bluuebunny/crossref_metadata_2025 huggingface dataset:
TROPiCS–03: A phase II open-label study of sacituzumab govitecan (SG) in patients with metastatic solid tumors.
Authors: Saxena Ashish , Michel Loren S. , Hong Quan , Hilsinger Karrie , Kanwal Charu , Pichardo Cabilia , Goswami Trishna , Santin Alessandro
Published: May 2020

TPS3648

Background: Trophoblast cell surface antigen (Trop-2) is highly expressed in many epithelial cancers (non–small-cell lung cancer [NSCLC], endometrial cancer, urothelial carcinoma [UC], and triple-negative breast cancer [TNBC]) and has been linked to aggressive disease and poor prognosis. SG is a Trop-2–directed antibody drug conjugate containing SN-38 (active metabolite of irinotecan) with a 7.5:1 drug-to-antibody ratio and unique hydrolyzable linker that allows for extracellular bystander effect. The phase 1/2 IMMU-132-01 basket study reported clinical activity with SG in patients with multiple tumor types not selected for Trop-2 expression including NSCLC (objective response rate [ORR]: 17%), TNBC (ORR: 33%), and UC (ORR: 31%).1-3 Results from the overall safety population (N=420) from this study found that SG was tolerable, with a predictable and manageable safety profile, and low discontinuation rates due to AEs. Methods: To test a biomarker-enrichment strategy with Trop-2, the TROPiCS-03 (TROP-2 Investigations in Cancer with SG) study was initiated. TROPiCS-03 (NCT03964727) is a multi-cohort, open-label, phase 2 study in patients with metastatic solid tumors - presently NSCLC (adenocarcinoma and squamous cell carcinoma), head and neck squamous cell carcinoma, and endometrial cancer - selected based on elevated Trop-2 expression by a validated IHC assay. Patients receive SG (10 mg/kg IV, days 1 and 8 every 21 days) and continue treatment until lack of clinical benefit or unacceptable toxicity. The primary endpoint is objective response rate (local assessment) and additional endpoints include clinical benefit rate, duration of response, progression-free survival, and safety. Females or males ≥18 years old who are histologically documented to have locally advanced or metastatic (M1, stage 4) solid tumors of the above types are eligible. Patients must have ECOG 0 or 1 and adequate clinical laboratory results to be enrolled. All subjects will have progressed after prior platinum-based chemotherapy and programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) directed therapy. Patients who have previously received topoisomerase I inhibitors and those with known active CNS metastases are excluded. Approximately 160 patients will be enrolled in the trial overall; enrollment in the NSCLC cohort is currently in progress. References: Heist RS et al. J Clin Oncol. 2017;35:2790-7, Bardia A et al., NEJM. 2019;380:741-51.,Tagawa ST et al., Oral presentation; ASCO-GU 2019, San Francisco, CA. Clinical trial information: NCT03964727 .
Phase I study of the antibody-drug conjugate ABBV-321 in patients with non-small cell lung cancer and squamous head and neck cancer with overexpression of the epidermal growth factor receptor.
Authors: Carneiro Benedito A. , Bestvina Christine M. , Shmueli Einat Shacham , Gan Hui Kong , Beck Joseph Thaddeus , Robinson Randy , Fischer JuDee S. , Wong Amber , Ansell Peter J , Jin Janet Yikai , Naumovski Louie , Papadopoulos Kyriakos P.
Published: May 2020

TPS3649

Background: ABBV-321 (serclutamab talirine) is an epidermal growth factor receptor (EGFR)-targeted antibody-drug conjugate that consists of a humanized immunoglobulin G1 anti-EGFR monoclonal antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer via a maleimidocaproyl-valine-alanine linker. Once bound, ABBV-321 is internalized, the maleimidocaproyl-valine-alanine linker undergoes proteolytic cleavage, and the cytotoxic PBD is released, causing DNA cross-links and cell death. Preclinical studies have shown cytotoxicity in numerous human xenograft and patient (pt)-derived tumor models. This first-in-human trial is assessing the safety, pharmacokinetic (PK), and preliminary antitumor activity of ABBV-321 in pts with advanced solid tumor types likely to exhibit elevated levels of EGFR. Methods: This is a 2-part, multicenter phase 1 study (NCT03234712) of ABBV-321 monotherapy in pts (≥18 years; Eastern Cooperative Oncology Group performance status 0–1) with advanced solid tumors associated with overexpression of EGFR. EGFR overexpression will be determined by centralized testing using an RNA-based assay. Primary objectives of the completed part 1 (dose escalation) were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of ABBV-321 and assess the PK and toxicity and safety profile; part 2 (dose expansion) will evaluate safety and PK profile at the RP2D in specific cohorts (NSCLC and HNSCC). Secondary objectives include assessment of preliminary antitumor activity. Pts will receive escalating doses of ABBV-321 until the MTD/RP2D is determined. Dose-limiting toxicities will be assessed during the first cycle of dosing. Adverse events (AEs) will be evaluated per National Cancer Institute Common Terminology Criteria for AEs (version 4.03). Blood samples for PK analysis (ABBV-321, total antibody, unconjugated PBD) will be collected at designated time points throughout the study. The multinational trial is active, with the first pt screened on 1 Feb 2018. The dose-escalation phase has been completed; screening and enrollment for the expansion phase of the study in NSCLC and HNSCC is underway. Clinical trial information: NCT03234712 .
First-in-human phase I study of SY-5609, an oral, potent, and selective noncovalent CDK7 inhibitor, in adult patients with select advanced solid tumors.
Authors: Papadopoulos Kyriakos P. , Sharma Manish , Hamilton Erika Paige , Richardson Debra L. , Hodgson Graeme , Zhou Li , Volkert Angela , Jolin Hina A. , Madigan Catherine , Kelly Michael , Roth David A.
Published: May 2020

