bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1/1b multicenter trial of TPST-1120, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist as a single agent (SA) or in combination in patients with advanced solid tumors.
Authors: Laport Ginna , Powderly John D. , Chokshi Saurin , Luke Jason J. , Bendell Johanna C. , Enstrom Amanda , Whiting Chan C , Dubensky Thomas Walter
Published: May 2019

TPS2665

Background: Tumor cells initially favor glucose metabolism via aerobic glycolysis. As tumors rapidly proliferate and metastasize, glucose stores are depleted and facilitated by a hypoxic tumor microenvironment (TME) and metabolic reprogramming shifts intracellular metabolism(IcM) towards fatty acid oxidation (FAO). Fatty acids support metabolism of suppressive immune cells in the TME in addition to tumor growth. PPARα is a ligand-activated nuclear transcription factor which regulates lipid metabolism and FAO. TPST-1120 is a first in class, oral selective PPARα antagonist that blocks transcription of PPARα target genes leading to an intracellular metabolism shift from FAO to glycolysis. Reduction of fatty acids in the TME leads to direct killing of tumor cells dependent on FAO, skews macrophages from immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells. TPST-1120 also restores thrombospondin-1, a known natural inhibitor of angiogenesis, to homeostatic levels within the TME. TPST-1120 has an IC50 of 0.04 nM with > 35 fold selectivity over other PPAR isoforms. Preclinical studies in multiple tumor models show efficacy of TPST-1120 as a SA and in combination(combo) with an anti-PD1 monoclonal antibody (mAb) and chemotherapy. Methods: We have initiated a phase 1/1b multicenter, open label Dose Escalation (DEs) and Dose Expansion (DEx) trial to evaluate TPST-1120 as a SA and in combo with nivolumab, an anti-PD1 mAb; docetaxel, a chemotherapeutic agent and cetuximab, an anti-EGFR mAb. Objectives: 1) evaluate safety and tolerability of continuous dosing of TPST-1120 2) identify a recommended phase 2 dose (RP2D) and 3) evaluate efficacy. Eligibility: 1) patients with select advanced solid tumors who have failed 1 and up to 5 prior therapies. This phase 1/1b adaptive design has 4 DEs arms, 1 SA arm and 3 combination arms in which TPST-1120 is combined with nivolumab, docetaxel or cetuximab. The RP2D of TPST-1120 to proceed to DEx will be determined by safety and biomarkers during DEs. The DEx arms have 8 histology-specific cohorts, 4 SA arms and 4 combo arms and will follow a 2-stage expansion design. Biomarker analyses include gene expression profiling of PPARα-associated genes, tumor markers of immune modulation and serum lipid profiling. The total sample size is up to 338 pts. This trial is accruing at U.S sites. Clinical trial information: NCT03829436.
An open label, multicenter, phase 1b/2 study of rebastinib (DCC-2036) in combination with carboplatin to assess safety, tolerability, and pharmacokinetics in patients with advanced or metastatic solid tumors.
Authors: Tolcher Anthony W. , Munster Pamela N. , Rosen Lee S. , Murphy Curran , Argueta Christian , Kuida Keisuke , Ruiz-Soto Rodrigo , Janku Filip
Published: May 2019

TPS2666

Background: Rebastinib is a potent, orally administered, kinase switch control inhibitor selectively targeting the tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells and has critical roles in angiogenesis. In addition, TIE2 is highly expressed in a subset of macrophages, TIE2-expressing macrophages (TEMs), which are known to have proangiogenic, pro-metastatic, and immunosuppressive properties. Accumulating evidence suggests that chemotherapies, such as carboplatin, increase the recruitment and activity of pro-tumoral TEMs, leading to chemotherapy resistance. Taken together, investigation of rebastinib in combination with a chemotherapy such as carboplatin, one of the most commonly used agents across different tumor types, is warranted in advanced solid tumors. Methods: This study is an open-label, Phase 1b/2, multicenter study in patients with advanced or metastatic solid tumors. The study has two parts: the first part is the 3+3 dose escalation phase designed to evaluate the safety, tolerability and pharmacokinetics of 50 mg and 100 mg rebastinib twice daily in combination with carboplatin of AUC 5 or 6 administered once every three weeks to determine the recommended phase 2 dose (RP2D). Patients who have exhausted all therapies and for whom carboplatin is considered appropriate treatment will be enrolled. The second part is the dose expansion phase with three cohorts: previously treated breast cancer, recurrent, platinum-sensitive ovarian cancer, and malignant mesothelioma to evaluate the safety, tolerability, and efficacy of the RP2D. A Simon’s two-stage design will be used in the second part and initially up to 18 patients will be enrolled into each cohort. If more than 4 responses are observed, then the cohort will be expanded up to 33 patients. This trial is expected to enroll up to 117 patients in total, with approximately 18 patients in the first part and up to 99 patients in the second part. The study is currently open only in the US. Clinical trial information: NCT03717415.
First-time in-human study of VMD-928, an allosteric and irreversible TrkA selective inhibitor, in patients with solid tumors or lymphoma.
Authors: Chung Vincent , Wang Ling , Fletcher Margaret S. , Massarelli Erminia , Reckamp Karen L. , Cristea Mihaela C. , Prajapati Nikeeta , Parikh Aruna , Whiting Roger Lewis , Wang Maggie , Wu Jay
Published: May 2019

