bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1/2, multicenter, non-randomized, open-label, multiple-dose first-in-human study of U3-1402 (anti-HER3 antibody drug conjugate) in subjects with HER3-positive metastatic breast cancer.
Authors: Kogawa Takahiro , Yonemori Kan , Naito Yoichi , Noguchi Emi , Shimizu Chikako , Tamura Kenji , Hosono Ako , Matsubara Nobuaki , Sugihara Masahiro , Ogawa Hayao , Majima Shuji , Yu Channing , Ueno Suguru , Takano Toshimi
Published: September 2018

TPS1116

Background: There is a need for effective late-line treatments in metastatic breast cancer. HER3 overexpression in breast cancer is associated with poor prognosis, but there is as yet no approved targeted treatment against HER3. U3-1402 is a novel antibody-drug conjugate (ADC) comprised of a fully humanized anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio of ~8:1. Methods: This is a Phase 1/2, multicenter, non-randomized, open-label, multiple-dose, first-in-human study in subjects with HER3-positive metastatic breast cancer. The study consists of 3 parts: Dose Escalation, Dose Finding, and Phase 2. In Dose Escalation, safety and tolerability of U3-1402 are evaluated and the maximum tolerated dose is determined using the modified continuous reassessment method with escalation with overdose control. In Dose Finding, the recommended phase 2 dose (RP2D) of U3-1402 is determined using continued assessment of safety and efficacy as well as pharmacokinetic data of U3-1402. Efficacy and safety of the RP2D are further evaluated in Phase 2 part. Patients with locally advanced or metastatic breast cancer who have disease refractory to standard treatment, who cannot tolerate standard treatment, or for whom no standard treatment is available, will be enrolled. Key inclusion criteria include HER3-positive tumor, ECOG performance status 0–1, and measurable disease based on RECIST version 1.1. HER3 expression in tumor tissue will be evaluated with immunohistochemistry at a central laboratory. Prior chemotherapy regimens are restricted to 6 or fewer in Dose Finding and Phase 2, but not in Dose Escalation. Patients will receive U3-1402 intravenously every 3 weeks until unacceptable toxicity or disease progression. Enrollment of an estimated 80 patients is ongoing. Clinical trial information: 02980341.
A phase 1b study of safety and immune response to PVX-410 vaccine alone and in combination with durvalumab (MEDI4736) in HLA-A2+ patients following adjuvant therapy for stage 2/3 triple negative breast cancer.
Authors: Isakoff Steven J. , Tolaney Sara M. , Tung Nadine M. , Adams Sylvia , Soliman Hatem Hussein , Brachtel Elena F , Habin Karleen R. , Bauer Louisa J , Ellisen Leif W. , Severgnini Mariano , Barry William Thomas , Peterkin Doris
Published: September 2018

TPS1126

Background: Stage 2-3 triple negative breast cancer (TNBC) remains at high risk for recurrence despite modern adjuvant therapy. An important role for the immune system in TNBC has recently emerged. Tumor infiltrating lymphocytes (TILs) are correlated with improved prognosis and several PD-1/PD-L1 checkpoint inhibitors, including Durvalumab (DUR), demonstrated activity in metastatic TNBC. Vaccines are a promising approach to further enhance the immune response in many cancers including TNBC. PVX-410 (PVX) is a novel tetra-peptide vaccine against XBP1 (2 splice variants), CD138 and CS1 that was safe and induced immune responses in a phase 1b study in smoldering myeloma. XBP1 and CD138 are also over-expressed in TNBC. Methods: This Phase 1b multi-center, single arm study will enroll 20 HLA-A2+ female patients (pts) following completion of all adjuvant therapy for stage 2-3 TNBC. Pts will receive 6 doses of 800ug PVX (emulsified in Montanide (SC) and co-administered with Hiltonol (IM)) at 2-week intervals, and 2 doses of DUR 1500mg IV at the 4th and 6th vaccine visits. Eligible pts must be between 1-6 months from completing adjuvant therapy, have no prior autoimmune disease, and have residual disease if neoadjuvant therapy was used. The primary objective is to determine the safety and tolerability of the combination, and the key secondary objective is to determine the immune response to PVX + DUR. If ≤1 pt in the first 6 has a protocol defined dose limiting toxicity within 4 weeks after the first DUR dose, accrual will continue to 20 pts. Immune response will be assessed at baseline, pre-dose 4 PVX/dose 1 DUR, and 4 weeks after completing protocol therapy. Paired data in 20 pts provides 90% power to see a shift of 0.75 standardized units from baseline to 4 weeks post treatment with the signed rank test. Immune response will be determined by a FACs based assay of antigen specific CD3+CD8+ T lymphocyte response and IFN-γ production (intracellular staining) in patient PBMCs. Additional correlative studies, including T-cell PD-1 and tissue PD-L1, XBP1, and CD138, are planned. Currently 4 pts are enrolled. Clinical trial information: NCT02826434.
STELLAR: A phase 3, randomized, open-label study of eflornithine with lomustine vs lomustine for patients with first recurrence of anaplastic astrocytoma after RT and adjuvant temozolomide.
Authors: Levin Victor A. , Cruickshank Scott
Published: September 2018