TPS3662

Background: SY-5609 is an oral, noncovalent, highly selective and potent inhibitor of cyclin-dependent kinase 7 (CDK7), a key regulator of 2 biological processes that play critical roles in driving tumor development: transcription and cell cycle control. Evaluation of SY-5609 as a single agent in PDX models from a range of solid tumors, including breast, ovarian, lung and colorectal tumors, revealed robust antitumor activity including complete regressions, and activity in models known to be resistant to standard of care therapy. Models with genetic alterations in RB pathway genes demonstrated deep ( > 90% TGI) and sustained SY-5609-induced tumor regressions following treatment discontinuation, in contrast to models without genetic alteration in RB pathway genes, suggesting that tumor cells with aberrant cell-cycle control may be particularly sensitive to SY-5609 treatment. The study is designed to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of SY-5609, to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and preliminary antitumor activity of SY-5609, and to explore candidate biomarkers predictive of response to SY-5609. Methods: This is a multi-center, open-label Phase 1 trial expected to enroll approximately 60 adult patients with select advanced solid tumors for which standard treatment is no longer effective. The dose escalation phase of the trial is open to adult patients with ovarian, breast, colorectal, or lung cancer, and patients with any solid tumor histology with molecular evidence of deregulated RB cell cycle control. SY-5609 is being administered orally once daily, for each 4-week cycle. Initially, patients will be enrolled into single-patient accelerated titration cohorts; subsequent cohorts will transition to a 3 + 3 design. Following completion of DLT evaluation at a given dose level, additional patients may be enrolled at that dose to further characterize safety, PK, PD, and early clinical activity. Data from this trial will support dose selection for planned evaluations of antitumor activity of SY-5609 as a single agent and in combination. Clinical trial information: NCT04247126 .
Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies.
Authors: Hamilton Erika Paige , Patel Manish R. , Rodon Jordi , Hong David S. , Schram Alison M. , Janne Pasi A. , LoRusso Patricia , Sachdev Jasgit C. , Ou Sai Hong , Buck Elizabeth A , O'Connor Matthew , Waters Nigel , Witt Karsten , Cook Carl
Published: May 2020

TPS3665

Background: A significant unmet need exists for drugs targeting allosteric ErbB mutations (non-canonical mutations outside the ATP binding site). Current EGFR and HER2 tyrosine kinase inhibitors or mAbs have limited antitumor activity against allosteric mutations, resulting in toxicity before adequate drug exposure (Connell and Doherty, 2017). BDTX-189 is a potent and selective orally available irreversible inhibitor targeting unique oncogenic driver mutations of ErbB kinases in EGFR and HER2, while sparing WT EGFR. Preclinical studies demonstrated antitumor activity across a range of allosteric ErbB mutants, including extracellular domain allosteric mutations of HER2 as well as EGFR and HER2 kinase domain exon 20 insertions (Buck, 2019). This first-in-human trial (NCT04209465) is aimed to determine the recommended phase 2 dose (RP2) and schedule (Phase 1, P1), and evaluate the efficacy (Phase 2, P2) of BDTX-189. P1 primary objective is to determine the RP2 dose and schedule of monotherapy BDTX-189. Secondary objectives include assessment of safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) effects in tumor, and preliminary efficacy. The P2 primary objective is to assess antitumor activity of monotherapy BDTX-189. Methods: The study will enroll patients (pts) ≥18 yrs with histologically or cytologically confirmed locally advanced or metastatic solid tumors with no standard therapy available or for whom standard therapy is unsuitable or intolerable. P1 dose-escalation will use a BOIN design (Yuan, 2016) and will enroll ≤ 88 pts with allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplified or overexpressing tumor; or EGFR exon 19 deletion or L858R mutation. BDTX-189 will be dosed orally (PO) initially QD in 3 wk cycles. Regimen optimization will use PK, PD and safety data and may explore a BID schedule. An expansion cohort of ≤12 pts will further evaluate safety and preliminary efficacy of BDTX-189 prior to P2. P2, utilizing a Simon 2-stage design, will enroll ≤100 pts with NSCLC with EGFR or HER2 exon 20 insertion mutations (cohort 1); breast cancer with an allosteric ErbB mutation (cohort 2); tumors (except breast) with S310F/Y mutation (cohort 3); and other allosteric ErbB mutations not defined in cohorts 1-3 (cohort 4). Assessments include safety, tolerability, DLTs, evaluation of MTD, PK, PD, and preliminary antitumor activity. Enrollment began 1/2020. Clinical trial information: NCT04209465 .
A phase III study of comparing FOLFOX+/-bevacizumab with FOLFOX+/-bevacizumab+ high-dose intravenous vitamin C as first-line therapy in patients with advanced colorectal cancer.
Authors: Wang Feng , Xiao Jian , Zhang Yan-Qiao , Yuan Xianglin , Fang Weijia , Wang Wei , HU Xiaohua , Zhuang Zhixiang , Zhou Fuxiang , Ying Jieer , Yuan Ying , Guo Zeng-qing , Wu XiangYuan , Zou Qing-Feng , He Ming-ming , Guo Ying , Chen Shuang-Zhen , Xu Rui-hua
Published: May 2020