TPS3146

Background: Tropomysin receptor kinase A (TrkA) is a protein encoded by the NTRK1 gene. NTRK fusions involving the kinase domain are oncogenic for multiple tumor types and larotrectinib was recently approved for advanced solid tumors harboring NTRK gene fusions. Larotrectinib, an ATP-competitive, reversible pan-TrkA/B/C inhibitor, has shown impressive response rates in patients harboring these fusions; however, resistance can develop due to acquired ATP-site mutations. This has been previously identified in other oncogenic driver kinases such as ALK and EGFR treated with ATP-competitive kinase inhibitors. A newly approved allosteric ALK/EGFR inhibitor brigatinib was able to clinically overcome acquired resistance of many ATP-competitive ALK/EGFR inhibitors (1). Also, irreversible EGFR inhibitors such as afatinib (ATP-competitive) were active against tumors resistant to first-generation inhibitors (2), although their efficacy can be compromised by acquired ATP-site mutations (3). VMD-928 is the first oral small-molecule TrkA (NTRK1) selective inhibitor with dual allosteric and irreversible mechanisms of action. It inhibits TrkA non-competitively at an allosteric (non-ATP) site and has no resistance in vitro to acquired ATP-site mutations such as G667C. VMD-928 in vitro has little or no activity against 348 other kinases including TrkB (NTRK2) and TrkC (NTRK3). We are conducting the first time in human phase 1 trial of oral VMD-928, a novel allosteric and irreversible TrkA selective inhibitor. Methods: This is an open label, Phase 1 study investigating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral VMD-928 in adults with advanced solid tumors or lymphoma (NCT03556228). In part 1 of the study, an accelerated titration scheme will be utilized to determine the recommended phase 2 dose and evaluate PK / PD of VMD-928. In part 2, expansion cohorts including patients with thymic, pancreatic, triple-negative breast carcinoma, or solid tumors with TrkA alterations will be accrued to further evaluate safety and efficacy. Part 3 of the study will characterize the biologically active dose. The study is open and accruing patients at City of Hope. Clinical trial information: NCT03556228.
A first-in-human study of, NUC-7738, a 3'dA phosphoramidate, in patients with advanced solid tumors or lymphoma (NuTide 701).
Authors: Schwenzer Hagen P , Symeonides Stefan N. , Plummer Elizabeth Ruth , Bond Gareth P , Blagden Sarah Patricia
Published: May 2019

TPS3147

Background: Nucleoside analogs form the backbone therapy for both hematological and solid malignancies. However, their clinical effectiveness is severely limited by key cellular resistance mechanisms linked to increased breakdown, impaired activation and transport. NUC-7738 is a phosphoramidate transformation of cordycepin (3’-deoxyadenosine; 3’-dA), a derivative of adenosine that was first isolated from Cordyceps sinensis. The cytotoxic effect of 3’-dA is largely attributed to intracellular generation of the triphosphate metabolite, 3’-dATP, terminating DNA and RNA synthesis. Although 3’-dA has shown potent anti-tumor activity in non-clinical studies, it has not been successful in clinical studies mainly because of rapid enzymatic degradation by adenosine deaminase. NUC-7738 is not a substrate for adenosine deaminase and has been designed to bypass the key resistance pathways which have limited the clinical effectiveness of cordycepin. Methods: NuTide:701 is a two-part, first-in-human Phase I study in patients with advanced solid tumors and lymphoma who have exhausted all standard treatment options. The primary objective is to determine the RP2D and schedule of NUC-7738. Secondary objectives include safety, PK/PD and anti-tumor activity. Part 1, in patients with advanced solid tumors, will establish the RP2D and dose administration schedule of NUC-7738 for Part 2. Part 2 will further evaluate the selected RP2D and designated dosing schedule in an expansion cohort of patients with advanced solid tumors or lymphoma. The study initiated in Q1 2019. Clinical trial information: NCT03829254.
A phase I clinical study to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of FN-1501 monotherapy in patients with advanced solid tumors.
Authors: Richardson Gary Edward , Vaishampayan Ulka N. , Lin Lin , Bozon Viviana , Hui Ai-Min , Williamson Stephen K.
Published: May 2019

TPS3150

Background: Receptor tyrosine kinases (RTK), a group of transmembrane proteins, are responsible for growth factor signaling transduction in normal cellular functions. Abnormal RTK functions are associated with human tumorigenesis. FMS-like tyrosine kinase 3 (FLT3) belongs to the type III receptor tyrosine kinase family and plays a well-established role in normal growth and differentiation of hematopoietic precursor cells. FLT3 mutations have been reported to occur in approximately 30% newly diagnosed AML patients. The internal tandem duplications mutation (FLT3/ITD) is the major mutation and correlated with more aggressive progress and poor prognosis. FN-1501 is an inhibitor of various tyrosine kinases such as cyclin-dependent kinase 4/6(CDK4/6), platelet-derived growth factor receptor (PDGFR), KIT protein, anaplastic lymphoma kinase (ALK) and RET protein, particularly potent on FLT3. The preclinical data generated from biochemical, cell based and animal in vivo studies suggest that FN-1501 as a single agent could offer cancer patients clinical benefit by inhibiting multiple tyrosine kinases including FLT3, PDGFR, KIT, ALK, and RET. Methods: This is a Phase1, open label, multicenter, dose-escalation study that will evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of FN-1501 in up to 33 cancer patients with solid tumors. There is a dose escalation phase that will be followed by an expansion cohort. The dose escalation phase utilizes a standard “3 + 3” design where doses of FN-1501 will be escalated up to the Maximum-Tolerated Dose (MTD) or until the Recommended Phase 2 dose (RP2D) is identified. Once the MTD or RP2D dose is identified, an expansion cohort including patients with hematologic malignancies will be enrolled to further evaluate the safety and efficacy of FN-1501. Key exploratory analyses will include an evaluation of safety and efficacy and levels of expression and/or amplification of FLT3 mutations. As of February 8, 2019, cohorts 1 and 2 have been completed without a dose limiting toxicity (DLT). A total of 11 patients have been treated. Enrollment to cohort 3 is on-going. Clinical trial information: NCT03690154.
A phase I open label study evaluating VT1021 in patients with advanced solid tumors.
Authors: Cieslewicz Michael , Mahalingam Devalingam , Harb Wael A. , Patnaik Amita , Liu Joyce F. , Juric Dejan , Bullock Andrea J. , Zheng Lei , Moore Kathleen N. , Patel Manish R. , Guttendorf Robert , Wang Suming , Kerstein Kathy , Berk Gregory Ivan , Watnick Jing
Published: May 2019

