bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 2 trial of chemotherapy, pembrolizumab, and propranolol in patients with advanced esophageal/gastroesophageal junction adenocarcinoma (EGAC).
Authors: Mukherjee Sarbajit , Jatwani Karan , Chatley Sarah , Fountzilas Christos , Alarcon Velasco Sylvia Vania , Vadehra Deepak , Iyer Renuka V. , Attwood Kristopher , Farrugia Mark , Singh Anurag K. , Repasky Elizabeth A.
Published: June 2023

TPS4171

Background: Chronic stress suppresses the immune system and promotes cancer cell growth. In animal studies, we reported that this is mediated by the beta-adrenergic (BA) pathway. We further showed that concurrently blocking the BA pathway with β-blockers (BB) can improve immune checkpoint inhibitor (ICI) efficacy. Our retrospective data analysis revealed that esophageal cancer (EC) patients taking BB for other non-cancer reasons while receiving chemoradiation had significantly better survival and distant control than those not taking BB. We hypothesized that blocking the effects of adrenergic stress with a commonly used BB, propranolol, will improve response to therapies in EC patients. Methods: This is an open-label, non-randomized, phase 2 study of propranolol combined with pembrolizumab and standard chemotherapy in frontline unresectable/metastatic EGAC. Eligible patients must be treatment-naïve, have adequate organ function, have an ECOG performance status of 0 –1, and be able to swallow and retain oral medication. Patients with Her-2 positive cancer, active autoimmune disease, active HIV, Hepatitis B or C, or a history of non-infectious pneumonitis/interstitial lung disease that requires treatment, are ineligible. Patients who are on BB for various indications are also ineligible. Eligible patients will receive mFOLFOX6 every two weeks in combination with pembrolizumab 400 mg intravenously every six weeks and propranolol 30 mg orally twice daily. The mFOLFOX6 dosing regimen will consist of dl-LV 400 mg/m2 and oxaliplatin 85 mg/m2 followed by bolus 5-FU 400 mg/m2 and a 48-hour infusion of 5-FU 2400 mg/m2. The study will include an initial safety lead-in cohort of six patients. The primary endpoint is the overall response rate (ORR) determined by RECIST 1.1. Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS), and ORR as determined by iRECIST. Correlative studies will assess baseline levels or changes in the levels of biomarkers, like, peripheral T-cell subsets/myeloid-derived suppressor cells (MDSC)/cytokines/ and perceived stress scale PSS/chronotropic effects of exercise with efficacy (ORR, PFS, OS). Assuming a historic ORR of 50% with standard treatment, 37 evaluable pts are needed to show a 20% increase in ORR with our proposed treatment with 80% power at a one-sided significance level of α = 0.1. In stage 1, n1= 23 evaluable pts will be enrolled. If there are 13 or more ORRs, an additional n2= 14 pts will be enrolled in stage 2. If 24 or more ORRs are observed in the total n = 37 evaluable pts, the proposed treatment regimen will be considered promising for further study. The study is currently open to enrollment. Clinical trial information: NCT05651594 .
Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic esophageal and gastroesophageal carcinoma with dysphagia: A single arm phase 2 clinical trial, PALEO.
Authors: Day Fiona , Sridharan Swetha , Michael Michael , Christophersen Louise , Moore Melissa M. , Eastgate Melissa A. , Thompson Stephen , MWEEMPWA ANGELA , Oldmeadow Christopher , Fraser Allison , Martin Jarad
Published: June 2023

TPS4172

Background: Many patients diagnosed with esophageal cancer have dysphagia from their primary tumor and de novo metastatic disease. While multiple therapies are available, there is no accepted standard or sequence of therapies to both relieve dysphagia and control distant disease. Our preceding Phase I clinical trial showed that a 2 week hypofractionated chemoradiotherapy (CRT) protocol (30Gy/10# with concurrent weekly carboplatin and paclitaxel) is well tolerated and provides rapid dysphagia relief. Immune checkpoint inhibition has activity in esophageal and gastroesophageal (GEJ) cancer and concurrent radiotherapy may improve T cell priming through tumor antigen release. In PALEO, patients begin durvalumab concurrent with primary tumor CRT, and receive stereotactic body radiotherapy (SBRT) (24Gy/3#) to a single metastasis to maximize the breadth of tumor antigen exposure. Tissue and blood-based studies are planned to identify biomarkers for response, including immunosequencing to test for post-radiotherapy expansion in T cell receptor diversity. Methods: Eligible patients have biopsy-proven esophageal or GEJ cancer, either squamous cell or adenocarcinoma histology, with oligometastatic (1-5 metastases on FDG-PET scan outside the primary tumor radiotherapy field) or locoregionally advanced disease unsuitable for surgery, dysphagia (Mellow score >0), and ECOG PS 0-2. Key exclusion criteria are prior treatment, tumor HER2 positivity, prior thoracic radiotherapy, tracheo-esophageal fistula, esophageal stent in situ and contraindications to immunotherapy. Patients begin durvalumab 1500mg q4w with CRT to the primary tumour (30Gy/10# with weekly carboplatin AUC2 and paclitaxel 50mg/m2), and continuing to disease progression, unacceptable toxicity or 2 years. SBRT to one metastasis (24Gy/3#) is delivered in week 7. Trial primary endpoint is progression free survival rate at 6 months (PFS6) with the aim to rule out a PFS6 rate of 50% in favor of 67.5%, with 80% power and a one-sided 0.05 significance level. Secondary endpoints include dysphagia relief, nutritional status change (patient weight, removal of enteral feeding tubes, PG-SGA score), quality of life, response rate, toxicity, overall survival and exploratory translational endpoints. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG) for conduct at 8 sites in Australia and New Zealand. 6 of planned 54 patients have been enrolled. ACTRN12619001371189. Clinical trial information: Clinical trial information: ACTRN12619001371189 .
Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2+) pathogenic variants: SWOG S2001.
Authors: Chung Vincent , Guthrie Katherine A , Pishvaian Michael J , Reiss Kim Anna , Lowy Andrew M. , Sohal Davendra , Colby Sarah , Sharon Elad , Allegra Carmen Joseph , O'Reilly Eileen Mary , Chiorean E. Gabriela , Philip Philip Agop
Published: June 2023