TPS4115

Background: Previous studies showed that high dose vitamin C especially when administered intravenously might have anti-cancer effect. A recent preclinical study found that human colorectal cancer cells harboring KRAS or BRAF mutations are selectively killed by high dose vitamin C. Our phase I dose-escalation and expansion study has shown that high dose (up to 1.5g/kg) intravenous vitamin C with FOLFOX or FOLFIRI is well tolerated in patients with colorectal or gastric cancer. This trial is a randomized, multicenter, phase Ⅲ study of high dose vitamin C infusion combined with FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab as first-line therapy in patients with advanced colorectal cancer. Methods: This study has enrolled patients with histologically confirmed metastatic adenocarcinoma of colorectum, normal G6PD status and no prior treatment for metastatic disease. 432 patients are randomized 1:1 into one of two groups. Patients in the control group are treated with mFOLFOX6 (oxaliplatin 85 mg/m² d1 concurrent with leucovorin 400 mg/m², followed by bolus 5FU 400 mg/m² d1, followed by infusional 5FU 2400 mg/m² over 46 hours) with or without bevacizumab (5mg/kg, d1) every 2 weeks. Patients in the experimental group are treated with vitamin C intravenously (1.5g/kg/day, d1-3) in combination with mFOLFOX6 with or without bevacizumab every 2 weeks. Randomization is stratified by the location of primary site (left-sided or right-sided) and treatment with bevacizumab (with or without). The primary endpoint is progression free survival (assessed by investigator per RECIST v1.1). Secondary endpoints are overall survival, response rate, assessment of treatment-related adverse events, progression free survival and overall survival in RAS or BRAF mutant patients. Genome, microbiome and metabolome are also assessed. Clinical trial information: NCT02969681 .
Multimodal fluorescence-guided surgery of colorectal peritoneal metastases, a phase I/II clinical trial.
Authors: de Gooyer Jan-Marie , Elekonawo Fortuné , Bremers Andre J.A. , Boerman Otto , Rijpkema Mark , de Wilt Johannes H.W.
Published: May 2020

TPS4119

Background: Successful treatment of patients with colorectal peritoneal carcinomatosis highly depends on complete surgical tumor resection of all tumor. Oncological outcomes can potentially be improved by intraoperative imaging using a tumor-targeting antibody conjugated to a fluorophore and a radiotracer. This enables preoperative radionuclide imaging, real-time intraoperative fluorescence imaging and gamma detection. In this study we investigate the feasibility, accuracy and safety of CEA-targeted preoperative SPECT/CT and intraoperative fluorescence imaging in patients with colorectal PC. Methods: In this phase I/II single arm protein dose escalation study patients with peritoneal metastases of colorectal origin who are scheduled for cytoreductive surgery and HIPEC will receive an intravenous injection of the CEA-targeting tracer 111In-DOTA-labetuzumab-IRDye800CW. The first 15 patients will receive a single dose of 2,10 or 50 mg 6 to 7 days prior to surgery. Four to five days after injection SPECT/CT imaging of the thorax and abdomen is performed to determine intra-abdominal tumor load and detect extra-abdominal metatases. At day 6/7 after injection, standard cytoreductive surgical resection extended with real-time near-infrared fluorescence imaging and radio guidance is performed. After surgery, the peritoneal cavity will be re-examined for residual disease with fluorescence imaging. Resected specimens are analyzed microscopically, immunohistochemically (CEA and H&E) and by gamma counting. Blood samples are drawn for farmacokinetics and safety analysis at 180 minutes, 4 days, 6 days and 3 weeks after tracer injection. In the phase II dose expansion cohort, 14 more patients will receive the optimal dose as determined in the phase I trial. The primary objectives of the trial are to assess the safety, feasibility and accuracy of preoperative SPECT/CT and intraoperative fluorescence imaging after administration of 111In- labetuzumab-IRDye800CW in patients with peritoneal carcinomatosis of colorectal origin who will undergo cytoreductive surgery and HIPEC. The secondary objectives are to assess whether additional malignant lesions can be visualized by fluorescence imaging after cytoreductive surgery, to assess the intensity of fluorescence in malignant and non-malignant tissue, to assess the correlation between localization of the dual-labeled antibody and CEA expression in tumor and healthy tissue and to determine blood concentrations of the dual labelled antibody at several time points in patients. Clinical trial information: NCT03699332 .
A phase II study of induction PD-1 blockade in subjects with locally advanced mismatch repair-deficient rectal adenocarcinoma.
Authors: Cercek Andrea , Stadler Zsofia Kinga , Cohen Jenna L. , Weiss Jill A , Lamendola-Essel Michelle F. , Krishnan Asha , Yaeger Rona , Segal Neil Howard , Connell Louise Catherine , El Dika Imane H. , Kemeny Nancy E. , Saltz Leonard B. , Smith Jesse Joshua , Nash Garrett Michael , Paty Philip , Garcia-Aguilar Julio , Weiser Martin R. , Diaz Luis A.
Published: May 2020