TPS2081

Background: Eflornithine irreversibly inhibits ornithine decarboxylase an enzyme that catalyzes the biosynthesis of putrescine, one of 3 polyamines in mammalian cells. Over 390 patients with anaplastic gliomas (AG) received eflornithine alone, with a nitrosourea, or the PCV combination in past clinical trials. A phase 3 randomized study of adjuvant chemotherapy with PCV vs eflornithine-PCV in 228 patients with AG found a median overall survival (mOS) increase from 61.1 to 75.8 months in the eflornithine-PCV arm. Methods: Patients must have histologically proven diagnosis of WHO grade 3 anaplastic astrocytoma (AA) with unequivocal evidence of first AA tumor progression or recurrence ≤ 3 months prior to randomization following surgical resection or biopsy, RT and temozolomide chemotherapy. Patients must have RT ≥ 6 months prior to randomization and have a KPS of ≥ 70. Randomization of 280 patients will be 1:1 with stratification to: Age (≤ 45 yrs, > 45 yrs), region (US, Ex-US), IDH1 status (wild, mutant), and prior surgeries (biopsy, 1-2 resections). Patients will receive eflornithine 2.8 g/m2 orally every 8 h on a 2 week on, 1 week off schedule, and lomustine 110 mg/m2 orally once every 6 weeks, or lomustine alone dosed at 110 mg/m2 orally once every 6 weeks. Lomustine will be limited to 6 cycles or 12 months of therapy. Eflornithine can be given up to 24 months in the combination arm. The primary endpoint will be OS. Secondary objectives include PFS and objective response rate (ORR) based on MRI. The study sample size was calculated by assuming true mOS of 12 months for lomustine monotherapy and true mOS of > 18 months for the eflornithine plus lomustine arm. Such an improvement represents a true hazard ratio of 0.667 (investigational arm/control arm). Inferential comparisons of OS will be performed using a stratified log-rank test with 137 patients per arm and total information of 194 deaths with 80% power to detect a 33% reduction in the OS failure hazard rate. The study is open at 55 sites in the USA, Germany and Italy with an additional 10-15 sites being evaluated in 3 additional countries. Study enrollment is expected through 2018. Clinical trial information: NCT02796261.
EphA2 gene targeting using neutral liposomal small interfering RNA (EPHARNA) delivery: A phase I clinical trial.
Authors: Naing Aung , Lopez-Berestein Gabriel , Fu Siqing , Tsimberidou Apostolia Maria , Pant Shubham , Piha-Paul Sarina Anne , Janku Filip , Hong David S. , Sulovic Selma , Meng Xialong , Jazaeri Amir A. , Ng Chaan S. , Karp Daniel D. , Subbiah Vivek , Meric-Bernstam Funda , Mitra Rahul , Wu Sherry , Sood Anil , Coleman Robert L.
Published: September 2018

TPS2604

Background: EphA2 is a member of the largest subfamily of receptor tyrosine kinases, with over 14 receptors and 8 ligands. EphA2 overexpression is common in many human cancers, including lung, breast, prostate, colorectal, pancreatic, melanoma, esophageal and endometrial cancers. EphA2 can function as an oncoprotein when introduced into cells with low expression. In addition, downregulation of constitutive expression reduces tumorigenicity in breast, endometrial, ovarian and pancreatic cancers in vitro and in vivo models. EphA2 is a desirable target because of its selective expression in cancer (vs. adult normal tissue), and its important role in promoting tumor growth and metastasis. It has kinase-dependent and independent functions, making it an ideal target for RNAi-based targeting. We have previously reported that EphA2 siRNA incorporated in DOPC nanoliposomes (EPHARNA) was highly effective in reducing EphA2 protein levels after a single dose. In addition, three weeks of treatment with EPHARNA (150 μg/kg twice weekly) in an orthotopic mouse model of ovarian cancer (HeyA8 or SKOV3ip1) significantly reduced tumor growth compared with non-silencing siRNA, and demonstrated synergistic anti-tumor activity when combined with conventional chemotherapy. EPHARNA underwent GLP development in 2 animal models (murine and primate) at M.D. Anderson to support the IND (#72924). The first-in-human trial (NCT01591356) is ongoing and recruiting study subjects. Methods: Adult Patients > 18 years of age with histologic proof of advanced recurrent solid tumors, who are not candidates for known regimens or protocol treatments of higher efficacy or priority. All patients (dose escalation and dose expansion phases) must be willing to undergo pre- and post-treatment biopsies. For dose expansion phase, patients must have EphA2 overexpression by IHC evaluation. Enrollment is ongoing for the dose escalation with the plan for dose expansion. A total of 16 patients have been enrolled and treated in the dose escalation phase. Clinical trial information: NCT01591356.
A multicenter, open-label, phase II study of PGG beta-glucan and pembrolizumab in patients (pts) with advanced melanoma (MEL) following progression on treatment with checkpoint inhibitors (CPI) or triple negative breast cancer (TNBC) failing front-line chemotherapy for metastatic disease.
Authors: Iglesias Jose Luis , Prathikanti Radha , Ma Bo , Mattson Paulette , Kedrowski Deb , Lowe Jamie , Bose Nandita , Ertelt Katie E. , Ottoson Nadine , Uhlik Mark T. , Graff Jeremy , Huhn Richard Dale , Chisamore Michael Jon
Published: September 2018