TPS4198

Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Several clinical studies in solid tumors have shown preliminary efficacy with the combination of PARP plus immune checkpoint inhibitors. Based upon these data, SWOG S2001 aims to further improve the PFS of gBRCA1/2+ mPDA pts. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in December 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 pathogenic variants identified with standard of care germline genetic testing and progression-free after receiving at least 16 weeks of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to compare PFS in mPDA pts treated with olaparib + pembrolizumab versus olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha=0.10, this design requires enrolling 88 pts for a total of 78 eligible and evaluable pts. As of February 2023, 26 participants have been accrued. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Clinical trial information: NCT04548752 .
ExoLuminate: An observational registry study for detection of pancreatic adenocarcinoma (PDAC) in high-risk or clinically suspicious patients.
Authors: Dhani Harmeet , Hinestrosa Juan Pablo , Izaguirre Carbonell Jesus , Balcer Heath , Kurzrock Razelle , Billings Paul R.
Published: June 2023

TPS4203

Background: The detection of pancreatic ductal adenocarcinoma (PDAC) at early-stages is critical to improving patient survival. However, the lack of a clinically useful biomarker assay poses a challenge for earlier detection. A liquid biopsy test (ExoVita Pancreas) which uses extracellular vesicles (EV) protein biomarkers has been developed for detection of PDAC. In a previous case-control study of n=715 (75 cases of PDAC Stage I and II, 640 controls), the EV-protein biomarker assay yielded a sensitivity of 96.0% and specificity of 91.1%. By optimizing the assay for high sensitivity, we aim to generate evidence for earlier detection of PDAC in high-risk and clinically suspicious patients in the hope of impacting PDAC patient diagnostic journeys. Methods: ExoLuminate is a prospective, multi-center, observational registry study to demonstrate that early detection of PDAC using ExoVita is non-inferior to current standard of care methods of surveillance. The study duration will be 36 months (24-month accrual, 12-month follow-up), with a minimum of 1000 subjects to be enrolled between two cohorts as described below. The first cohort enriches for “high-risk” individuals without a cancer suspicion or diagnosis including those with intraductal papillary mucinous neoplasms (IPMNs), personal or family history of pancreatitis, family member(s) who have at least one first-degree relative affected by pancreatic cancer, patients over 50 years of age with new-onset diabetes (NOD), and germline mutations known to be associated with PDAC. The second cohort includes patients with clinical findings suspicious for early-stage PDAC or those with biopsy-proven PDAC. Patients enrolled in the study will have their blood obtained at six-month intervals. The performance of ExoVita liquid biopsy will be compared to standard-of-care imaging and biomarkers such as CA19-9. Through this registry, which began enrollment in December 2022 and is open for accrual (NCT0562552), we aim to demonstrate the clinical utility of a novel liquid biopsy based on detection of EV-derived biomarkers for early diagnosis of PDAC which can provide credence to a new paradigm in early detection to improve patient outcomes. Clinical trial information: NCT0562552 .
SOGUG-vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.
Authors: de Velasco Guillermo , Alvarez-Fernandez Carlos , Alvarez Marquez Francisco Jose , Reig Torras Oscar , Virizuela Juan Antonio , Anido Urbano , Azkarate Aitor , Gajate Pablo , Garcia Carbonero Iciar , Iranzo Sabater Aina , Lozano Rebeca , Pujol Eduardo
Published: June 2023