TPS3158

Background: VT1021 is a cyclic pentapeptide that functions as a potent inducer of thrombospondin-1 (Tsp-1) expression in the tumor microenvironment (TME). By triggering the production of Tsp-1, VT1021 reprograms the TME from one that is immune-suppressive and tumor-promoting, to one that activates the adaptive immune system and is tumor-inhibiting. Tsp-1 reprograms the TME to: (i) induce apoptosis in tumor cells that express CD36 on their cell surface, (ii) convert macrophages from M2 to M1 polarization, which promotes phagocytosis and blunts immunosuppression and (iii) inhibit angiogenesis. Preclinical studies have shown robust anti-tumor activities of VT1021 in animal models of ovarian, pancreatic and breast cancer, including complete tumor regression and reprogramming of the immune TME. These observations led to the initiation of the first-in-human study of VT1021. Methods: This study is a first-in-human, Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) in advanced solid tumors. The primary objectives are to assess the safety and tolerability of VT1021, to assess dose-limiting toxicities (DLT), and to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Secondary objectives include the evaluation of pharmacokinetics (PK) and pharmacodynamic (PD) effects of VT1021 in tumor and tumor microenvironment, and assessment of preliminary antitumor activity. VT1021 is administered intravenously twice weekly. DLTs will be assessed in the first cycle (Days 1-28) of the dose escalation cohort and are defined as grade 3 adverse events related to VT1021. In Part 1 of the study, 24-30 patients will be enrolled to determine the MTD and RP2D for expansion. In Part 2 of the study, 80-100 patients will be enrolled, grouped into cohorts based on disease subtypes (ovarian, pancreatic, Triple-negative breast cancers, and glioblastoma). Blood samples and biopsy samples from patients will be collected to assess PK properties and PD responses systemically as well as in the TME. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US. Clinical trial information: NCT03364400.
Phase I study of procaspase activating compound -1 (PAC-1) in combination with temozolomide (TMZ) for the treatment of recurrent malignant glioma.
Authors: Nicholas Martin Kelly , Holdhoff Matthias , Peterson Richard A. , Danciu Oana Cristina , Tarasow Theodore M. , Hergenrother Paul J. , Dudek Arkadiusz Z.
Published: May 2019

TPS3164

Background: The caspase family of cysteine proteases play key roles in the initiation and execution of apoptosis. The activation of procaspase-3 to caspase-3 is critical in both the intrinsic and extrinsic apoptotic cascades. Procaspase-3 levels are elevated in many cancers, including glioblastoma (GBM). As a result, caspase-3 levels are abnormally low in these tumors; thus they avoid apoptosis. PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. PAC-1 has activity against a wide range of cancer cell lines, and in animal models of cancer. PAC-1 crosses the blood brain barrier and has been shown to synergize with TMZ in both canine malignant glioma and meningioma that arise spontaneously. Methods: This Phase I dose escalation study uses a modified- Fibonacci 3+3 design to determine the MTD of PAC-1 when combined with TMZ in patients with recurrent malignant gliomas: anaplastic astrocytoma (AA) and GBM (open to enrollment). Here, we focus on component 2 of the study. Primary objectives: to establish MTD of PAC-1 when combined with a fixed dose of TMZ, tolerability, and toxicity using CTCAE v.4. Secondary and correlative objectives: pharmacokinetics, pharmacodynamics, preliminary anti-tumor activity correlation with procaspase-3 expression in tumor tissue, radiographic response using the Response Assessment in Neuro-Oncology (RANO) criteria, and neurocognitive function using a validated test battery. Inclusion criteria: diagnosis of recurrent high grade glioma (AA or GBM), ECOG PS 0-2, adequate organ function. Exclusion criteria: received prior cytotoxic therapy in the last 3-6 weeks (duration based on prior therapy) or uncontrolled chronic illness. Administration and design, Component 2: PAC-1, orally administered, is dosed at 375-650 mg daily (up to 3 dose levels) on days 1-21 of each 28-day cycle. A fixed dose of TMZ, (150 mg/m2), is administered orally, days 8 -12 of each cycle. The study is currently enrolling patients for Component 2. Clinical trial information: NCT02355535.
Prospective observational study for treatment resistance-related gene screening using plasma circulating tumor DNA in the third generation EGFR TKI osimertinib therapy elucidator.
Authors: Tamiya Akihiro , Isa Shun-Ichi , Taniguchi Yoshihiko , Ando Masahiko , Atagi Shinji , Koh Yasuhiro
Published: May 2019

