and postmenopausal women with HR+, HER2– advanced breast cancer. Given these findings and considering the role of CDK4/6–Rb–E2F pathway dysregulation in ET resistance, there is a rationale for evaluating whether RIBO + ET prevents, or delays acquired resistance to ET in the adjuvant setting, to improve invasive disease-free survival (iDFS). Methods: The phase 3 multicenter, randomized, open-label NATALEE trial will evaluate the efficacy and safety of RIBO + ET as adjuvant treatment in patients with HR+, HER2– EBC. Eligible women (any menopausal status) and men aged ≥ 18 years will be randomized to RIBO 400 mg/day (3 weeks on/1 week off) + ET or ET alone. In both arms, ET will comprise daily continuous letrozole 2.5 mg/day or anastrozole 1 mg/day; men and premenopausal women will also receive goserelin 3.6 mg once every 28 days. Treatment with RIBO will last 36 months whereas treatment with ET (in both arms) will last 60 months. Patients must have had American Joint Committee on Cancer (8th ed.) Anatomic Stage II (either N0 with grade 2-3 and/or Ki67 ≥ 20% or N1) or III EBC, with an initial diagnosis ≤ 18 months prior to randomization, and completed chemotherapy and radiotherapy (if indicated). Patients receiving standard (neo)adjuvant ET are eligible only if this treatment was initiated within 12 months of randomization. Key exclusion criteria include previous CDK4/6 inhibitor treatment and clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality. The primary endpoint is iDFS using STEEP (Standardized Definitions for Efficacy End Points) criteria as assessed by the investigator; secondary endpoints include recurrence-free survival, distant DFS, overall survival, patient-reported outcomes, and RIBO pharmacokinetics. Safety and tolerability will also be evaluated. Estimated enrollment is 4000 patients from 425 sites in 21 countries. Recruitment is ongoing. Clinical trial information: NCT03701334.
ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early-stage triple-negative breast cancer.
Authors: McArthur Heather L. , Ignatiadis Michail , Guillaume Sebastian , Bailey Andrew , Martinez Jorge Luis , Brandao Mariana , Metzger Otto , Lai Catherine , Fumagalli Debora , Daly Fergus , Bouhlel Aicha , Karusinova Valeria , Freeman Christie , Viale Giuseppe , Honvault Vanessa , Dufrane Carter , Nguyen Duc Anh , Piccart Martine J. , Winer Eric S. , Gelber Richard D.
Published: May 2019

TPS598

Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer and promising clinical activity has been reported with the anti–PD-L1 antibody, atezolizumab, in Phase 1/1b metastatic TNBC trials. Furthermore, the randomized phase 3 IMpassion130 study demonstrated enhanced anti-tumor activity when atezolizumab was co-administered with chemotherapy in the first line metastatic setting, with benefit mainly observed in PD-L1+ cohort. ALEXANDRA/IMpassion030 will evaluate the efficacy and safety of atezolizumab in combination with standard anthracycline/taxane adjuvant chemotherapy in early TNBC patients. Methods: ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard chemotherapy versus chemotherapy alone in early TNBC. In total, 2300 patients with operable stage II or III TNBC, confirmed by central pathology review, will be randomized. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant treatment will consist of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. The primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first patient was enrolled on August 2nd 2018, and approximately 430 sites are expected to be opened globally in 30 countries. Clinical trial information: NCT03498716.
EACH: A randomised phase II study evaluating the safety and anti-tumour activity of the combination of avelumab and cetuximab relative to avelumab monotherapy in recurrent/metastatic head and neck squamous cell cancer.
Authors: Forster Martin David , Sacco Joseph J. , Kong Anthony Hee , Wheeler Graham , Forsyth Sharon , Bhat Reshma , Blair Kameka , Lowe Helen , Spanswick Victoria J , Ensell Leah , Hartley John A. , White Laura
Published: May 2019