TPS4606

Background: The current standard of care in non-progressors to first-line platinum-based chemotherapy for unresectable locally advanced or metastatic urothelial carcinoma (UC) is maintenance treatment with avelumab plus best supportive care (BSC). The Checkmate 032 trial showed that the highest ORR (42.4%) was achieved by the combination of Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg in refractory mUC (1), with a manageable safety profile and better outcomes compared to other treatment arms. The trial aims to consolidate the clinical benefit achieved from first-line chemotherapy with the combination of nivolumab 1mg/kg plus ipilimumab 3mg/kg followed by nivolumab. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of Ipilimumab and nivolumab followed by nivolumab maintenance therapy in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line chemotherapy. Main eligibility criteria include: Male or female subjects ≥ 18 yrs old with written informed consent, ECOG performance status 0 or 1, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium (UCC), patient inclusion within 3-12 weeks after the last chemo dose, no progressive disease per RECIST v1.1, available tumor tissue at baseline, adequate normal organ and marrow function (Haemoglobin ≥ 9.0 g/dL, ANC > 1500 per mm3, platelets ≥ 100,000 per mm3, bilirubin ≤ 1.5 X ULN, transaminases ≤ 2.5X ULN, creatinine clearance > 30 mL/min). The primary endpoint is Progression Free Survival (PFS). Secondary objectives include: objective response rate (ORR), duration of response (DoR), overall survival (OS), chemotherapy overall survival (cOS), and chemotherapy progression-free survival (cPFS). Additionally, the study also has safety secondary objectives. Dynamic biomarker analysis will be performed. As of January 2023, 5 out of the planned 66 patients have been enrolled in the study. 1) Sharma P et al. J Clin Oncol. 2019. Clinical trial information: EudraCT 2021-005364-22 .
A phase (Ph) I/II trial of abiraterone acetate in combination with tildrakizumab (anti-IL23 monoclonal antibody) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Guo Christina , Crabb Simon J. , Pacey Simon , Coyle Vicky , Danson Sarah , Villacampa Guillermo , Chandran Khobe , Paschalis Alec , Riisnaes Ruth , Ferreira Ana , Carreira Suzanne , Bertan Claudia , Crespo Mateus , Figueiredo Ines , Matthews Ruth , Turner Alison Joanne , Yap Christina , Alimonti Andrea , Sharp Adam , De Bono Johann S.
Published: June 2023

TPS5105

Background: Tumor-infiltrating inflammatory myeloid cells promote prostate cancer (PC) growth and therapeutic resistance. Myeloid inflammatory cells release interleukin-23 (IL-23) to fuel tumor growth via JAK2-STAT3 signalling and facilitate tumor-promoting T helper 17 (TH17) differentiation in PC models in vivo. IL-23 blockade reverses resistance to AR-targeting in vivo; we hypothesise that targeting IL-23 can be an effective therapeutic strategy for CRPC. Tildrakizumab, an anti-IL-23 (p19) monoclonal antibody, is FDA/EMA approved for treating moderate-severe psoriasis. In progress is the first clinical trial to combining IL-23 and AR signalling blockade in humans. Methods: This is an open-label, single-arm, Ph 1/2, dose-escalation and expansion study evaluating safety and tolerability of tildrakizumab and abiraterone acetate combination therapy in patients with mCRPC. Eligible patients must have progressed on androgen deprivation therapy, plus abiraterone and/or enzalutamide. The Ph 1 trial will adopt a one-stage Bayesian Continual Reassessment Method design exploring escalating doses of 4-weekly, IV tildrakizumab (100 mg, 300 mg, and 600 mg), in combination with standard fixed doses of abiraterone acetate and methylprednisolone, with the aim of determining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Depending on the number of responses observed, tolerable dose levels may be expanded up to 10 patients after review by the Safety Review Committee (SRC). The RP2D and MTD determination will be based on the rate of toxicity and efficacy, reviewed by the SRC. Once RP2D is determined, the Ph 2 study will enrol up to 25 response-evaluable patients using a Simon’s two-stage design. Primary endpoint of the Ph 2 trial is overall response rate. Adverse events are assessed according to CTCAE v5. Tumor response is determined according to RECIST v1.1, confirmed PSA decline of at least 50%, and/or CTC conversion. PK analyses is being performed for both drugs to identify potential drug-drug interactions. PD analyses is being performed on archival and serial tumour biopsies and blood samples to investigate putative predictive biomarkers and confirm on-target and downstream effector modulation. The trial began enrolling in January 2021 in the United Kingdom and Switzerland. As of January 22th 2023, 12 patients were included in the study. Clinical trial information: NCT04458311 .
The Maverick trial: A phase 2 study of abivertinib in patients (pts) with metastatic castration resistant prostate cancer (mCRPC).
Authors: McKay Rana R. , Armstrong Andrew J. , Emamekhoo Hamid , Gourdin Theodore Stewart , Heath Elisabeth I. , Hussain Arif , Ornstein Moshe Chaim , Sharifi Nima , Viscuse Paul Vincent , Yan Ying , Royal Mike A.
Published: June 2023