TPS4123

Background: The treatment of patients with locally advanced rectal cancer includes total neoadjuvant therapy with chemotherapy, chemoradiation followed by surgery. While most rectal cancers respond to combination induction chemotherapy, patients with mismatch repair deficient (dMMR) or MSI-H tumors have a significantly higher chance of progression with this treatment regimen. dMMR or MSI-H tumors have shown remarkable responses to PD-1 blockade, but the effect of neoadjuvant checkpoint inhibition has not been well studied. In this trial we will determine the pathologic complete response rate (pCR) of neoadjuvant anti-PD-1 blockade followed by standard chemoradiation in dMMR or MSI-H locally advanced rectal cancer. We hypothesize that treatment naïve dMMR or MSI-H rectal cancers will achieve a robust clinical response to PD-1 blockade and that the total neodjuvant therapy with PD-1 blockade followed by chemoradiation will improve pCR rates. Methods: Eligible patients ≥18 years of age with Stage II (T3-4, N-) or Stage III (any T, N+) histologically confirmed dMMR or MSI-H (by NGS) rectal adenocarcinoma will be enrolled. Patients will receive TSR-042 (500mg IV) every 3 weeks for a maximum of 8 cycles (6 months of treatment). Imaging, internal endoscopic exam and ctDNA blood draw will be performed at 6 weeks and every 3 months during induction anti-PD-1 treatment. Adverse events and surgical complications will be graded according to the NCI CTCAE v5 and the Clavien-Dindo classification, respectively. Following neoadjuvant checkpoint blockade, patients will undergo conventional chemoradiotherapy followed by surgical resection. The primary endpoint is pathologic complete response compared with historical control in pMMR patients. Patients will be followed up every 6 months for assessment of disease-free survival for up to five years. Clinical trial information: NCT04165772 .
A phase II study of selective HDAC6 inhibition with KA2507 for second-line treatment of advanced biliary tract cancer (ABC-11).
Authors: Bridgewater John A. , Beer Philip , Bendall Jennifer , Dehbi Hakim-Moulay , Duggan Marian , Hung Michelle , King Justine , McElwaine-Johnn Hilary , White Laura
Published: May 2020

TPS4652

Background: The ABC-02 trial provided Level A evidence supporting the use of cisplatin plus gemcitabine as first-line chemotherapy for advanced biliary tract cancer (ABC) [Valle, 2010]. In second line therapy oxaliplatin and 5FU and ivosedinib for IDH1 mutated cancers are options [Lamarca, 2019; Abou-Alfa, 2019] however there remains significant unmet need for patients without actionable alterations. Histone deacetylase 6 (HDAC6) is over-expressed in cholangiocarcinoma, reducing primary cilia. This is mediated through increased resorption in normal human cholangiocytes via tubulin deacetylation in the ciliary axoneme. Inhibition of HDAC6 elicits both cell intrinsic and extrinsic anti-cancer activity. HDAC6 inhibition reversed oncogenic loss of ciliation and demonstrated preclinical efficacy in a syngeneic rat orthotopic biliary cancer model [Gradilone, 2013]. KA2507 is a potent and selective small molecule inhibitor of HDAC6. Phase I dose escalation study identified an oral dose of 800mg bid for further development, being well tolerated and showing evidence of selective target engagement. Methods: ABC-11 is a Phase II multi-centre, open-label study of KA2507 in 40 evaluable patients with advanced biliary tract cancer previously treated with standard of care chemotherapy. The study follows a single-arm single-stage design using A’Hern’s methodology. Eligible patients receive continuous 28-day cycles of fixed daily oral dose of KA2507 until death, disease progression or other pre-defined reason for study drug discontinuation. Tumour assessment is made at baseline and at 8-weekly intervals using RECIST 1.1 criteria until disease progression; primary endpoint is PFS at 4 months. Independent Data Monitoring Committee will review 4 month PFS and other data after first six patients, after a total of 17 patients (futility analysis, corresponding to cut-off of the Simon’s minimax 2-stage design; 33% was set as the target 4-month PFS rate expected with KA2507) and at least annually thereafter. Subject to availability of adequate tissue, mandatory pre-treatment and on-study tumour biopsy samples will undergo multiparameter flow cytometry of immune cell subsets, immunofluorescence analysis of immune cell subsets (activation status and topology) and T cell repertoire studies. The study received regulatory and ethical approval to proceed in January 2020 and enrolment is in progress. Clinical trial information: NCT04186156 .
Etctn 10388: A phase I trial of triapine and lutetium Lu 177 dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Authors: Chauhan Aman , Kunos Charles , El Khouli Riham , Kolesar Jill , Weiss Heidi , Carson William Edgar , Evers Mark B , Kidd Mark S. , Beumer Jan Hendrik , Arnold Susanne M. , Kohn Elise C. , Anthony Lowell Brian
Published: May 2020