TPS3171

Background: Osimertinib (Osi) is a third-generation epidermal growth factor receptor (EGFR) – -tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations (mu). O showed superior efficacy compared with first generation EGFR-TKIs in patients (pts) with previously untreated advanced NSCLC harboring sensitizing EGFR mu in the prior phase III trial. Therefore, Osi is one of the most important standard therapies in EGFR mu positive pts. However, there are few reports about mechanisms of Osi resistance as the first line (1L) EGFR-TKI. Understanding of 1L Osi resistance mechanisms is essential to conduct future therapeutic strategy for EGFR mu NSCLC pts. We planned the analysis of the resistant mechanism by the ultra-sensitive next-generation sequence (NGS) using the circulating tumor (ct) DNA to clarify a resistant mechanism of 1L Osi. Methods: We prospectively collect ctDNA samples from EGFR mu positive NSCLC who will be treated with Osi as 1L. Planned enrollment is 180 cases, we estimate an analysis case at exacerbation to be 120 cases in a registration period and the observation period of for each two years. ctDNA samples are collected at treatment initiation, 3 and 12 months after Osi treatment, and disease progression. We will analyze the mechanisms of 1L Osi by the ultra-sensitive NGS using ctDNA. The key inclusion criteria are histologically or cytologically proven NSCLC, EGFR mu positive, pts treated with Osi as 1L, and written informed consent. The key exclusion criteria are patients who were deemed unsuitable for participation by an attending physician due to other conditions. The primary outcome is to clarify the incidence and ratio of Osi resistance by the ultra-sensitive NGS method using ctDNA at treatment initiation and progression disease. And key secondary endpoint is to examine how the detection quantity of the Osi resistance association mu in ctDNA at treatment initiation influences progressive disease. Clinical trial information: jRCTs031180051.
The Global POLAR program: Two pivotal placebo-controlled studies of calmangafodipir used on top of modified FOLFOX6 to prevent chemotherapy-induced peripheral neuropathy (CIPN).
Authors: Lustberg Maryam B. , Pfeiffer Per , Qvortrup Camilla , Muro Kei , Bengtson Marie Helene , Nittve Malin , Sonesson Christian , Nagahama Fumiko , Sonehara Yusuke , Carlsson Carl Stefan
Published: May 2019

TPS3616

Background: Oxaliplatin (OXA), is approved in combination with 5-FU/FA (5-fluorouracil/folinic acid; FOLFOX) for metastatic as well as in adjuvant colo-rectal cancer (CRC) treatment. CIPN is a common adverse event, after OXA treatment. The incidence of chronic CIPN is approximately 15% after a cumulative dose of 780 to 850 mg/m² and 50% after a cumulative dose of 1170 mg/m². OXA induced neuropathy, results in greatly reduced nitrated manganese superoxide dismutase (MnSOD) activity. Treatment with a superoxide dismutase mimetic, such as calmangafodipir (CAL), prevents and reverses oxaliplatin-induced neuropathies. This has been demonstrated in the PLIANT study, with CAL (Glimelius et al. 2017). Methods: The POLAR program is a Phase 3, multicenter, placebo (PLC)-controlled program of CAL to prevent CIPN, recruiting in US, Europe (B, D, ES, F,ES, I and UK) and Asia (J, SK, TW and HK) and is described below; POLAR A Patients with CRC, treatment of patients with Stage III or high-risk Stage II who are indicated for adjuvant modified FOLFOX6 (mFOLFOX6) chemotherapy for up to 6 months, randomized in a 1:1 ratio, each arm n = 140: A: CAL (5 µmol/kg) + mFOLFOX6 chemotherapy B: PLC + mFOLFOX6 chemotherapy POLAR M Patients with metastatic colorectal cancer (mCRC), who are indicated for first-line mFOLFOX6 chemotherapy for at least 3 months, without any pre-planned treatment breaks and will be randomized in a 1:1:1 ratio, each arm n = 140: A: CAL (2 µmol/kg) + mFOLFOX6 chemotherapy B: CAL (5 µmol/kg) + mFOLFOX6 chemotherapy C: PLC + mFOLFOX6 chemotherapy Primary objective is to compare CAL vs PLC with respect to the proportion of patients with moderate or severe chronic CIPN. The primary endpoint is; Patient reported symptoms as proportion of patients scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e., FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, assessed 9 months after the first dose of chemotherapy. In addition to conventional safety endpoints, Progressive Free Survival and Overall Survival are assessed in the POLAR M study. In the POLAR A study Disease Free Survival is one additional safety endpoint assessed. Results are expected during second half 2020. Clinical trial information: NCT03654729.
A phase IIb study of ramucirumab in combination with TAS102 versus TAS102 monotherapy in metastatic, chemotherapy refractory colorectal cancer patients: The RAMTAS trial of the German AIO (KRK-0316).
Authors: Kasper Stefan , zur Hausen Gerrit , Stein Alexander , Stintzing Sebastian , Berger Andreas , Loges Sonja , Hofheinz Ralf , Trarbach Tanja , Graeven Ullrich , Fischer von Weikersthal Ludwig , Goetze Thorsten Oliver , Hagen Volker A. , Burock Susen , Hoffmeister Albrecht , Dechow Tobias Nicolaas , Pauligk Claudia , Virchow Isabel , Siveke Jens T , Al-Batran Salah-Eddin , Schuler Martin H.
Published: May 2019