TPS5106

Background: Abivertinib is a potent, small molecule third-generation tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), Bruton tyrosine kinase (BTK) receptor, and bone marrow tyrosine kinase gene on chromosome X (BMX). Abivertinib irreversibly binds to the BTK receptor, preventing the phosphorylation of the receptor, and also BMX. The adrenal-permissive HSD3B1(1245C) allele, which is present in upwards of 50% of men with prostate cancer, encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from extragonadal precursor steroids and promotes poor clinical outcomes. 3βHSD1 must be phosphorylated by BMX for androgen biosynthesis. Preclinical studies suggest BMX inhibition blocks 3βHSD1, androgen biosynthesis and CRPC in xenograft models. These provide the rationale for use of the combination of abivertinib and abiraterone to block residual androgen synthesis that escapes abiraterone inhibition. Methods: The Maverick Trial is a multicenter, open-label phase 2 study within the US Dept of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC) of abivertinib with abiraterone in pts with mCRPC harboring the adrenal-permissive HSD3B1(1245C) allele (germline heterozygous or homozygous). HSD3B1 status will be confirmed centrally prior to enrollment via CLIA testing at the Cleveland Clinic. The study includes two cohorts: abiraterone-naïve and abiraterone-progressing. There will be cap of 50% of accrual in each cohort for pts heterozygous for the HSD3B1(1245C) allele. An interim futility analysis is embedded in each cohort, and toxicity rates will be continuously monitored for early stoppage according to predefined rules. Pts receive continuous treatment with abivertinib 200 mg BID with abiraterone 1000 mg QD + prednisone 5 mg BID until radiographic progression, unacceptable toxicity, intercurrent illness, or other reason, such as subject withdrawal. The primary endpoint is 6-month rPFS defined as percent of subjects alive and without progression by RECIST version 1.1 for measurable disease and PCWG3 criteria for bone metastases. Secondary and exploratory endpoints include objective response rate, duration of response, PSA progression, pharmacokinetics, pharmacodynamic tissue changes, and mechanisms of response and resistance to therapy via sequential tissue and blood sampling. The study is currently open at 1 site and will activate at 9 additional sites. It is sponsored by Sorrento Therapeutics, Inc, and managed by the Prostate Cancer Clinical Trials Consortium. Trial Registration: NCT05361915 Funding Source: Sorrento Therapeutics, Inc, the trial’s sponsor who is funding the trial. Clinical trial information: NCT05361915 .
CRI-CCTG-0003/IND.240: An immunotherapy platform study in platinum-resistant high grade serous ovarian cancer (IPROC).
Authors: Mackay Helen , Tinker Anna , Nelson Brad , Zamarin Dmitriy , Odunsi Kunle , Lheureux Stephanie , Ellard Susan , Smrke Alannah , Gaudreau Pierre-Olivier , Faulkner Tess , Saez-Ibanez Ana Rosa , Tu Dongsheng , Dancey Janet Ellen
Published: June 2023

TPS5617

Background: Identifying new treatments for patients with platinum-resistant high grade serous ovarian cancer (HGSC) is a priority. Although several biological features of HGSC suggest inherent immunogenicity, immunotherapy has had limited efficacy to date. IPROC is an adaptive platform trial designed to evaluate multiple immunotherapy combinations selected and informed by an expert panel. IPROC accommodates both biomarker-agnostic and biomarker-directed combinations. Protocol and sub study specific translational studies are conducted on archived diagnostic tissue and serial prospective blood and tumor sample collection. Methods: IPROC is an open-label, multi center, phase II platform trial. Eligibility includes HGSC histology; progression within 6 months of the last platinum regimen; <1 prior line of chemotherapy for platinum resistant disease (unlimited prior lines for platinum sensitive); prior treatment with immunotherapy allowed (provided not discontinued for toxicity), ECOG 0/1. Patients must be willing and able to undergo study procedures. The primary endpoint is ORR (RECIST1.1). Secondary endpoints include iRECIST ORR, RECIST/iRECIST progression free and overall survival and safety. Exploratory objectives include whole exome sequencing and immune profiling of tumor and blood samples to identify biomarkers and new immunotherapy strategies/combinations for future evaluation. Tumor biopsy occurs at baseline, cycle 2 and progression (voluntary) with blood and plasma collected at each cycle and on progression. All sub studies use Simon 2-stage design with 10 patients (pts) enrolled in each stage. At the end of stage 1, in the absence of response, a modified cohort based on biomarker selection may be created through protocol amendment. In each substudy a null hypothesis that the objective response rate (ORR) is ≤5% is tested against a one-sided alternative that the ORR is ≥ 25%. A combination would be accepted as active if ≥4/20 pts respond with α=0.02 and power of 0.76. As of January 19, 2023, 2 sub studies are open and 12 patients have accrued. Sub study A is evaluating the combination of durvalumab and BA3011, a conditionally active anti-AXL humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) in AXL overexpressing HGSC. Sub study B is evaluating durvalumab plus BA3021, a CAB anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to MMAE in ROR2 overexpressing HGSC. Further sub studies are planned (NCT04918186). Clinical trial information: NCT04918186 .
First trial of chemotherapy de-escalation in ovarian cancer (OC): A phase III randomized, open label study of niraparib maintenance after carboplatin and paclitaxel in patients with optimally debulked advanced (homologous recombination deficient) HRD high-grade ovarian cancer in first line therapy (N-PLUS/NOGGO-ov53/ENGOT-ov62).
Authors: Braicu Elena Ioana , Pietzner Klaus , Zocholl Dario , Estévez-García Purificación , Katsaros Dionyssios , Van Gorp Toon , Berger Regina , Keller Maren , Sehouli Jalid
Published: June 2023