TPS3105

Background: Imprime PGG (Imprime) is a Pathogen- Associated Molecular Pattern that enhances innate immune cell killing, counteracts immune suppression and triggers activation and maturation of antigen presenting cells. Imprime’s ability to trigger a coordinated innate and adaptive immune response is critical for enhancing the efficacy of CPIs in several pre-clinical tumor models. We are now exploring the combination of PGG beta-glucan and Pembrolizumab, a humanized mAb against programmed death receptor-1 (PD-1) in the clinic. In previous trials, Pembro yielded a 33% ORR and 23 mo mOS in 655 pts with advanced MEL and an 18.5% ORR and 11.2 mo mOS in 27 evaluable pts with metastatic/recurrent TNBC (Ribas et al., 2016; Nanda et al., 2016). Pre-treatment levels of anti-beta glucan antibodies (ABA) are correlated with pt response to Imprime. Methods: This Phase 2 study is enrolling ABA positive pts with advanced MEL following progression on treatment with a CPI or metastatic TNBC failing front-line chemotherapy. The study is a Simon optimal 2-stage design with sample size of 12 pts of each tumor type in Stage 1. If response and AE criteria (≤ 4 [or ≤ 33%] pts with grade 3/4 in Cycle 1) for each tumor type are met, an additional 17 pts with MEL and 30 pts with TNBC will be enrolled in Stage 2. Primary endpoints of the study are ORR (based on RECIST 1.1) and safety. Secondary endpoints include TTR, CRR, DoR, PFS, and OS. PK data will be profiled. Exploratory endpoints include ORR and PFS based on irRECIST, analysis of an ABA biomarker, immune cell activation markers, and changes in the tumor immune microenvironment. Screening and enrollment are underway in the US. Biothera Pharmaceuticals, Inc. is sponsoring the trial (ClinicalTrials.gov NCT02981303) under a collaborative agreement with Merck. Clinical trial information: NCT02981303.
PROCLAIM-001: A first-in-human trial to assess tolerability of the protease-activatable anti-PD-L1 Probody CX-072 in solid tumors and lymphomas.
Authors: Spira Alexander I. , Middleton Mark R. , Naing Aung , Autio Karen A. , Nemunaitis John J. , Bendell Johanna C. , Gordon Michael , Humphrey Rachel W. , Wong Chihunt , Rizvi Naiyer A.
Published: September 2018

TPS3107

Background: CX-072 is a novel Probody therapeutic (PbTx) targeting PD-L1. PbTxs are fully recombinant antibody prodrugs designed to be converted to active antibodies by tumor-associated proteases that are highly expressed malignant tissue; the PbTx remains largely inactive in normal tissues. In pre-clinical tumor models, a PD-L1-directed PbTx provided comparable anti-tumor efficacy to its parental anti-PD-L1 antibody, but displayed reduced auto-immunity in a model of Type 1 diabetes. Based on these pre-clinical data, CX-072 has the potential to enable combination therapies that are otherwise poorly tolerated. This Phase 1/2 study (PROCLAIM-001 (PRObody CLinical Assessment In Man) assesses the tolerability and antitumor activity of CX-072 in humans with an emphasis on immune-related adverse events, particularly in combinations. CX-072 will be administered as monotherapy (Part A), in combination with 2 schedules of ipilimumab (Parts B1 and B2) and in combination with vemurafenib (Part C). The expansion cohort (Part D) will include CX-072 monotherapy in PD-L1 responsive tumor types. Methods: Key eligibility criteria are as follows: Parts A and B1: checkpoint inhibitor-naive patients with advanced, refractory solid tumor or lymphoma (unmeasurable disease allowed) for whom approved PD agents are not available. Part B2: advanced, refractory solid tumors or lymphomas with measurable disease who have progressed on a previous treatment with a PD-(L)1 inhibitor, but did not discontinue due to toxicity. Part C: checkpoint inhibitor, BRAF-inhibitor and MEK-inhibitor-naïve metastatic V600E BRAF-mutated melanoma. Patients without an active autoimmune disease, ongoing infection, and ECOG PS 0-1 may be eligible to participate in the study. Dose escalation follows the 3+3 design in all arms. Ipilimumab (Parts B1 and B2) is dosed at the approved 3 mg/kg every 3 weeks x 4. The dose of vemurafenib (Part C) is 960 mg/kg twice daily. Exploratory biomarkers are used to characterize tumor protease activity, inflammatory changes within the tumor, and CX-072 activation in tumor versus peripheral blood. Clinical trial information: NCT03013491.
Phase 1-2 study of TI-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies.
Authors: Evans T.R. Jeffry , Italiano Antoine , Eskens Ferry , Symeonides Stefan Nicholas , Bexon Alice Susannah , Graham Philippa , Hinds David , Manning Pamela , Chanda Sanjay , Karr Robert , Bhargava Pankaj
Published: September 2018