TPS4660

Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium Lu 177 Dotatate (Lutathera) is a beta-emitting radionuclide, recently FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 17% ORR. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Ribonucleotide reductase (RNR) is the only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. Radiation is a potent inducer of DNA double-strand breaks (DSBs), and RNR is the rate-limiting enzyme in the repair of DNA in this setting. Triapine is an inhibitor of RNR. This study will test the hypothesis that radiation sensitizer triapine can be safely combined with peptide receptor radionuclide therapy and ultimately may improve antitumor activity of Lutetium Lu 177 Dotatate. Methods: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation with help of Bayesian optimal interval design (BOIN) and dose expansion cohorts. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Patients will be treated with 177 lutetium dotatate in combination with triapine. Triapine will be administered orally (100 mg once a day starting dose) from D1-14 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate recommended phase II dose (RP2D). Secondary endpoints are to evaluate safety, pharmacokinetics, and clinical activity (ORR and PFS). We are also evaluating NETEST, a novel blood based test that evaluates levels of 51 neuroendocrine tumor gene transcripts. In addition, the study will correlate clinical outcome with baseline somatostatin receptor density, somatic tumor mutations and germline mutations. Clinical trial information: 04234568 .
NAPOLI-3: An open-label, randomized, phase III study of first-line liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin versus nab-paclitaxel + gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Wainberg Zev A. , Bekaii-Saab Tanios S. , Hubner Richard , Macarulla Teresa , Paulson Andrew Scott , Van Cutsem Eric , Maxwell Fiona , Moore Yan , Wang Haofei Tiffany , Zhang Bin , O'Reilly Eileen Mary
Published: May 2020

TPS4661

Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT04083235 .
EndoTAG-1 plus gemcitabine versus gemcitabine alone in patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas failed on FOLFIRINOX treatment (NCT03126435).
Authors: Chen Li-Tzong , Su Muh-Hwan
Published: May 2020

TPS4669

Background: Pancreatic cancer (PC) is the 3rd deadliest cancer in the United State surpassing breast cancer in 2016, with the overall survival rate of - 9% for those newly diagnosed individuals. The notorious disease is set to become the 2nd leading cause of death from cancer by 2020 in US (National Cancer Institute, NIH). FOLFIRINOX regimen is one of the standard 1st-line treatments for PC patients with good performance status; however, there is currently no standard of care in 2nd-line therapy after FOLFIRINOX failure. EndoTAG-1 is a novel formulation of cationic liposomes embedded with Paclitaxel, which specifically displays antivascular and antiangiogenic activities. By binding and internalizing at tumor endothelial cells after intravenous administration, the cytostatic activity of paclitaxel will be targeted to the activated tumor endothelial cells. Methods: Eligible patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas failed on FILFIRINOX treatment will be screened and randomized (1:1) into one of the two arms in the study (n=218). The primary endpoint of the study is overall survival (OS), with secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and quality of life (QoL). Arm A: EndoTAG-1 plus Gemcitabine: Patients will receive intravenous injection with EndoTAG-1 (22 mg/m2) twice weekly plus gemcitabine (1,000 mg/m2) once weekly for consecutively 3 weeks followed by 1 week rest. The treatment will be repeated every 4 weeks, with 8 weeks per cycle. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. Arm B: Gemcitabine: Patients will receive gemcitabine (1,000 mg/m2) once weekly for consecutive 3 weeks followed by 1 week rest. The treatment will be repeated every 4 weeks, with 8 weeks per cycle. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. The phase III trial began enrollment since November 2018. The trial will continue as planned from the last review in January 2020. Clinical trial information: NCT03126435 .
Phase I study of AMG 509, a STEAP1 x CD3 T cell-recruiting XmAb 2+1 immune therapy, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kelly W. Kevin , Danila Daniel Costin , Edenfield William Jeffery , Aggarwal Rahul Raj , Petrylak Daniel Peter , Sartor A. Oliver , Sumey Christopher Joseph , Dorff Tanya B. , Yu Evan Y. , Adra Nabil , Waterhouse David Michael , Armstrong Andrew J. , Horvath Lisa , Pook David William , Appleman Leonard Joseph , Lau Aubrey , Salvati Mark , Kouros-Mehr Hosein
Published: May 2020

TPS5589

Background: Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen that is highly expressed in prostate cancer. AMG 509 is a potent bispecific XmAb 2+1 immune therapy designed to direct T-effector cells to STEAP1-expressing cells. AMG 509 contains two identical humanized anti-STEAP1 Fab domains that bind STEAP1-expressing cells, an anti-CD3 scFv domain that binds T cells, and an Fc domain, engineered to lack effector function, that extends serum half-life. In preclinical studies, AMG 509 induced potent and specific T-cell-mediated lysis of STEAP1-expressing cancer models. Methods: This open-label, phase I, first-in-human study will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 in patients with relapsed/refractory mCRPC. The dose exploration phase (n=40) will estimate the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) using a Bayesian logistic regression model. The dose expansion phase (n=30) will confirm safety, PK, and pharmacodynamics at the MTD or RP2D and collect further safety, efficacy, and biomarker data. Efficacy will be assessed by prostate-specific antigen response, circulating tumor cell response, and objective tumor response per RECIST 1.1 with Prostate Cancer Working Group 3 modifications. Key inclusion criteria: men ≥18 years with histologically/cytologically confirmed mCRPC who are refractory to novel hormonal therapy (e.g., abiraterone and/or enzalutamide) and have failed 1–2 taxane regimens or are medically unsuitable for or have refused taxanes; ongoing castration with total serum testosterone ≤50 ng/dL; evidence of progressive disease; ECOG performance status 0–1; life expectancy ≥3 months; and adequate hematologic, renal, hepatic, and cardiac function. In the dose exploration phase, novel antiandrogen therapy must have been given in the metastatic setting. Key exclusion criteria: pure small-cell or neuroendocrine carcinoma of the prostate; untreated CNS metastases or leptomeningeal disease; any anticancer therapy or immunotherapy, radiation therapy, or major surgery <4 weeks from first dose; history of or current autoimmune disease or any disease requiring immunosuppressive therapy (≤10 mg/d prednisone permitted); prior STEAP1-targeted therapy; infection requiring IV antimicrobials <7 days from first dose. The study opened in January 2020 and is recruiting patients. Clinical trial information: NCT04221542 .
A phase Ib trial of enzalutamide with venetoclax in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Gopalakrishnan Dharmesh , Kirk Jason , Davis John , George Saby , Levine Ellis Glenn , Beumer Jan Hendrik , Appleman Leonard Joseph , Tang Dean , Chatta Gurkamal S.
Published: May 2020