TPS5620

Background: OC is the fifth most common cause of death from cancer in women. More than 70% of the patients are diagnosed with advanced disease and less than 40% of women with OC are cured. Currently, the standard therapy in HRD OC is surgical debulking followed by 6 cycles of chemotherapy with subsequent maintenance treatment with poly ADP ribose polymerase (PARP) inhibitors. Within the last decades, no focus was set on the benefits of fewer cycles of chemotherapy, even though there is evidence for comparable efficacy and less toxicity in comparison to more cycles. Chemotherapies are usually associated with side effects, which can be severe and even lead to therapy discontinuation. The data available about the needed number of chemotherapy cycles is weak, especially in the context of PARP inhibition. Furthermore, patients with stage III/IV with optimal cytoreduction are underrepresented in previous studies. In the N-PLUS trial, we hypothesize that recurrence-free survival (RFS) in patients receiving 3 cycles of chemotherapy followed by maintenance with niraparib is not inferior to 6 cycles of chemotherapy followed by niraparib in advanced HRD high-grade OC patients with no visible disease following primary tumor debulking. Methods: In this multicenter, randomized, open-label study 650 patients with advanced HRD high-grade OC with no residual tumor mass following primary tumor debulking will be enrolled. Patients will be randomized 1:1 to receive either 3 cycles carboplatin + paclitaxel and maintenance therapy with niraparib (Arm A) or 6 cycles carboplatin + paclitaxel and maintenance therapy with niraparib (Arm B) for a maximum of 36 months. Randomization will be performed according to the results of the NGS analysis and stratified either to BRCAm/LOH-independent or BRCAwt/LOHhigh, FIGO stage III vs. IV, and participating countries. The primary endpoint will be RFS, secondary endpoints will be OS, TFST, TWIST, PFS2, Quality of Life and safety assessments. Clinical trial information: NCT05460000 .
GLORIOSA: A randomized, open-label, phase 3 study of mirvetuximab soravtansine with bevacizumab vs. bevacizumab as maintenance in platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.
Authors: O'Malley David M. , Myers Tashanna K. N. , Zamagni Claudio , Diver Elisabeth , Lorusso Domenica
Published: June 2023

TPS5622

Background: Elevated folate receptor-alpha (FRα) expression is a characteristic of epithelial ovarian cancer (EOC), thereby providing a rational target for antibody drug conjugate (ADC) development in ovarian cancer. Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has received accelerated approval for patients with FRα positive platinum resistant ovarian cancer. MIRV in combination with BEV has demonstrated clinically meaningful activity, along with acceptable tolerability, in patients with FRα expressing ovarian cancer.1 Methods: GLORIOSA is a randomized, open-label, phase 3 study designed to evaluate the efficacy of in combination with bevacizumab compared with bevacizumab alone as maintenance for patients with FRα-positive recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancers who have not progressed after second line platinum-based chemotherapy plus bevacizumab (which may be given on protocol for patients with high FRα tumor expression). Confirmation of high FRα positivity by immunohistochemistry using the Ventana FOLR1 CDx Assay (high expression; ≥ 75% of viable tumor cells staining at 2+ intensity) and 1 prior line of therapy is required for inclusion. GLORIOSA is designed to randomize 418 patients, 1:1 receiving intravenous MIRV at a dose of 6 mg/kg adjusted ideal body weight plus bevacizumab 15mg/kg every 3 weeks or receiving bevacizumab 15mg/kg every 3 weeks until disease progression or unacceptable toxicity. Radiological assessments will be conducted every 9 weeks (± 2 weeks) for 72 weeks, and subsequently every 18 weeks (± 3 weeks) until progressive disease (PD), death, the start of new anticancer therapy, or withdrawal of consent from the study (whichever occurs first). The primary efficacy endpoint is progression-free survival by investigator and will also be assessed as a sensitivity analysis. The secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. GLORIOSA is a global study that opened for enrollment in December 2022. Reference: 1. Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023; 170: 241–247 Clinical trial information: NCT05445778 .
CCTG EN10: A phase II study of tailored adjuvant therapy in POLE-mutated and p53-wildtype/NSMP early-stage endometrial cancer (EC)—RAINBO BLUE and TAPER.
Authors: McAlpine Jessica N. , Han Kathy Chai-Zung , Kinloch Mary , Barkati Maroie , Ferguson Sarah E. , Fyles Anthony W. , Huang Fleur , Kong Iwa , Kwon Janice S. , Mackay Helen , Carey Mark Stafford , Welch Stephen , Bosse Tjalling , Creutzberg Carien L. , Horeweg Nanda , Leary Alexandra , Liu WenLing , Tu Dongsheng , Parulekar Wendy R.
Published: June 2023

TPS5632

Background: Molecular classification of EC provides an opportunity to personalize treatment for patients with early disease based on prognosis. We hypothesize that de-escalated adjuvant treatment in patients with early-stage POLE-mutated ( POLEmut) or p53wt/NSMP (p53 wildtype/no specific molecular profile) EC is feasible and associated with favourable disease control, QOL and health economics. Methods: EN.10 is a Canadian Cancer Trials Group led phase II trial that enrolls two independent cohorts of patients with early stage EC based on tumour molecular status: POLEmut (substudy A) and p53wt/NSMP (substudy B). The primary objective is to estimate the 3-year rate of pelvic recurrence. Secondary objectives include estimated 3-year isolated vaginal recurrence, para-aortic recurrence, distant metastasis, survival (recurrence-free, EC-specific, overall survival) and to describe the patient decisional conflict and fear of recurrence. Tertiary objectives: QOL, economic evaluation and interrogation/discovery of additional prognostic biomarkers. Statistical Design: Registration to Substudy A or B is based on molecular classification. Treatment will be deescalated in both substudies; to surveillance-only (all early stage POLEmut, and a proportion of NSMP), or vaginal brachytherapy (proportion of NSMP), with NSMP stratification based on histological grade, and lymphovascular invasion. Substudy A can enroll endometrioid, serous, clear cell, un/dedifferentiated and carcinosarcomas whereas Substudy B is confined to endometrioid histotype. Both arms require ECOG 0-2 and hysterectomy+BSO with nodal assessment required for stage II and grade 3 EC. A total of 120 patients with POLEmut (Sub-study A) and 180 with p53wt/NSMP ER+ (Sub-study B) EC will be recruited in 3 years. If the upper 95% confidence limit is less than 5% in either of Substudy A, Cohort A1 and Sub-study B or both, it will be concluded that patients in one or both groups have an acceptable low risk of pelvic recurrence at 3 years with molecularly-tailored de-escalated adjuvant treatment An additional estimated 25 patients with higher risk POLEmut EC will be enrolled for an exploratory analysis. Conduct to Date: Study activation Dec 19 2022. Enrollment January 31, 2023: 36 Supported by Canadian Cancer Society, Canadian Institutes of Health Research, Gynecologic Cancer Initiative, BC Cancer Foundation. Clinical trial information: NCT05640999 .
A phase 2 open-label study of conditionally active biologic ozuriftamab vedotin (BA3021) in failed PD-1/L1 treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Authors: Ho Alan Loh , Adkins Douglas , Lorch Jochen H. , Thomas Jacob Stephen , Grewal Jaspreet Singh
Published: June 2023