TPS3109

Background: The cell surface protein CD47 is expressed or over-expressed on many tumor types. CD47 binds to signal regulatory protein alpha (SIRPα) on macrophages resulting in a “don’t eat me” signal that blocks host cell phagocytosis of the tumor cells, thus allowing them to escape removal by the innate immune system. Recent data indicate that anti-CD47 antibodies also contribute to an effective anti-tumor T cell response in immune-competent mice. Therefore, anti-CD47 antibodies are a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. Ti-061 is a novel IgG4 humanized monoclonal antibody that specifically binds to CD47 with Kd values range from 100 – 500 pM. Ti-061 exhibits cross-species binding to cynomolgus monkey, mouse and rat CD47, enabling efficacy and toxicity testing across species. Ti-061 binds to CD47 on RBCs; however, it does not cause agglutination of RBCs in vitro from any of the species tested. Ti-061 exhibits anti-tumor activity in several in vivo mouse tumor models. This ongoing Phase 1-2 study will assess the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of Ti-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies. Methods: Part A is an open-label, dose-escalation study of Ti-061 administered as a weekly 1-hour IV infusion at doses ranging from 1 to 20 mg/kg. Once the MTD/RP2D or “active dose” is determined, patients with specific solid tumors and high CD47 expression will be enrolled in 4 or more expansion cohorts. Up to 160 patients with histologically confirmed solid tumors, ECOG PS 0-1, adequate blood counts (Hb≥ 10 g/dL), organ function, and archival or fresh tumor tissue will be enrolled in Part A, and will be treated until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is safety, which will be assessed using NCI-CTCAE v4.03. Secondary endpoints include PK, PD, objective response rate (ORR) and progression-free survival (PFS), which will be assessed using RECIST v1.1. The results of this study will support further development of Ti-061 in combination with checkpoint inhibitors (Part B) and other anti-cancer agents.
A phase I dose escalation (DE) and cohort expansion (CE) study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors.
Authors: Hashimoto Kenji , Perera Ayesh , Sugaya Naofumi , Ogita Yoshitaka , Nakamura Mikiko , Rossi Sheila , Ishiguro Takahiro , Sano Yuji , Shimada Sumire , Frings Werner , Komatsu Shun-ichiro , Kaneko Akihisa , Ueda Masamichi , Matsushima Junnosuke , Kishishita Shohei , Gianella-Borradori Athos ,   ASCO ERY
Published: September 2018

TPS3112

Background: Bispecific antibodies to facilitate T-cell directed cytotoxicity (TDCC) is a proven therapy strategy in cancer. ERY974 is a humanized IgG4 bispecific antibody designed to simultaneously bind to cytotoxic T-cell CD3 receptors and GPC3 (a glycoprotein expressed on cell surface of several tumors) to elicit T-cell activation and TDCC. The objectives of this multi-country, phase 1 study of ERY974 is to determine the maximum tolerated dose (MTD) and to perform a preliminary assessment of anti-tumor activity in patients with solid tumors expressing GPC3. Methods: ERY974 is dosed IV weekly. All patients receive premedication with dexamethasone (DEX) prior to 1st and 2nd ERY974 dose. DE uses an accelerated titration design (ATD), then a modified continual reassessment method (mCRM) described by one-parameter logistic model, to determine MTD, where DLT occurrence rate is 0.25. Combining ATD and mCRM is to permit rapid dose escalation whilst minimizing patient numbers exposed to sub-therapeutic doses, and to accurately determine MTD. Once grade 2 (G2) cytokine release syndrome (CRS) is observed, DEX is increased. If ≥G2 CRS is again observed, then at all subsequent doses the 1st dose of ERY974 is fixed at the last dose level when < G2 CRS was not seen, DE proceeds with the 2nd dose. ATD commences with n = 1, increasing to n = 3 once drug-related ≥G2 toxicity is seen. mCRM starts after 1st dose limiting toxicity (DLT), with the modifications of at least 3 patients required to dose escalate and up to 1.5x increment to minimize risk of toxicity. CE has 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors. A 2-stage design is used to allow CE to stop early for futility. Subjects are adults with histologically confirmed, measurable malignant solid tumors and/or metastatic disease not amenable to standard therapy, and life expectancy ≥3 months. Patients with > 1cm or > 1 brain metastasis, current/previous interstitial lung disease, and acute/chronic infection are excluded. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017. Clinical trial information: NCT02748837.
A phase I study of the safety and immunogenicity of a multipeptide personalized genomic vaccine in the adjuvant treatment of solid cancers.
Authors: Kyi Chrisann , Sabado Rachel Lubong , Blazquez Ana , Posner Marshall R. , Genden Eric Michael , Miles Brett A. , Khorasani Hooman , Dottino Peter Remsen , Irie Hanna , Port Elisa R. , Wolf Andrea S , Cho Hearn J. , Parekh Samir S. , Mandeli John , Galsky Matthew , Oh William K. , Gnjatic Sacha , Schadt Eric E. , Friedlander Philip Adam , Bhardwaj Nina
Published: September 2018