TPS5599

Background: Androgen receptor (AR) signaling plays an important role in prostate cancer (PCa) cell survival and proliferation. Xenograft and PDX models demonstrate that untreated PCa harbors AR−/lo stem cells not critically dependent on androgens for survival.1 Furthermore, castration and enzalutamide (enza) leads to expansion of both AR−/lo and AR+/hi resistant clones in xenograft tumors, resulting in two distinct CRPC-propagating populations.2 However, most current CRPC treatments are directed towards AR+/hi cells. RNAseq revealed that BCL-2 is highly up-regulated in AR−/lo tumors post-castration and in AR+/hi CRPC tumors post-enza.2 Strikingly, BCL-2, but not BCL-XL and MCL-1, was selectively up-regulated in these xenograft tumors. These results were subsequently validated in patient CRPC datasets.2,3 Venetoclax (ven), a potent and selective BCL-2 inhibitor, inhibits enza resistance in AR+/hi CRPC and tumor growth in AR−/lo xenograft models.2 A recent phase I trial of ven combined with tamoxifen showed promising activity in ER+ and BCL2+ metastatic breast cancer.4 We hypothesize that co-targeting AR−/lo and AR+/hi PCa clones with ven and enza will prevent the emergence of enza resistance in human mCRPC. Methods: This is a phase Ib, single-center, single-arm trial of enza (160mg/d) with ven in patients with mCRPC that has progressed on previous therapies which may include anti-androgens. Three dose-levels of ven (400mg, 600mg and 800mg/d q28d) will be evaluated using a 3+3 study design. Fifteen to 18 patients will be enrolled in this phase to assess dose-limiting toxicities, maximum tolerated dose, and recommended phase II dose. Aims of correlative studies include (1) assessing the pharmacokinetic interaction between enza and ven, (2) identification of potentially predictive blood and tissue biomarkers (including pre- and post-treatment CTC levels, expression of BCL2, AR, ARv7 in pre-and post-treatment biopsies and CTCs), (3) measurement of pre- and post-treatment BCL2 expression in peripheral blood mononuclear cells as a surrogate for ven activity, and (4) the development of 3D organoid models from CTCs and biopsies. The trial is open with 3 patients enrolled to dose-level 1, and 2 patients currently at dose-level 2. Correlative studies are ongoing. References: (1) Qin J, et al. Cell Stem Cell. 10(5): 556-69, 2012 (2) Li Q, et al. Nat Commun. 9(1): 3600, 2018 (3) Rajan P, et al. Eur Urol. 66 (1):32-9, 2014 (4) Lok SW, et al. Cancer Discov. 9(3):354-69, 2019. Clinical trial information: NCT03751436 .
PREDIX II HER2: Improving pre-operative systemic therapy for human epidermal growth factor receptor 2 (HER2) amplified breast cancer (BC).
Authors: Kornalijnslijper-Altena Renske , Andersson Anne , Brandberg Yvonne , Kessler Luisa Edman , Elinder Ellinor , Hartman Johan , Hellstrom Mats , Johansson Hemming , Killander Fredrika , Linderholm Barbro Kristina , Lindman Henrik , Valachis Antonios , Wennstig Anna Karin , Xie Hanjing , Hatschek Thomas , Bergh Jonas C. S.
Published: May 2020

TPS605

Background: Neo-adjuvant systemic therapy (NAT) is the standard of care for most patients with early HER2-amplified and triple negative breast cancer (BC). Increasing the rate of pathological complete response (pCR) is highly meaningful for those patients, as pCR is strongly predictive for improved long-term disease-related outcomes. Clinical and preclinical evidence support the hypothesis that pCR-rates may be augmented by the addition of checkpoint inhibitors, such as monoclonal antibodies targeting the Programmed Death Ligand receptor 1 (PD-L1), to standard systemic NAT. Studies in different BC patient cohorts (e.g., IMPassion130, PANACEA, KATE2) have indicated that PD-L1 protein expression on tumor-infiltrating lymphocytes (TIL’s) is a predictive marker for checkpoint inhibitor efficacy. Methods: We have initiated a phase II open-label, 2:1 randomized clinical trial where women with early HER2-amplified, PD-L1+ BC (cT2-3 and/or cN+) are treated with standard NAT (composed of anti-HER2 antibodies with a chemotherapy backbone of sequentially taxanes + carboplatin and epirubicin + cyclophosphamide [EC]) +/- atezolizumab during EC. N = 190 patients will be accrued in nine centers in Sweden to be able to demonstrate a 20% increase in pCR-rate, with a power of 80% and a two-sided alpha of 10%. Firstly, a prescreening is performed to select patients with a PD-L1 expression of > 1% on TIL’s. Important exclusion criteria are significant organ dysfunction and (with some exceptions) active auto-immune diseases. Extensive translational side-studies are performed to explore predictive markers for treatment efficacy, including clinicopathologic studies, molecular imaging and microbiome analyses, as well as monitoring of acute and chronic treatment-related toxicity, objective cognitive function and quality of life. As of February 11th, 4 patients have been prescreened and 1 enrolled in the trial. The clinical trial registry number is NCT03894007. Clinical trial information: NCT03894007 .
A phase Ib/II, multicenter, open-label study of DSP-7888 dosing emulsion in combination with immune checkpoint inhibitors (CPI) nivolumab or pembrolizumab in adult patients (pts) with advanced solid tumors, including platinum-resistant ovarian cancer (PROC).
Authors: Origuchi Makoto , Korth Chris , Li Zhonggai , Braendle Edgar E.
Published: May 2020