TPS6107

Background: Ozuriftamab vedotin (BA3021) is a conditionally active biologic (CAB) anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) using a cleavable linker (CAB ROR2 ADC) (Short, et al., 2014, Chang, et al. 2021). Conditional and reversible binding by CABs is designed to reduce off-tumor toxicity and immunogenicity, avoid tissue-mediated drug deposition, and improve pharmacokinetics (PK). ROR2 is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including head and neck squamous cell cancer (HNSCC). Increased ROR2 expression has been associated with tumor resistance to chemotherapy, programmed death-1 (PD-1) inhibitors, molecular targeted therapy, and radiation therapy. A pronounced unmet need exists as the majority of patients with recurrent or metastatic HNSCC experience disease progression with existing therapies (Chow 2020). Methods: BA3021-002 is a multi-center, open-label, single-arm Phase 2 study (n=40) designed to evaluate the efficacy and safety of BA3021 in patients previously treated with PD-(L)1 with ROR-2 expressing recurrent or metastatic HNSCC. Eligible patients include those with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. Failure to prior treatment is defined as documented disease progression after no more than one PD-1/L1 inhibitor either administered as monotherapy or in combination therapy. Pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and biomarker assessments will be performed. Enrollment is ongoing (NCT05271604) References: Chang, H.W., Frey, G., Liu, H., Steinman, L., Boyle, W.J. and Short, J.M. Proc. Natl. Acad. Sci. 2021 Mar. 2; 118(9). Chow LQ. Head and neck cancer. N Engl J Med. 2020 Jan 2;382(1):60–72. doi: 10.1056/NEJMra1715715. Short, J.M. Nature Biotechnology 2014 Nov 8, 13(20). Clinical trial information: NCT05271604 .
Response-adapted therapy for locally advanced nasopharyngeal carcinoma based on clinical response and circulating Epstein-Barr virus DNA level post induction chemotherapy.
Authors: Hu Chaosu , Ou Xiaomin
Published: June 2023

TPS6112

Background: For locally advanced nasopharyngeal carcinoma (NPC), the mainstay treatment is cisplatin-based concurrent chemoradiation (CCRT). Recent phase III clinical trials have demonstrated that induction chemotherapy (ICT) plus CCRT, compared with CCRT alone, further improved progression-free survival (PFS). However, not every patient has good response to ICT. Evidence has accumulated that those with poor response to ICT, or those with detectable Epstein-Barr Virus (EBV) DNA post ICT, correlated with poorer PFS. In addition, real-time monitoring of plasma EBV DNA response adds prognostic information, and has the potential utility for risk-adapted treatment intensification in NPC. The aim of this study is to clarify whether response-adapted strategy based on clinical efficacy and EBV DNA response confers survival benefit to patients with locally advanced NPC. Methods: This is an open-label, 3-arm, phase II study. Patients with pathologically confirmed, locally advanced NPC (III-IVA, excluding T3N0M0, 8th AJCC staging system), with pretreatment detectable plasma EBV DNA level and ECOS PS 0-1 were eligible. Patients will receive one cycle of GP-based ICT. After one cycle of ICT, plasma EBV DNA and head and neck MR are performed. Based on clinical efficacy (evaluated per RECIST 1.1 criteria) and changes of plasma EBV DNA after one cycle, patients will be divided into three arms. Patients with good response (Arm A: Early Responders, undetectable EBV DNA level and CR/PR) will directly receive CCRT. Patients with intermediate response (Arm B: Intermediate Responders, detectable EBV DNA and CR/PR/decreased SD; or undetectable EBV DNA yet without CR/PR) will be randomized to experiment subgroup (GP combined with Toripalimab for two additional cycles then CCRT and maintenance Toripalimab treatment) and standard subgroup (GP for two additional cycles then CCRT). Patients with poor response (Arm C: Treatment Resistant, increased EBV DNA level, or PD/enlarged SD) will be switched to TP regimen combined with Toripalimab, followed by CCRT and maintenance Toripalimab treatment. Sample size calculation is based on 2-year PFS rate for arm B as the primary endpoint (one-sided α = 0.10, power = 0.80). Our target sample size is estimated to be 198-240, among them 168 for arm B. Secondary endpoints include adverse events determined by CTCAE v5.0, ORR at 3 months post-CRT, 2-year locoregional recurrence-free survival (LRFS) rate, 2-year distant metastasis-free survival (DMFS) rate, 2-year overall survival (OS) rate, as well as quality of Life for arm B. Exploratory endpoints include 2-year PFS rate, LRFS rate, DMFS rate, OS rate, ORR at 3 months post-CRT, adverse effects, and quality of life for arm A and arm C. This trial opened to accrual in July 2022 and the recruitment is ongoing. Clinical trial information: NCT05628922 .
MRD assay to evaluate recurrence and response via a tumor-informed assessment: MARIA-Breast observational trial.
Authors: Esplin Edward D. , Swan Kelli , Ifhar Lee , Heald Brandie , Nielsen Sarah M. , Pineda Alvarez Daniel Esteban , O'Callaghan William D. , Daber Robert , Chaudhuri Aadel A
Published: June 2023