TPS3114

Background: Mutation-derived tumor antigens (MTAs) arise as a direct result of somatic variations, including nucleotide substitutions, insertions, and deletions that occur during carcinogenesis. These somatic variations can be characterized via genetic sequencing and used to identify MTAs. We propose a platform for a fully-personalized MTA-based vaccine in the adjuvant treatment of solid tumors. Methods: This clinical trial is a single-arm, open label, proof-of-concept phase I study designed to test the safety and immunogenicity of the Personalized Genomic Vaccine 001 (PGV001). The single-center study will enroll 20 eligible subjects with histological diagnosis of the following tumor types: (a) head and neck squamous cell cancer, (b) non-small cell lung cancer, (c) ductal or lobular breast cancer, (d) serous carcinoma of the ovary, uterine adnexa, (e) urothelial carcinoma of renal pelvis or bladder, (f) cutaneous squamous cell cancer. Subjects must have no measurable disease at time of first vaccine administration, and 5-year disease recurrence risk of > 30%. Patients will receive 10 doses of PGV001 as well as 10 doses of poly-ICLC (toll-like receptor-3 agonist, vaccine adjuvant), administered 1 day after PGV001 vaccination. Toxicity (endpoint 1) will be defined by Common Terminology Criteria for Adverse Events v5.0. Blood samples will be collected at various time points for immune response monitoring of MTA-specific humoral and cellular immune responses. For each patient, immunogenicity (endpoint 2) will be defined as an epitope-specific T cell response, detectable in peripheral blood samples after PGV001 vaccination. The change in the frequency of vaccine-induced epitope-specific T lymphocyte populations post-vaccination relative to baseline will be determined using mixed effects linear regression modeling. Conclusions: Our clinical trial will test for the first time the safety and immunogenicity of PGV001 in patients with multiple solid cancers. The information learned from this clinical trial will instruct the next generation of MTA-based vaccines, future development of immunotherapeutic approaches and rational combinations. Clinical trial information: NCT02721043.
EORTC1527/JCOG1609INT: Diffusion-weighted MRI (DW-MRI) assessment of liver metastasis to improve surgical planning (DREAM).
Authors: Kataoka Kozo , Caballero Carmela Aves , Collette Laurence , Nakamura Kenichi , Kishi Yoji , Starlinger Patrick , Onaya Hiroaki , Suto Takeshi , Ducreux Michel , Shimada Yasuhiro , Tejpar Sabine , Rubbia-brandt Laura , Brown Gina , Shiozawa Manabu , Evrard Serge ,   EORTC GI Tract Cancer Group and Imaging Group, Japan Clinical Oncology Group (JCOG), European Society of Surgical Oncology (ESSO)
Published: September 2018

TPS3633

Background: For patients with initially unresectable colorectal liver metastases (CRLM) with good clinical response to chemotherapy, the presence of disappearing liver metastases (DLMs) diagnosed by CT is a major independent prognostic factor. DW-MRI as well as contrast enhanced (CE)-MRI is recommended to detect and characterize CRLM. However, the correlation between radiological and pathological complete response has not been fully investigated using these latest imaging and pathology techniques. Our main aim is to demonstrate the added value of DW-MRI, CE-MRI to that of CT alone to provide precise assessment of the viability of DLMs. In addition, we aim to optimize the therapeutic management of CRLM patients. No prospective study has been conducted to determine the predictive value of DW-MRI combined with CE-MRI in confirming sites of DLMs and assessing their true status. Methods: This is the first collaborative study between EORTC, ESSO and JCOG with an integrated quality assurance program for imaging, surgery and pathology. Patients with unresectable CRLM will receive standard systemic chemotherapy and liver resection if resectable. Both CT and MRI (DW-MRI, CE-MRI and T1/T2) will be used to identify confirmed DLMs (cDLMs). cDLMs will be either resected or, if resection is not possible, followed-up without resection until 2 years after surgery to evaluate the true status of the cDLMs. The primary endpoint is negative predictive value (NPV) of DW-MRI, CE-MRI, T1/T2 and CT in confirming the status of cDLMs using as reference either the histopathological complete response or the absence of a local recurrence at the site of cDLMs during the follow up period of 2 years. The study aims at excluding a NPV≤0.85 and is powered under the alternative that the NPV≥0.95. The planned sample size is 92 evaluable (resected or left behind) cDLMs, with a 1-sided alpha of 5% and a power of 90% adjusting for within-patient correlation between cDLMs of 0.2 and an average number of 2 cDLMs per patient. Approximately 400 patients will be registered from European, Japanese and US sites over 3 years. As of February 2017, 2 patients have been enrolled. Clinical trial information: NCT02781935.
A randomized phase III trial comparing adjuvant chemotherapy with S-1 vs. surgery alone in patients with resectable biliary tract cancer (JCOG1202: ASCOT).
Authors: Ikeda Masafumi , Nakachi Kohei , Konishi Masaru , Mitsunaga Shuichi , Mizusawa Junki , Uesaka Katsuhiko , Saiura Akio , Yanagimoto Hiroaki , Morinaga Soichiro , Eba Junko , Katayama Hiroshi , Fukuda Haruhiko , Ishii Hiroshi , Okusaka Takuji , Furuse Junji
Published: September 2018