TPS6091

Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) have low response rates to licensed second line therapies, including PD-1 inhibitors nivolumab and pembrolizumab, and represent an area of unmet clinical need. The chimeric IgG1 epithelial growth factor receptor (EGFR) monoclonal antibody cetuximab potentiates the activity of radiotherapy in locally advanced HNSCC and chemotherapy in R/M HNSCC and is also licensed with modest activity as a single agent. Cetuximab initiates Natural Killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), resulting in an anti-tumour immune response and the potential to augment the activity of PD-1/PD-L1 inhibition. EACH aims to examine the safety and efficacy of the potentially synergistic interaction between cetuximab and avelumab, a fully human IgG1 anti-PD-L1 monoclonal antibody in R/M HNSCC. Methods: EACH is a randomised phase II trial preceded by a safety run-in phase. Eligible patients have histologically or cytologically confirmed measurable recurrent or metastatic squamous cell carcinoma of any site in the safety run-in phase, and HNSCC in phase II, that is considered incurable by local therapies. The safety run-in has a single arm de-escalating design, aiming to establish the safety of cetuximab with avelumab and determine the optimal dose of cetuximab within this combination. The safety run-in has a dosing schedule of avelumab (10 mg/kg) + cetuximab (500 mg/m2) intravenously every 2 weeks, with de-escalation of cetuximab to 400 mg/m2 and 300 mg/m2 if necessary. The safety run-in phase commenced recruitment in July 2018 and is ongoing. The phase II component will randomize 114 HNSCC patients between either avelumab + cetuximab at the dose determined by the safety run-in phase or avelumab (10 mg/kg) alone. Treatment will be in 4-week cycles for up to one year. The primary endpoint in the safety run-in phase is the occurrence of dose limiting toxicities, and in phase II is Disease Control Rate at 24 weeks, using iRECIST. Blood and fresh tissue will be collected for exploratory translational studies, which will focus on the identification of potential novel predictive biomarkers for response. Clinical trial information: NCT03494322.
Multicenter randomized controlled phase III study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy.
Authors: Busch Chia-Jung , Muenscher Adrian , Betz Christian Stephan , Dogan Volkan , Schafhausen Philippe , Bokemeyer Carsten , Binder Mascha
Published: May 2019

TPS6095

Background: Surgically treated locally advanced head and neck squamous cell carcinoma (LA HNSCC) often requires postoperative chemoradiation with high risk of acute and late toxicity. Disease-free survival (DFS) after 2 years is approximately 70%. Combining Nivolumab (N), a PD-1inhibitor, and Ipilimumab, a CTLA4 inhibitor, as maintenance therapy may improve DFS due to anti-tumor effects of immunotherapy by enhancing cross-presentation of tumor antigens. The IMSTAR HN study compares neoadjuvant N and N±I 6 months after adjuvant therapy vs the standard therapy as first-line treatment for LA HNSCC. Methods: Eligible pts are ≥18 years old with treatment-naive LA HNSCC (oral cavity, oropharynx p16-, hypopharynx, and larynx), ECOG PS ≤1, and no distant metastasis. 276 pts will be randomized (2:1) into 2 arms and approximately 10 centers in Germany will be involved. Standard of care (arm II) consists of surgical resection followed by risk-adapted adjuvant (chemo)radiation. The experimental arm I receives neoadjuvant N 3mg/kg. After treatment according to standard arm a second randomization will be performed: In arm Ia N 3mg/kg will be given every 2 weeks until progression or up to 6 months. In arm Ib I 1mg/kg will be applied additionally every 6 weeks also until progression or up to 6 months. Primary endpoints is DFS in arms I and II. Secondary endpoints: Local regional control (LRC), distant metastasis free survival (DMFS), overall survival (OS), quality of life (QoL), survival depending on PD-L1 status, comparison of arm Ia vs arm II and Ib vs. II. AEs, graded per CTCAE v4.03, are evaluated for at least 12 months after randomization. The translational program includes investigations concerning immunmodulation, mutational load in general, but also specific mutations in targets involved in immune function and antigen presentation. Recruitment started in August 2018. Clinical trial information: NCT03700905.
Design and accrual of S1417CD: Development of a prospective financial impact assessment tool in patients with metastatic colorectal cancer (mCRC).
Authors: Shankaran Veena , Unger Joseph M. , Darke Amy K. , Suga Jennifer Marie , Wade James Lloyd , Kourlas Peter , Chandana Sreenivasa R , O'Rourke Mark Allen , Satti Suma , Liggett Diane , Hershman Dawn L. , Ramsey Scott David
Published: May 2019