TPS3617

Background: Patients with metastatic colorectal cancer (mCRC) with progressive disease on/after or who are intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic and anti-EGFR therapies have limited therapeutic options and a dismal prognosis, with a median survival below 6 months. Recently, Trifluridin/Tipiracil (TAS102) significantly improved survival in patients with refractory mCRC and ramucirumab has been approved in combination with FOLFIRI for the treatment of patients with mCRC after prior FOLFOX/bevacizumab first line therapy. Previous studies on both components provide a strong rationale to conduct a randomized study evaluating the efficacy and safety of ramucirumab in combination with TAS102 in patients with refractory mCRC to improve efficacy and prevent resistance. Methods: This is an interventional, randomized, open label, multicenter, phase IIb study in patients with advanced mCRC. Eligible patients will be randomized 1:1 and receive either ramucirumab and TAS102 (ramucirumab 8 mg/kg on d1+15, q4w and TAS102 35 mg/m² on d1-5 and d8-12, q4w) or TAS102 alone. Primary endpoint is overall survival as assessed by the Kaplan-Meier method, assuming a 6 months survival probability of 70% with ramucirumab in combination with TAS102 and 58% with TAS102 alone. Treatment groups are compared using the log-rank test. A total of 144 patients will be enrolled at 30 sites (1-sided alpha 0.10, power 0.80). Main secondary endpoints are overall response rate, disease control rate, progression free survival and quality of life. In addition, a large comprehensive translational research program will be conducted to identify novel predictive and prognostic biomarkers. The study started in December 2018. By February 2019, a total of 3 patients have been enrolled. Clinical trial information: NCT03520946.
PRODIGE 53-UCGI 30 (SULTAN): A randomized phase II study comparing treatment intensification with hepatic arterial infusion chemotherapy plus systemic chemotherapy to systemic chemotherapy alone in patients with liver-only colorectal metastases considered still non resectable after at least two months of systemic induction chemotherapy.
Authors: Boige Valerie , Pignon Jean-Pierre , Wagner Mathilde , Dupont Bierre Eric , Le Sourd Samuel , Audemar Franck , Ulusakarya Ayhan , Guerin-Meyer Veronique , Pezzella Veronica , Gelli Maximiliano , Goere Diane , Taieb Julien
Published: May 2019

TPS3619

Background: In the first-line setting, current combination chemotherapy (CT) achieve high objective response rates (ORR) ranging from 40% to 80% and leads to complete resection rate (CRR) of colorectal cancer liver metastasis (CRCLM) in 25% to 50% of patients with initially non-resectable CRLM. However, when patients with CRLM are still not amenable to resection after induction CT, ORRs (~5-30%) and CRRs ( < 10%) obtained with second-line systemic CT are much lower. Combining hepatic arterial infusion (HAI) and systemic (SYS) CT for unresectable CRLM lead to high ORR and the potential of cure in the second-line and further setting. Methods: This multicenter randomized phase II trial conducted in 20 centers in France plans to include 140 patients with CRLM still not amenable to a curative intent-treatment after at least two months of first-line induction SYS CT whatever the tumor response. Patients are randomized (1:1) between intensified biweekly regimen combining HAI oxaliplatin (100 mg/m²) and SYS FOLFIRI (leucovorin 400 mg/m², irinotecan 180 mg/m², and 5-FU 2.4 g/m²over 48 h) plus cetuximab 500 mg/m² or bevacizumab 5 mg/kg (according to RAS status and prior response/tolerance to SYS induction CT) or SYS CT alone according to current guidelines. The primary endpoint is to evaluate and compare the curative-intent (R0-R1) resection (and/or ablation) rate (CRR) of CRLM in both arms. A gain of 20% in CRR is expected (30% in the experimental arm vs. 10% in the control arm; α 5% [two-sided]; β 20%). Stratification factors at randomization are prior adjuvant or SYS induction oxaliplatin-based CT, tumor response to SYS induction CT, and center. Secondary endpoints include progression-free (overall, hepatic and extrahepatic) and overall survival, ORR, relative change in the sum of longest diameters of RECIST target lesions (DoR) and feasibility/tolerability. Since study start, 3 patients have been enrolled to date (planned accrual period: 3 years). Clinical trial information: NCT03164655.
Phase II study of durvalumab following neoadjuvant chemoRT in stage II-IV rectal cancer: NSABP FR-2.
Authors: George Thomas J. , Yothers Greg , Lee James J. , Deutsch Melvin , Jacobs Samuel A. , Allegra Carmen Joseph , Wolmark Norman
Published: May 2019

TPS3620

Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. This prospective phase II trial will test that hypothesis in addition to confirming the safety of this approach using a “window-of-opportunity” study design with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT). Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling who are undergoing CRT with intent to proceed to surgical resection. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion. Surgery must be within 8-12 wks of the final CRT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls targeting a 20% relative risk reduction in DFS and 3-4% absolute OS improvement. Secondary endpoints include OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, circulating immunologic profiles, and molecular predictors of response. A safety run-in phase has completed as a precedent to full enrollment. Enrollment now continues to 47 total pts to achieve 41 surgically evaluable pts. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.
Efficacy of aspirin for stage III colorectal cancer: A randomized double-blind placebo-controlled trial (JCOG1503C, EPISODE-III trial).
Authors: Takashima Atsuo , Miyamoto Kenichi , Sato Yuya , Okita Natsuko , Shiozawa Manabu , Yamaguchi Shigeki , Inada Ryo , Nishizawa Yusuke , Ohue Masayuki , Takiguchi Nobuhiro , Mizusawa Junki , Katayama Hiroshi , Nakamura Kenichi , Shibata Taro , Fukuda Haruhiko , Shimada Yasuhiro , Kanemitsu Yukihide , Hamaguchi Tetsuya
Published: May 2019