TPS4144

Background: No standard adjuvant treatment has been established for patients with curatively resected biliary tract cancer (BTC). S-1, which is one of the oral fluoropyrimidine derivatives, showed promising efficacy with a mild toxicity profiles in patients with advanced BTC, and the survival benefit of adjuvant S-1 therapy has been demonstrated in patients with resected gastric cancer and pancreatic cancer. The aim of this open-label, multicenter, randomized phase III trial is to assess whether adjuvant S-1 would prolong the overall survival in patients with resected BTC. Methods: The main eligibility criteria are as follows: 1) curatively resected carcinoma of the extrahepatic bile duct, gallbladder or ampulla of Vater (T2-4, N0, M0 or T1-4, N1, M0), or carcinoma of the intrahepatic bile duct (T1-4, N0-1, M0) (7th UICC classification), 2) histologically confirmed adeno (squamous) carcinoma, 3) R0 or R1 residual disease, 4) age 20 to 80 years, 5) ECOG performance status 0 or 1, 6) no prior chemotherapy or radiotherapy, 7) adequate organ functions, 8) written informed consent. Patients are randomly assigned to the surgery alone arm (arm A) or the adjuvant S-1 arm (arm B) by the minimization method for balancing institution, primary site of cancer and lymph node metastasis between the arms. Patients in arm A do not receive any anti-cancer treatment, while patients in arm B receive 4 cycles of oral S-1 chemotherapy at the dose of 40 mg/m2 twice daily for 4 weeks followed by 2 weeks of rest. The primary endpoint is overall survival, while the secondary endpoints are relapse-free survival, incidence of (serious) adverse events, and proportion of treatment completion. We assumed a 3-year survival in arm A of 47% and a 10% increase in the 3-year survival in arm B. The sample size was calculated as a total of 350, with a one-side alpha of 5% and power of 70%; planned accrual period is 4 years, and follow-up period, 3 years. Primary analysis will be conducted at 3 years and updated analysis will be conducted at 5 years after closing of accrual. As of Jan 31, 2016, a total of 285 patients have already been enrolled in this trial from Sep 2013. Clinical trial information: UMIN000011688.
CanStem111P trial: A phase III study of napabucasin (BBI-608) plus nab-paclitaxel (nab-PTX) with gemcitabine (gem) in adult patients with metastatic pancreatic adenocarcinoma (mPDAC).
Authors: Bekaii-Saab Tanios S. , Li Chung-Pin , Okusaka Takuji , O'Neil Bert H. , Reni Michele , Tabernero Josep , Qin Shukui , Van Cutsem Eric , Borodyansky Laura , Li Chiang
Published: September 2018

TPS4148

Background: Cancer stem cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapeutic agents, including nab-PTX and gem. Encouraging anticancer activity in mPDAC was observed in a phase Ib (El-Rayes et al, ASCO 2016) study of 37 pts, reporting 93% (28/30) disease control rate (DCR) and 50% (15/30) overall response rate (ORR), with 1 complete and 14 partial responses and prolonged disease control ( > 24 wks) in 57% (17/30) of pts who have had a RECIST evaluation. On the basis of these data, a phase III trial is being conducted in North America, Europe, Australia and Asia. Methods: This study (ClinicalTrials.gov NCT02993731) will assess the efficacy of napabucasin+nab-PTX+gem vs nab-PTX+gem in pts with mPDAC (n = 1132). Pts must have been diagnosed with mPDAC < 6 weeks prior to randomization and not have received treatment for metastatic disease. Pts are randomized in a 1:1 ratio to receive napabucasin 240 mg PO twice daily continuously plus nab-PTX+gem IV weekly for 3 out every 4 weeks, or nab-PTX+gem IV weekly for 3 out every 4 weeks. Pts will be stratified by geography, performance status and presence of liver metastases. Treatment will continue until disease progression, death, intolerability or patient/investigator decision to stop. Primary endpoint is overall survival (OS) in the general study population (HR 0.80 for OS improvement from 8.5 to 10.63 months); secondary endpoints include progression free survival (PFS), OS and PFS in the biomarker positive sub-population, ORR and DCR, safety and quality of life. In addition, blood and tumor archival tissue will be assessed for pharmacokinetic and biomarker analyses. Global enrollment is underway. Clinical trial information: NCT02993731.
Alliance for clinical trials in oncology trial A021501: Preoperative extended chemotherapy vs. chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas.
Authors: Katz Matthew H. G. , Ou Fang-Shu , Herman Joseph , Ahmad Syed A. , Wolpin Brian M. , Marsh Robert de Wilton , Shi Qian , Hubbard Joleen Marie , Meyerhardt Jeffrey A. , Chuong Michael , O'Reilly Eileen Mary
Published: September 2018

TPS4151

Background: Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and an R0 resection was achieved in 64% of operations. However, the individual contributions of preoperative chemotherapy and radiation therapy are poorly defined.This study, Alliance for Clinical Oncology Trial A021501, will help define a standard preoperative treatment regimen for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials. Methods: In this recently activated randomized phase II trial, 134 patients with a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed radiographic criteria for borderline resectable disease are randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33-40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy undergo pancreatectomy and subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site. Clinical trial information: NCT02839343.
A phase III, double-blind, randomized clinical trial comparing S-1 in combination with DC vaccine loaded with WT1 peptides (TLP0-001) or placebo for the patients with advanced pancreatic cancer refractory to standard chemotherapy.
Authors: Katsuda Masahiro , Miyazawa Motoki , Kawai Manabu , Hirono Seiko , Okada Ken-Ichi , Shimizu Atsushi , Kitahata Yuji , Yamaue Hiroki
Published: September 2018