TPS6652

Background: Few studies have assessed the financial impact of cancer diagnosis (dx) in diverse patients (pts) and caregivers (cgs) using objective and standard financial measures. S1417CD, led by the SWOG Cancer Research Network, is the first prospective cohort study assessing financial outcomes to be conducted in the NCI Community Oncology Research Program (NCORP). We present our experience with design and accrual. Methods: Pts age ≥ 18 within 120 days of mCRC dx were considered eligible and asked to identify a caregiver (cg) who could participate concurrently. The primary endpoint is incidence of treatment-related financial hardship, defined as ≥ 1 of the following: debt accrual, selling/refinancing home, ≥ 20% income decline, or borrowing money. Measures include 1) pt and cg surveys (baseline (BL), 3, 6, 9 and 12 months (mo)) assessing out-of-pocket spending, financial impacts, cg burden, and quality of life and 2) pt credit reports (BL, 6, and 12 mo). Linkage to records from TransUnion, a national credit agency, required pt social security number (SSN) and processes for batched credit report transfer via secure web portal. The accrual goal was n = 374 pts in 3 years. The study activated on Apr 1, 2016 and closed on Feb 1, 2019 after reaching its accrual goal. A total of 380 pts (median age 59.7 years) and 155 cgs enrolled (41% cg participation). Enrollment steadily increased during the study period; 56% enrolled in the last 12 mo. Credit data were not obtainable for 76 (20%) pts due to early death, lack of credit, or inability to match records. S1417CD, the first cooperative group led study assessing financial outcomes in the community setting, completed enrollment faster than anticipated. Required SSN collection was not a barrier to enrollment, which improved as sites became familiar with data security measures. Robust accrual to S1417CD demonstrates pts’ and cgs’ desire to improve understanding of financial toxicity and its solutions. Follow-up will conclude in 12 mo with results to follow. SWOG plans to launch a randomized study (S1912) assessing the impact of financial navigation on household finances, using credit data for primary endpoint assessment. Clinical Trials Registry Identifier NCI-2015-01885. Clinical trial information: NCT02728804.
TACTICAL: A phase I/II trial to assess the safety and efficacy of MSCTRAIL in the treatment of metastatic lung adenocarcinoma.
Authors: Davies Alice , Sage Beth , Kolluri Krishna , Alrifai Doraid , Graham Rebecca , Weil Ben , Rego Rita , Bain Owen , Patrick P. Stephen , Champion Kim , Day Alex , Popova Bilyana , Wheeler Graham , Fullen Dan , Kalbur Tammy , Forster Martin , Lowdell Mark , Janes Sam
Published: May 2019

TPS9116

Background: Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma allowing them to act as vehicles for delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells however short biological half-life has its limited therapeutic efficacy. We have transduced umbilical cord MSCs with a lentiviral vector to express TRAIL (MSCTRAIL). These cells trigger apoptosis selectively in cancer cells with evidence of synergistic activity with other systemic anti-cancer therapies. Given their immune-privileged nature we are delivering ex vivo pooled MSCTRAIL from third party donors without tissue matching or immunosuppression. Efficacy has been demonstrated using in vitro co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with intravenous MSCTRAIL [1]. Methods: TACTICAL is a phase I/II trial assessing safety and efficacy of MSCTRAIL in combination with first line standard of care (SOC); pemetrexed (500mg/m2) and cisplatin (75mg/m2) and/or pembrolizumab (200mg), in treatment naïve patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1. Phase I is a dose de-escalation study, patients receive SOC on day 1 and 4x108 MSCTRAIL cells on day 2 of a 21 day cycle for 3 cycles. A Bayesian adaptive design will recommend dose reductions if excessive toxicities occur. Primary outcomes are to determine recommended phase II dose along with safety and tolerability of MSCTRAIL. 46 patients will then be randomised into a multi-centre phase II double blind, placebo-controlled trial to receive SOC and either MSCTRAIL or placebo (1:1). Primary outcome is tumour response rate by RECIST (v 1.1) criteria at 12 weeks. Secondary outcomes include, best overall response, duration of response, progression free survival and overall survival. TACTICAL is the first clinical trial of this novel cell and gene therapy and if successful will pave the way for future allogeneic MSC therapy in cancer. 1. Loebinger, M.R., et al., Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 2009. 69(10): p. 4134-42. Clinical trial information: NCT03298763.