TPS622

Background: The recognition that cancers release nucleic acids into the peripheral circulation of the patient has enabled a new paradigm for disease detection and surveillance. Detectable ctDNA in patients with solid tumors has been associated with disease prognosis pre-treatment, assessing response to therapy in the form of minimal residual disease (MRD), and monitoring for recurrence after curative intent treatment. Utilizing patient-specific genomic mutation profiling of an individual’s cancer from a tissue sample, in conjunction with the patient’s germline DNA, to create a personalized sequencing panel to then systematically analyze for a subset of these genetic mutations from ctDNA in blood is a strategy that has high sensitivity in detection of MRD. Studies have shown that pretreatment levels of ctDNA using this approach are a potential early indicator of disease recurrence after surgery, that ctDNA clearance may be an early predictor of favorable outcomes and have been shown to correlate with pathologic complete response (Forde et al. N Engl J Med. 2022, PMID:35403841), and that this approach has high sensitivity in its ability to detect recurrence for patients in advance of the current standard of care (Abbosh et al. Cancer Res (2020) 80 (16_Supplement): CT023). Methods: This is a multi-site, prospective, observational trial in the United States of 200 patients with early stage breast cancer undergoing curative intent treatment, who have FFPE tissue available from resection sufficient for a patient-specific bespoke MRD assay who are willing to provide serial whole blood specimens for ctDNA analysis. Participants are asked to provide study specimens prior to initial treatment intervention, after curative intent surgical resection, during adjuvant therapy (as applicable) and pre-recurrence follow-up. ctDNA will be analyzed with an NGS-based, tumor-informed MRD assay that identifies somatic mutations from DNA obtained from the patient’s tumor tissue, subtracts germline variants via NGS-based analysis of the patients germline DNA, and detects a selected set of between 18-50 tumor-specific ctDNA in their blood. All primary tumor specimens will undergo full exome sequencing using the Personalized Cancer Monitoring (PCM) assay. Impact of results of this CLIA-approved MRD assay on clinical decision making will be captured. The primary objective is to assess the ability of MRD to predict post-treatment recurrence. Further objectives are to correlate MRD status with pathologic complete response, determine the lead time to detection of recurrence compared to standard of care, and the association of MRD status with overall survival. Active enrollment started in March, 2022. Clinical trial information: NCT05219734 .
ORACLE-RIPA study: A phase II, randomized, open-label, parallel-group study comparing the immune modulation effect of neoadjuvant ribociclib, palbociclib, and abemaciclib in early ER+/HER2- breast cancer.
Authors: Chen I-Chun , Lin Ching-Hung , Chang Dwan-Ying , Chen Tom Wei-Wu , Ma Wei-li , Wang Ming-Yang , Lu Yen-Shen
Published: June 2023

TPS632

Background: CDK4/6 inhibitors (CDK4/6i), ribociclib, palbociclib, and abemaciclib, provide similar progression-free survival (PFS) benefits when combined with endocrine therapy in ER+/HER2- metastatic breast cancer (MBC) patients. However, not all CDK4/6i have demonstrated overall-survival (OS) benefits in their respective phase III trials. Both, ribociclib and abemaciclib, have shown significant OS benefits in ER+/HER2- MBC patients, but palbociclib has not. Because of similar benefits of the 3 CDK4/6i on PFS, the OS benefit is likely not a result of differences in their synergistic efficacy of a CDK4/6i with endocrine therapy. CDK4 inhibition on cancer cells can also result in upregulation of MHC-I and MHC-II expression on cell surface and Rb-dependent interferon-gamma secretion. CDK6 inhibition might inhibit T cell and NK cell proliferation causing a negative effect on the tumor microenvironment. CDK6 inhibition can also reduce regulatory T cell numbers and increase cytokine production to enhance cytotoxic T cell function. Thus, we hypothesize that the differential impact of the 3 CDK4/6i on OS might be resulting from different immunomodulation effects. To investigate the functional alterations of the CDK4/6i on the BC microenvironment, the neoadjuvant treatment setting is best to compare the immune modulation effects of CDK4/6i from pre-treatment and post-treatment tumor tissues. Methods: This phase II multicenter, randomized, open-label, parallel-group study evaluates the immunomodulation effects of the 3 different CDK4/6i (ribociclib, palbociclib, or abemaciclib) combined with letrozole in neoadjuvant early ER+/HER2- breast cancer patients. A total of 20 patients will be enrolled into each treatment arm. The major inclusion criteria are female patients aged ≥ 20 years old, having a histologically and/or cytologically confirmed diagnosis of ER+ ( > 10%) and/or PR+, HER2 negative (IHC 0+/1+, or IHC 2+ plus FISH negative) breast cancer, stage II/III, and adequate organ function. The treatment will12 weeks of letrozole plus a CDK4/6i. Premenopausal patients will receive GnRH agonist. Breast tumor biopsy, blood and stool samples will be collected prospectively at the time prior to treatment initiation, at 2 weeks after treatment, and at surgery. A description summary will be utilized to compare the results between the 3 CDK4/6i. The trial results will address questions about differences or similarities of the 3 CDK4/6i within the same study. The study is currently enrolling at 3 medical centers s in Taiwan. Clinical trial information: Pending formal number assignment .
A phase 1b study to evaluate the efficacy, safety, and pharmacokinetics of an investigational microbiome therapeutic, SER-155, in adults undergoing hematopoietic stem cell transplantation.
Authors: Ponce Doris M. , Kosuri Satyajit , Khera Nandita , DeFilipp Zachariah Michael , Lombardo Mary-Jane , Ford Christopher B. , Peled Jonathan U. , Van Den Brink Marcel R. M. , von Moltke Lisa , Tejura Bindu
Published: June 2023