TPS3623

Background: Adjuvant chemotherapy is the current standard treatment for stage III colorectal cancer after curative resection. However, the prognosis of stage III colorectal cancer is still poor even after curative resection and adjuvant chemotherapy. Recently, several observational studies suggested the anti-tumor effect of aspirin for advanced colorectal cancer. The main mechanism of the anti-tumor effect by aspirin may be to suppress cyclooxygenase activity in the arachidonic acid cascade and to inhibit the production of prostaglandins involved in tumor growth. So far, aspirin showed a prolongation of survival for colorectal cancer in several retrospective studies. However, in these studies, aspirin was given not to be evaluated the effect on prognosis of colorectal cancer in adjuvant setting but to prevent cardiovascular event. In addition, baseline patient characteristics were imbalanced between aspirin group and non-aspirin group and both dosage amount and dosing period of aspirin were different among patients. Methods: We planned a randomized double-blind placebo-controlled phase III trial commenced in Japan in March 2018 to confirm the superiority of aspirin in terms of disease-free survival (DFS) over placebo for stage III colorectal cancer patients after curative resection. Patients receive aspirin (100 mg/day) or placebo for 3 years with the standard adjuvant chemotherapy of mFOLFOX6, CAPOX or capecitabine until relapse or unacceptable toxicities. The primary endpoint is DFS and the secondary endpoints are overall survival, relapse-free survival, relative dose intensity, adverse events, and serious adverse events. We assumed the 3-year DFS of aspirin arm as 74% based on two previous trials conducted by JCOG and expected a 6% increase in the 3-year DFS with aspirin adding to standard adjuvant chemotherapy after curative surgery. A total of 880 patients will be accrued from 20 Japanese institutions within 3 years, and 47 patients were enrolled as of Jan 31, 2019. Both aspirin and placebo are provided by Bayer Yakuhin Ltd. This trial has been registered at Japan Registry of Clinical Trials as jRCTs031180009 (https://jrct.niph.go.jp/detail/589). Clinical trial information: jRCTs031180009.
Aspirin as adjuvant treatment for colorectal cancer: Rationale and progress of the Add-Aspirin trial.
Authors: Langley Ruth E , Wilson Richard H. , Cafferty Fay Helen , Joharatnam Nalinie , Graham Janet Shirley , Swinson Daniel , Iveson Timothy , Din Farhat Vanessa Nasim , Steele Robert J.C. , Henson Verity , Crossley Anne , Pramesh C S. , Walther Axel , Adams Richard , Dawson Lesley K. , Agarwal Roshan , Khabra Komel , Parmar Mahesh K B ,   The Add-Aspirin Trial Management Group
Published: May 2019

TPS3624

Background: There is now a body of evidence indicating a potential role for aspirin in colorectal cancer (CRC) prevention. In cardiovascular trials, effects on incidence of cancer metastases and short-term mortality suggest further possible roles in the treatment setting, supported by observational studies of aspirin use after cancer diagnosis. In the prevention setting, aspirin use has been limited by toxicity concerns, particularly of serious bleeding. In the adjuvant setting, benefits associated with reducing recurrence and subsequent treatment may outweigh these risks. The Add-Aspirin trial will investigate this, and will also consider possible mechanisms of action for aspirin effects, including the impact of PIK3CA mutations, where there are currently several theories and conflicting data. Methods: Add-Aspirin (ISRCTN74358648) is an international, phase III, double-blind, randomised, placebo-controlled trial recruiting patients who have undergone surgery and relevant adjuvant treatment for stage II or III CRC, as well as those with completely resected CRC liver metastases. Parallel randomised cohorts will address the question in breast, gastro-oesophageal and prostate cancer. Participants take aspirin 100mg daily for an 8-week run-in, to assess adherence and toxicity, and those suitable to proceed are randomised (1:1:1) to aspirin 100mg, aspirin 300mg or placebo daily for at least 5 years. A number of measures – including blood pressure control and PPI use where relevant - are in place to reduce bleeding risk. The primary outcome is disease-free survival (target hazard ratio = 0.8, n = 2600 in 5 years) with a long term analysis of survival planned across the tumour groups. Translational work includes a sub-study monitoring urinary thromboxane B2 as a marker of platelet activation in a subgroup (n = 500) to investigate mechanisms of action. Add-Aspirin opened in 2015 and recruited 1505 CRC patients during the first 3 years from 137 UK centres. 1282 (85%) proceeded to randomisation. A pre-planned feasibility analysis of run-in data (n = 2253 across all 4 tumour groups) provided reassuring data on safety, tolerability and adherence, and recruitment continues with centres in India and Republic of Ireland recently joining. Clinical trial information: 74358648.
RAP: A phase II trial with ramucirumab, avelumab, and paclitaxel as second line treatment in gastro-esophageal adenocarcinoma of the arbeitsgemeinschaft internistische onkologie (AIO).
Authors: Högner Anica , Breithaupt Kirstin , Stein Alexander , Hinke Axel , Lorenz Mario , Al-Batran Salah-Eddin , Thuss-Patience Peter C.
Published: May 2019