TPS6099

Background: DSP-7888 is a therapeutic cancer vaccine composed of two synthetic peptides derived from Wilms’ tumor 1 (WT1) to promote both cytotoxic and helper T-lymphocyte-mediated immune responses against WT1-expressing tumors. WT1 is overexpressed in various solid tumors, including ovarian cancer. Combining cancer vaccines like DSP-7888 with a CPI may reduce resistance to immunomodulators and improve clinical benefit. A phase Ib/II study is being conducted to evaluate DSP-7888 in combination with a CPI in pts with advanced solid tumors, including PROC (NCT03311334). Methods: This phase Ib/II, open-label, multicenter, two-part dose-search/dose-expansion study investigates DSP-7888 + nivolumab or pembrolizumab in pts with advanced solid tumors (phase Ib), including PROC (phase II). The phase Ib primary objectives are safety, tolerability, and identification of the recommended phase II dose (RP2D). The phase II primary objective is evaluation of objective response rate (ORR); secondary objectives are clinical activity, safety, and tolerability. Pts aged ≥18 years with unresectable, metastatic cancer approved for treatment with nivolumab (phase Ib, Arm 1, n=6–12, 7 enrolled) or pembrolizumab (phase Ib, Arm 2, n=6–12, 6 enrolled), or with PROC (phase II) are eligible. Phase II will enroll ~40 pts into two groups based on programmed death-ligand 1 status (combined positive score of ≥10 [Group 1] or <10 [Group 2]). Clinical activity will be assessed continuously using Bayesian analysis and actual enrollment may increase by ~20 pts/group based on this analysis. Pts in phase II will receive DSP-7888 intradermally (RP2D from phase Ib) once a week (wk) for 6 wks in the induction phase then every 3 wks in the maintenance phase. Beginning Day 1, pembrolizumab will be administered intravenously every 3 wks. In phase II, objective disease will be assessed every 6 wks for 24 wks, then every 12 wks until progression. Endpoints include ORR (per RECIST v1.1) (primary), duration of response, disease control rate (DCR), progression-free survival (PFS), 6-month PFS rate (per RECIST v1.1), and overall survival, immune (i)ORR, iDCR, and iPFS (per iRECIST) (secondary). Exploratory endpoints include blood and tumor tissue biomarkers. Safety and tolerability, assessed by adverse events, will be evaluated throughout the duration of the study and follow-up. This study is currently recruiting patients. Clinical trial information: NCT03311334.
The AIM-HN and SEQ-HN study: A pivotal study evaluating the efficacy of tipifarnib in patients with head and neck squamous cell carcinoma (HNSCC) with hras mutations (AIM-HN) and the impact of hras mutations on response to first line systemic therapies for HNSCC (SEQ-HN).
Authors: Haddad Robert I. , Harrington Kevin Joseph , Licitra Lisa F. , Psyrri Amanda , Saba Nabil F. , Rajicic Natasa , Balsara Binaifer , Kurman Michael R. , Scholz Catherine Rose , Gualberto Antonio , Ho Alan Loh
Published: May 2020

TPS6593

Background: HRAS mutations define a unique molecular subset of ~ 5% of HNSCC. Evidence suggests that these tumors respond poorly to standard systemic therapy but the impact of HRAS missense mutations on clinical outcomes has not been formally characterized. Tipifarnib is a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity. Phase 2 Proof of concept for tipifarnib in HRAS mutant HNSCC was recently achieved in study KO-TIP-001 (NCT02383927, Ho et. al. ESMO 2018). Methods: The AIM-HN and SEQ-HN Study (KO-TIP-007, NCT03719690) is an ongoing international, multicenter, open-label, 2 cohort (AIM-HN and SEQ-HN), pivotal trial designed to determine the Overall Response Rate (ORR) of tipifarnib in patients (pts) with HRAS mutant HNSCC (AIM-HN). SEQ-HN will retrospectively investigate how the ORR to first line treatment compares between the accrued HRAS mutant pts to matched-case control HRAS wild type (wt) HNSCC pts. Information on subsequent lines of therapy for HRAS mutant and wt pts will also be collected. AIM-HN will enroll at least 59 pts (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) who are refractory or have relapsed from at least one prior line of systemic platinum-based therapy and have measurable disease by RECIST 1.1. AIM-HN pts must have tumors with >35% HRAS mutant variant allele frequency (VAF) or >20% VAF if serum albumin is >3.5 g/l. AIM-HN pts will receive treatment with tipifarnib at 600 mg bid on days 1-7 and 14-21 of 28-day cycles. Using Simon's Two-Stage Minimax design, if true ORR is > 30%, the study will have 80% power to detect ORR > 15% at 0.025 significance level. Both interim (after first 31 pts) and final analysis, 2-sided 95% CI on ORR, will be performed on the modified intent to treat population. The SEQ-HN observational cohort will enroll ~225 control pts who will receive standard of care treatment. A subset of SEQ-HN pts will be matched to the HRAS mutant AIM-HN pts according to defined patient characteristics and compared for responses to therapy. Clinical trial information: NCT02383927 .
Window-of-opportunity trial of nivolumab with or without the IDO inhibitor BMS-986205 in patients with resectable squamous cell carcinoma of the head and neck (SCCHN).
Authors: Luginbuhl Adam , Johnson Jennifer Maria , Harshyne Larry , Tuluc Madalina , Gargano Stacey , Leiby Benjamin , Curry Joseph M. , Cognetti David M. , Axelrod Rita Susan , Bhateja Priyanka , Old Matthew O. , Rodeck Ulrich , Argiris Athanassios
Published: May 2020