TPS4153

Background: The development of new potent therapeutic is strongly called for treating pancreatic cancer. Dendritic cells (DCs) are a type of antigen-presenting cells that play an important role in adaptive immune system, and this property has prompted their recent application to therapeutic cancer vaccines. DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce therapeutic anti-tumor immunity. Wilms' tumor gene WT1 is expressed in various kinds of cancers including pancreatic cancer. In pilot clinical trials of DC vaccination loaded with WT1 peptides for patients with advanced pancreatic cancer, induction of anti-tumor WT1 specific immune responses and tumor regressions have been observed (Kimura et al, Pancreas, 2012 / Kobayashi et al, Cancer Immunol Immunother, 2014 / Mayanagi et al Cancer Sci, 2015). TLP0-001 is activated Dendritic cells loaded with epitope peptides derived from WT-1. Methods: This is an investigator initiated, phaseIII, multicenter, double-blind, randomized trial of TLP0-001+S-1 versus placebo+S-1 for the patients with locally advanced or metastatic pancreatic cancer refractory to standard chemotherapy. Patients are allocated to either DC vaccine (TLP0-001) + S-1 group or placebo + S-1 in 1:1 ratio by dynamic allocation method. The primary endpoint is overall survival. Sample size is estimated presuming the effects will be observed from the time point of 50% cumulative survival rate. Assuming a type I error alpha (two-sided) level of 5% and a power of 80% or more for hazard ratio 0.644, sample size necessary is estimated as 174 patients. When the first 6 patients are administerd TLP0-001, the independent Data Monitoring Commitee checks safety data to assess continuation of the study. Enrollment begins in March 2017.
The ABC-study: A randomized phase III study comparing one course of adjuvant bleomycin, etoposide, and cisplatin (BEP) and one course of carboplatin AUC7 in clinical stage I seminomatous testicular cancer.
Authors: Tandstad Torgrim , Stahl Olof , Dahl Olav , Glimelius Ingrid , Haugnes Hege Sagstuen , Karlsdottir Asa , Langberg Carl Wilhelm , Soderstrom Karin , Solberg Arne , Stierner Ulrika K. , Wall Najme , Cohn-Cedermark Gabriella Elisabeth ,   SWENOTECA Group
Published: September 2018

TPS4593

Background: Clinical stage I seminomatous testicular cancer is by far the most frequent presentation of testicular cancer. Treatment options include surveillance or adjuvant treatment, internationally one course of adjuvant carboplatin (AUC7) is the preferred adjuvant treatment. Tumor size and stromal invasion in the rete testis can be used to identify patients with a higher risk of relapse. Recent data have showed only a modest effect of adjuvant carboplatin in preventing relapse, and more potent adjuvant therapies should be explored to this group of patients. Methods: The ABC-study is a investigator initiated randomized, open, phase III study comparing standard adjuvant chemotherapy in the form of one course carboplatin AUC7 to one course of BEP (Bleomycin, etoposide and cisplatin), in patients with one or two risk factors. Based on SWENOTECA data from one course of adjuvant carboplatin AUC7 we estimate the relapse rate in patients with one or two risk factors to be 9 %. We consider a reduction in relapse free survival of 7 % to be the minimum difference that will lead to routine use of one course of adjuvant BEP. To demonstrate an improvement in relapse rate from 9 to 2 % with an α = 0.05 and β = 0.80, 332 evaluable patients are required. We expect a dropout rate of maximum 5 %, and therefore intend to randomize a total of 348 patients. Enrollment in the study started in 2015, and as of February 1. 2017 a total of 66 patients have been enrolled. Accrual have been slower than expected, but the current accrual rate is about 6-7 patients a month. We invite institutions and collaboratory groups to participate in this study. NCT02341989. EUDRACT 2014-004075-23. Clinical trial information: NCT02341989.
A phase III randomized study comparing perioperative nivolumab vs. observation in patients with localized renal cell carcinoma undergoing nephrectomy (PROSPER RCC).
Authors: Harshman Lauren Christine , Puligandla Maneka , Haas Naomi B. , Allaf Mohamad , Drake Charles G. , McDermott David F. , Signoretti Sabina , Cella David , Gupta Rajan T , Bhatt Rupal Satish , Van Allen Eliezer Mendel , Choueiri Toni K. , Lara Primo , Kapoor Anil , Heng Daniel Yick Chin , Shuch Brian M. , Jewett Michael A.S. , George Daniel J. , Michaelson M Dror , Carducci Michael Anthony ,   On Behalf of the PROSPER RCC Investigators
Published: September 2018

TPS4596

Background: The anti-PD-1 antibody nivolumab (nivo) improves overall survival (OS) in metastatic treatment refractory RCC and is generally tolerable. In 2017, there is no standard adjuvant therapy proven to increase OS over surgery alone in non-metastatic (M0) disease. Mouse solid tumor models have revealed an OS benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivo in RCC patients (pts) have shown preliminary feasibility and safety with no surgical delays or complications. The PROSPER RCC trial will examine if the addition of perioperative nivo to radical or partial nephrectomy can improve clinical outcomes in pts with locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in M0 RCC, we propose a three-pronged, multidisciplinary approach of presurgical priming with nivo followed by resection and adjuvant PD-1 blockade. Methods: Tumorbiopsy prior to randomization is mandatory to ensure the correct diagnosis and will permit unparalleled correlative science in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. 766 pts with clinical stage ≥T2 or any node positive M0 RCC of any histology will be enrolled. The study arm will receive nivo 240mg IV for 2 doses prior to surgery followed by nivo adjuvantly for 9 months (q2 wks x 3 mo followed by q4 wks x 6 mo). The control arm will undergo the current standard of care: surgical resection followed by observation. Pts are stratified by clinical T stage, node positivity, and histology. There is 84.2% power to detect a 14.4% absolute increase in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 yrs (HR 0.70). The study is also powered to detect a significant OS benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the significance of the baseline immune milieu and changes after neoadjuvant priming and to identify predictive gene expression patterns. Additional collaborations are welcomed.
PROfound: A randomized Phase III trial evaluating olaparib in patients with metastatic castration-resistant prostate cancer and a deleterious homologous recombination DNA repair aberration.
Authors: De Bono Johann S. , Hussain Maha , Thiery-Vuillemin Antoine , Mateo Joaquin , Sartor A. Oliver , Chi Kim N. , Fizazi Karim , Twardowski Przemyslaw , Agarwal Neeraj , Sandhu Shahneen Kaur , Olmos David , Shore Neal D. , Saad Fred , Liu Sherry , Goessl Carsten Dietrich , Burgents Joe
Published: September 2018