TPS4148

Background: Combination of ramucirumab and paclitaxel resembles the standard treatment option in second line therapy with improvement of response rate and overall survival (REGARD, RAINBOW). Response rates to PD-1/L1 blockade in gastro-esophageal cancer patients rank within 10–20%, whereby PD-1/L1 blockade is reported to impressively extend survival rates in responders. Trials investigating either the synergistic effect of anti-angiogenesis and anti-PD-L1 or chemotherapy combined with anti-PD-L1 are promising. Based on these data we hypothesize benefit from combining immunotherapy by checkpoint inhibition with VEGF-directed treatment and chemotherapy induced increase of immunogenicity of tumor cells. This study investigates the incorporation of PD-L1 blockade by avelumab in the second line setting by combination with the actual best second-line chemotherapy regimen in metastatic gastric cancer patients (paclitaxel+ramucirumab). Methods: The RAP trial (AIO-STO-0218, registered at ClinicalTrials.gov) is a single arm multicenter phase II trial. A total of 59 patients with metastatic or locally advanced gastric or gastro-esophageal junction adenocarcinoma, ECOG 0–1, who progressed after having received first-line therapy with platinum and fluoropyrimidine doublet with or without anthracycline, docetaxel or trastuzumab within the last six months will receive avelumab and ramucirumab on day 1, 15 and paclitaxel on day 1, 8 and 15 of a 28-day cycle until disease progression (RECIST v1.1), intolerable toxicity, withdrawal of consent or at a maximum treatment of 1 year. The primary endpoint is the overall survival rate (OSR) at 6 months. Sample size calculation is based on a Simon 2-stage design with a one-sided alpha error of 10% and a power of 80%, an expected OSR at 6 months of ≥ 65% and a 0 hypothesis ≤ 50%. Secondary endpoints include OS, OSR at 12 months, PFS, safety and tolerability, duration of response. Ethics commission approved the study protocol in January 2019. Updated patient accrual will be presented. Clinical trial information: AIO-STO-0218.
Ramucirumab and irinotecan in patients with previously treated gastroesophageal adenocarcinoma.
Authors: Park Haeseong , Trikalinos Nikolaos , Sanjeevaiah Aravind , Pedersen Katrina , Bagegni Nusayba Ali , Nixon Andrew B. , Huffman Jesse , Tan Benjamin R. , Suresh Rama , Lim Kian-Huat , Amin Manik A. , Wang-Gillam Andrea , Lockhart A. Craig
Published: May 2019

TPS4150

Background: Ramucirumab is used for treatment of metastatic gastroesophageal adenocarcinoma after disease progression on first-line chemotherapy. Superior survival outcome is expected when combined with paclitaxel. However, many patients suffer from neuropathy after oxaliplatin-containing first-line chemotherapy and are unable to tolerate paclitaxel. Irinotecan has shown survival benefit as a single agent or in combination with other agents, but has not been used in combination with ramucirumab for treatment with gastroesophageal cancer. We hypothesize that this combination regimen of irinotecan plus ramucirumab administered as second-line treatment will be well-tolerated with improved outcomes similar to paclitaxel plus ramucirumab in patients with advanced gastroesophageal cancer. Circulating levels of angiogenic factors are correlatives of particular interest in this study. Methods: This is a multi-institutional, single-arm phase II clinical trial of ramucirumab and irinotecan. Primary objective of the study is to determine the progression-free survival in patients treated with this combination after disease progression on first-line chemotherapy. Secondary objectives are to determine other indices of efficacy including overall survival, time to progression, objective response rate, and clinical benefit rate; and to evaluate toxicity and tolerability. Patients with confirmed diagnosis of gastroesophageal adenocarcinoma with measurable disease are included. Patients are required of have disease progression during or within 4 months of first line chemotherapy. Key exclusion criteria include squamous histology; prior irinotecan or ramucirumab use; active brain metastases; or other contraindications to ramucirumab including recent history of gastrointestinal bleeding or perforation, thromboembolic event, and uncontrolled hypertension. Patients receive ramucirumab 8mg/kg with irinotecan 180mg/m2 IV every 14 days. We plan to enroll 40 patients which will provide 85% power at a 0.05 significance level to detect a median progression free survival time of 4 months compared to historic control of 2.5 months. 25% of patient accrual is complete as of February 2019. Clinical trial information: NCT03141034.
Phase 3 (COSMIC-312) study of cabozantinib (C) in combination with atezolizumab (A) versus sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy.
Authors: Kelley Robin Kate , Cheng Ann-Lii , Braiteh Fadi S. , Park Joong-Won , Benzaghou Fawzi , Milwee Steven , Borgman Anne , El-Khoueiry Anthony B. , Kayali Zeid K , Zhu Andrew X. , Rimassa Lorenza
Published: May 2019