TPS7080

Background: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is a rationally designed investigational cultivated microbiome therapeutic, hypothesized to improve clinical outcomes in HCT by restoring colonization resistance to potential pathogens, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study evaluating the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT. Methods: This study will enroll approximately 70 subjects ≥18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo. A variety of conditioning regimens, donor types, and GVHD-prophylaxis regimens are included. Exclusion criteria include history of severe colitis or active inflammatory bowel disease or total colectomy, umbilical cord blood or ex vivo T-cell depletion, exposure to fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, participants in both cohorts receive 2 treatment courses (one before and one after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, plus a conditional 3rd treatment course if the subject receives antibiotics. Safety outcomes are followed through 52 weeks post HCT. The primary endpoint is the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. Results: Cohort 1 enrollment is complete, with 13 participants receiving SER-155. In December 2022, the Data and Safety Monitoring Committee supported continuation to Cohort 2 enrollment following review of safety data from Cohort 1. Enrollment in Cohort 2 is underway. Conclusions: This Phase 1b study is designed to assess the safety, and clinical efficacy of SER-155 in allogeneic HCT, expanding the clinical experience of microbiome- directed interventions in allogeneic HCT recipients. Clinical trial information: NCT04995653 .
EXCEED-ET: A single-arm multicenter study to assess the efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft (P1101) in North American adults with essential thrombocythemia.
Authors: Masarova Lucia , Mascarenhas John , Qin Albert , Shih Weichung , Sato Toshiaki , Urbanski Raymond , Zagrijtschuk Oleh , Zimmerman Craig
Published: June 2023

TPS7088

Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by a high platelet count due to an overacting JAK-STAT pathway as a result of the most common mutations in JAK2, CALR and MPL genes. There is a high, unmet clinical need for safe and effective treatment options for patients with ET who require cytoreduction, both naïve and previously exposed to hydroxyurea (HU) or anagrelide (ANA). In addition to blood count control and thrombohemorrhagic risk reduction, treatment for ET should also halt/prevent disease progression to post-ET myelofibrosis. Reduction in variant allele frequency and changes in marrow morphology may lead to the elimination of the malignant clone, and treatment with an interferon may achieve this outcome. Interferons have been used in the treatment of MPNs for over 30 years with well-established improvements in hematological and molecular rates, but interferons are not approved by a regulatory agency for the treatment of ET. The objective of this study is to assess the efficacy of ropeginterferon alfa-2b-njft, a new generation interferon alfa, in adults with ET who live in the US or Canada. Methods: This single-arm, open-label study includes a 28-day screening period, a 12-month treatment phase, and a 28-day follow-up period, for a total trial duration of 14 months. An extension phase will supply ropeginterferon alfa-2b-njft to patients deriving benefit for a total of 3 years of treatment. Adults diagnosed with ET according to the WHO 2016 criteria with a platelet count at screening > 450 x 109/L, cytoreductive treatment naïve, or with prior use or currently on HU and/or ANA may participate. Prior treatment with an interferon is an exclusion factor. Patients with a history or presence of clinically relevant depression, risk of suicide, or autoimmune disease may not participate. Ropeginterferon alfa-2b-njft will be administered subcutaneously every 2 weeks at the starting dose of 250 mcg (Week 0), 350 mcg (Week 2), and target dose of 500 mcg (Week 4) and remain fixed for the 12-month treatment period. Subjects currently on HU or ANA will follow a pre-specified dose-tapering schedule. All subjects will receive low-dose aspirin unless contraindicated. The primary endpoint is a durable response defined as the proportion of subjects who achieve simultaneous peripheral blood count remission (platelets ≤400 x109/L and WBC < 10 x 109/L) for at least 80% of bi-weekly measurements consecutively between weeks 32-52, a durable resolution of disease-related symptoms according to the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), and absence of bleeding or thrombotic events. This study is being sponsored by PharmaEssentia USA. Clinical trial information: NCT05482971 .