TPS6595

Background: Indoleamine 2,3-dioxygenase (IDO1) catabolizes tryptophan to kynurenine and is highly expressed in multiple malignancies including SCCHN. Elevated IDO1 activity may contribute to an immunosuppressive tumor microenvironment and compromise therapeutic responses to immune checkpoint therapy. We designed a window-of-opportunity trial to test whether the IDO inhibitor BMS-986305 improves treatment responses and T cell function in SCCHN patients treated with nivolumab. Methods: Patients with previously untreated, resectable, pathologically confirmed SCCHN are eligible. Primaries of the oral cavity, oropharynx, larynx, hypopharynx, or nasal cavity/paranasal sinuses must be AJCC 8th edition stage II or higher (M0). Stage I oropharyngeal cancers with lymphadenopathy are also eligible. Patients are randomized 3:1 to receive either A) nivolumab 480 mg IV x 1 plus BMS-986205 100 mg PO daily starting a week prior to nivolumab and continuing for 4 more weeks (total of 5 weeks) or B) nivolumab 480 mg IV alone for 4 weeks. At the 5th week of treatment patients are assessed for response with physical exam and repeat CT scans for tumor volumes: if there is greater than 10% reduction in volume of either primary tumor or lymph node metastases, patients will be considered responders and receive another cycle of their originally assigned treatment, i.e. nivolumab 480 mg IV for a second dose +/- BMS-986205 100 mg PO daily for an additional 4 weeks followed by surgery in week 9. If tumor volume is stable or progression is noted in either the primary site or lymph nodes, patients are considered non-responders followed by definitive surgery in week 5 (i.e. after only one cycle of treatment). The primary endpoint of this study is the response rate after cycle 1 (using the criteria defined above). The projected sample size is 48 patients (36 in arm A and 12 in arm B). Secondary endpoints include safety, pathologic treatment effect and metabolic and molecular correlates of treatment in the tumor microenvironment. Clinical trial information: NCT03854032 .
The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer.
Authors: D'Abreo Nina , Crozier Jennifer A. , Brufsky Adam , Grady Ian , Diab Sami , Mavromatis Blanche H. , Dul Carrie L. , Layeequr Rahman Rakhshanda , Lee Laura A. , Gadi Vijayakrishna K. , Untch Sarah , Yoder Erin , Kling Heather M. , Truitt Amy , Audeh William ,   FLEX Investigators Group
Published: May 2020

TPS7088

Background: Genomic expression profiles have enabled the classification of breast cancers into molecular sub-types and provide prognostic information about the metastatic potential of the tumor, both of which have implications for the personalized treatment of breast cancer beyond clinical and pathological features. However, to precisely stratify tumors into actionable subgroups, full genome expression data should be combined with comprehensive clinical information. The FLEX Registry aims to aggregate a large, real-world dataset, which will enable discovery of novel genomic profiles, particularly for patient subsets that are underrepresented in traditional clinical trials and will contribute to improved precision in the management of breast cancer. Methods: The FLEX Registry (NCT03053193) is a multi-center, prospective, observational trial for patients with Stage I, II, and III breast cancer. Patients with stage I-III breast cancer who receive the 70-gene signature risk of recurrence test, with or without the 80-gene signature molecular sub-typing test, on a primary tumor are eligible for enrollment. The primary objective of FLEX is to create a large scale, population-based registry that links complete clinical data with full genome expression data to elucidate new prognostic and/or predictive gene associations in a real-world setting. The FLEX Registry employs a shared study infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials based on full genome expression data. The adaptable protocol is designed to be amended with the inclusion of targeted sub-studies. Patients enrolled in the initial study are eligible for inclusion in sub-studies for which they meet all eligibility criteria and additional consent is not required. Data will be collected on patients from diagnosis through 10 years of follow-up and any necessary additional clinical data will be collected as specified in the appendix protocols. Target enrollment is a minimum of 10,000 patients; >4,000 patients have enrolled since April 2017 at more than 80 sites, including seven National Cancer Institute-designated comprehensive cancer centers. The FLEX collaborative platform enables participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee. Fifteen sub-studies have been approved for investigation within the FLEX Registry. Clinical trial information: NCT03053193 .