TPS4157

Background: C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). C is approved for treatment of aHCC after prior S based on improved overall survival (OS) vs placebo in the phase 3 CELESTIAL trial (Abou-Alfa NEJM 2018). Standard of care for first-line treatment of aHCC is tyrosine kinase inhibition with S or lenvatinib, and phase 3 trials of immune checkpoint inhibitors (ICIs) in first- and second- line aHCC are ongoing. C may promote an immune-permissive tumor environment, which could enhance response to ICIs. C is being evaluated in combination with the anti-PD-L1 antibody A in multiple tumor types including HCC in a phase 1 study; and dose, preliminary clinical activity, and safety have been established in aRCC (Agarwal Ann Oncol 2018). A in combination with bevacizumab, an anti-VEGF antibody, has shown preliminary clinical activity in first-line aHCC (Pishvaian Ann Oncol 2018). Here, we present the study design of a phase 3 trial of C+A vs S in pts with aHCC who have not received prior systemic therapy. Methods: This international, randomized, open-label phase 3 trial (NCT03755791) is evaluating the efficacy and safety of C+A vs S as first-line treatment for aHCC. Eligibility criteria include age ≥18 years, BCLC stage B or C, Child-Pugh A, ECOG PS 0 or 1, and measurable disease per RECIST 1.1. Patients are randomized 6:3:1 to an experimental arm of C (40 mg qd) + A (1200 mg infusion q3w), a control arm of S (400 mg bid), and an exploratory arm of C monotherapy (60 mg qd). 640 pts are planned at ~200 sites globally. Randomization is stratified by disease etiology (HBV [with or without HCV], HCV [without HBV], or other), region (Asia, other), and the presence of extrahepatic disease and/or macrovascular invasion (yes, no). OS and progression-free survival are coprimary endpoints and objective response rate is a secondary endpoint. Additional endpoints include safety, pharmacokinetics, and correlation of biomarker analyses with clinical outcomes. Enrollment in COSMIC-312 is ongoing. Clinical trial information: NCT03755791.
Bacillus Calmette-Guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction: Phase III KEYNOTE-676 study.
Authors: Kamat Ashish M. , Shore Neal D. , Hahn Noah M. , Alanee Shaheen Riadh , Nishiyama Hiroyuki , Shariat Shahrokh F. , Nam Kijoeng , Kapadia Ekta , Frenkl Tara L. , Steinberg Gary D.
Published: May 2019

TPS4591

Background: Intravesical instillation of BCG is standard of care for patients (pts) with HR NMIBC. However, many pts have persistent/recurrent HR NMIBC after BCG induction and are at increased risk for progression to muscle-invasive disease. Interim data from the phase 2 KEYNOTE-057 study has shown that the PD-1 inhibitor pembro had promising efficacy in HR NMIBC as monotherapy. KEYNOTE-676 (NCT03711032) is a randomized, comparator-controlled, phase 3 trial to evaluate efficacy and safety of pembro plus BCG in pts with persistent/recurrent HR NMIBC after BCG induction therapy. Methods: Pts are randomly assigned 1:1 to continue BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment is stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Pts are eligible if they are ≥18 years of age with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy, have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks before randomization, have no concurrent extravesical disease, and have an ECOG PS score of 0-2. Responses are assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or pt/physician decision to withdraw. Primary end point is complete response rate in pts with CIS. Secondary end points are event-free survival (EFS), recurrence-free survival, overall survival, disease-specific survival, time to cystectomy, 12-month EFS rate in all pts, duration of response (DOR), 12-month DOR rate in pts with CR and safety and tolerability. Recruitment began in November 2018 and will continue until ~550 pts are enrolled. Clinical trial information: NCT03711032.
Pamiparib, an investigational PARP inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) and a circulating tumor cell (CTC) homologous recombination deficiency (HRD) phenotype or BRCA defects: A trial in progress.
Authors: Chowdhury Simon , Mateo Joaquin , Gross Mitchell , Armstrong Andrew J. , Cruz-Correa Marcia , Piulats Josep M. , Blay Jean-Yves , Li Miao , Rivas Delcia , Quintero Luis , Castro Henry , Nkobena Andong , Raponi Mitch , Pelham Robert , Landers Mark , Montgomery Robert B.
Published: May 2019

TPS5086

Background: Men with mCRPC who have a BRCA1/2 mutation ( BRCA1/2mut) or mutations in other genes resulting in HRD have a poor prognosis. A novel liquid biopsy test (EPIC Sciences) identifies CTCs with an HRD phenotype. Preliminary studies showed that these men may respond to treatment with a PARP inhibitor. Pamiparib, an investigational PARP1/2 inhibitor, has shown brain penetration and potent PARP–DNA complex trapping in nonclinical studies. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg orally twice daily (BID) was established as the recommended investigational dose. Methods: This open-label, global, phase 2 study (NCT03712930) evaluates the antitumor activity and safety/tolerability of pamiparib in mCRPC patients (pts) with CTC-HRD, assessed by the CTC-HRD assay, or deleterious germline/somatic mutations in BRCA1/2. Patients must have progressed on/after ≥1 androgen receptor-targeted therapy, received ≥1 taxane-based therapy, and have prostate-specific antigen (PSA) progression per PCWG3 criteria. Four cohorts of pts will receive pamiparib 60 mg BID in 28-day cycles. Cohort 1 will include ~50 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with measurable metastatic disease; Cohort 2 will include ~30 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with bone-only disease; Cohorts 3 & 4 will include ~20 pts with CTC-HRD-/unk + BRCA1/2mut mCRPC with measurable metastatic disease (Cohort 3), or bone-only disease (Cohort 4). Disease status will be assessed every 8 wks for 24 wks, then every 12 wks; PSA levels will be tested every 4 wks. Co-primary endpoints are radiographic ORR assessed by IRC (pts with measurable disease) and confirmed PSA response rate per PCWG3 criteria (pts +/- measurable disease). Secondary endpoints include ORR, time to PSA response/progression, duration of PSA response, time to symptomatic skeletal event, radiographic progression-free survival, overall survival, and safety. As of 05 December 2018, this study is actively enrolling. Clinical trial information: NCT03712930.