TPS5091

Background: The median overall survival for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) is short. Available agents may offer limited therapeutic benefit, but no molecularly stratified treatment has yet been approved for this heterogeneous disease. A sizable percentage of pts with mCRPC has loss of function aberrations in genes involved in homologous recombination repair (HRR) in tumor tissue, such as BRCA1/2 and ATM. These aberrations can confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition. A Phase II study indicated that the oral PARP inhibitor olaparib (Lynparza) had antitumor activity in 33% of mCRPC pts who had progressed after new hormonal agent (NHA) treatment and chemotherapy, with a strikingly higher composite response rate in pts with a deleterious HRR gene aberration (HRRa) (88%; 14/16) vs pts without a HRRa (6%; 2/33) (Mateo et al.2015). The PROfound study evaluates olaparib efficacy and safety versus physician’s choice of either abiraterone acetate or enzalutamide, in pts with mCRPC and a HRRa (NCT02987543). Methods: To be eligible for this multinational, open-label, Phase III study, mCRPC pts must have progressed on prior NHA treatment and have a tumor HRRa in one of 15 genes, as confirmed by an HRR Assay (Foundation Medicine, Inc.). Cohort A (n = 240 approx) includes pts with mutations in BRCA1, BRCA2 or ATM, while pts with a mutation in 12 other HRR genes will be assigned to Cohort B (n = 100 approx). Pts will be randomized (2:1) to olaparib tablets (300 mg orally bid) or physician’s choice of either enzalutamide (160 mg orally od) or abiraterone acetate (1000 mg orally od with 5 mg bid prednisone) and treatment continued until radiographic progression (as assessed by blinded independent central review) or lack of treatment tolerability. The primary endpoint of radiographic progression-free survival (rPFS) will be assessed in Cohort A using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria. Key secondary efficacy endpoints include confirmed objective response rate, time to pain progression, overall survival (all Cohort A) and rPFS (both cohorts combined). Clinical trial information: NCT02987543.
Abiraterone +/- cabazitaxel in defining complete response in prostatectomy (ACDC-RP) trial.
Authors: Joshua Anthony M. , Fleshner Neil Eric , Chin Joseph , Emmenegger Urban , Gleave Martin E. , Hotte Sebastien J. , Sweet Joan , Collins Colin , Boutros Paul Christopher , Lupien Mathieu , Pugh Trevor John , Chi Kim N.
Published: September 2018

TPS5095

Background: Given recent advances in the management of de novo metastatic hormone-sensitive prostate cancer with both docetaxel and abiraterone, as well as evidence of significant activity of cabazitaxel in the post-abiraterone castrate-resistant setting, we hypothesized that the addition of cabazitaxel to neoadjuvant abiraterone will improve pathological complete response rates by overcoming mechanisms of resistance in localized high-risk prostate cancer. Aim: To determine the relative efficacy of the addition of cabazitaxel to abiraterone in the neoadjuvant treatment of prostate cancer to achieve a complete response. Methods: Open label, randomized, 2-arm multi-centre, phase 2 clinical trial. Primary endpoint: Pathological complete response rate (pCR). Secondary endpoints: surgical outcomes (positive margins, extracapsular extension, seminal vesicle or nodal involvement), pharmacodynamic markers in residual tumour (apoptosis, androgen receptor expression, localization, and signaling), biomarkers (intra-prostatic androgen levels), and safety. Design: Study participants will be randomized in a 1:1 ratio to receive either: Arm A: Abiraterone (1000 mg/day), prednisone (5 mg b.i.d.), leuprolide (22.5 mg s.c. every 3 months), and cabazitaxel (25 mg/m2 starting at week 2, with 6 mg pegfilgrastim 24 h following cabazitaxel) or Arm B: Abiraterone (1000 mg/day), prednisone (5 mg b.i.d.) and leuprolide (22.5 mg s.c. every 3 months). Assessments will take place biweekly for the first 12 weeks, then monthly until the prostatectomy (scheduled for 24 weeks following start of treatment). Target accrual is 88 participants within 36 months. Study is powered to detect a 15% difference with 85% power, assuming a one-sided type 1 error rate of 20%. A 6 patient safety run-in is included. As of Jan 2017, 1 site is open in Canada, with 4 additional Canadian sites and 1 site in Australia pending. To date, 4 participants are randomized and undergoing treatment. ACDC-RP is an investigator-initiated trial led by the Princess Margaret Urology Trials Group with funding from Ontario Institute for Cancer Research (OICR) and in-kind contributions from Janssen and Sanofi. Clinical trial information: NCT02543255.