bluuebunny/crossref_metadata_2025 huggingface dataset:
ARST2031: A study to compare early use of vinorelbine and maintenance therapy for patients with high risk rhabdomyosarcoma.
Authors: Allen-Rhoades Wendy A , Mascarenhas Leo , Xue Wei , Donaldson Sarah S. , Casey Dana , Shern John Frederick , Rudzinski Erin R. , Skapek Stephen , Rodeberg David A. , Lautz Timothy , Shenoy Archana , Maianski Irit , Yedururi Sireesha , Maxa Kim , Crompton Brian D. , Fricke Lindsey , Su Zhong , Harrison Douglas James , Venkatramani Rajkumar
Published: June 2022

TPS11591

Background: Patients with high-risk rhabdomyosarcoma (HR-RMS) continue to have poor outcomes with 3-year event free survival (EFS) rates of 30% or less despite chemotherapy dose intensification on recent cooperative group RMS trials. Vinorelbine (VINO) has demonstrated clinical activity in RMS patients with relapsed/refractory disease and shown to provide a survival benefit when given with oral cyclophosphamide as maintenance chemotherapy for a select group of patients that achieved first complete remission. Methods: ARST2031 is a randomized Phase 3 trial with the primary aim to compare event-free survival (EFS) of patients with HR-RMS treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by maintenance with vinorelbine and oral cyclophosphamide (VINO-CPO) or vinorelbine, dactinomycin and cyclophosphamide (VINO-AC) followed by maintenance with VINO-CPO. Patients are stratified by histology and randomly assigned to VAC followed by VINO-CPO maintenance or VINO-AC followed by VINO-CPO maintenance. To be eligible, patients must be ≤ 50 years of age at the time of enrollment with newly diagnosed RMS except adult-type pleomorphic, based upon institutional histopathologic classification. All patients must have Stage 4 disease and patients diagnosed with embryonal RMS (ERMS) must be ≥ 10 years of age. Patients with malignant cytology in cerebrospinal fluid, intra-parenchymal brain metastases, or diffuse leptomeningeal disease are excluded. The study was activated on September 13, 2021 and is anticipated to enroll approximately 4 patients per month. The planned sample size is 100 patients, with approximately 50 patients randomized to each arm. Safety and feasibility of VINO-AC will be assessed in the first 8 patients prior to randomization. The study will have power of 0.8 to detect a hazard ratio of 0.61 (74 events in total) when the one-sided Type I error rate is 0.10, with 30 months of accrual and 2 years of follow-up. The hazard ratio of 0.61 was determined by assuming piecewise exponential distributions and specifying the 2-year EFS of 46% vs. 28% and long-term EFS of 32% vs. 16%, based on prior outcome data. Biospecimens will be collected and banked for future use. Clinical trial information: NCT04994132.
TTI-621-03: A phase I/II study of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma (LMS).
Authors: Chawla Sant P. , Kelly Ciara Marie , Gordon Erlinda Maria , Quon Doris V. , Moradkhani Ania , Chua-Alcala Victoria S. , Thompson Theresa M. , Scheuber Anita , Bruns Ingmar , Allgood Victoria E. , Movva Sujana
Published: June 2022

TPS11593

Background: Doxorubicin is a standard of care agent for patients with advanced soft tissue sarcoma, with a response rate of around 15%, progression-free survival of 5-7 months and cumulative cardiac toxicity that limits its use. TTI-621 is a recombinant soluble fusion protein that combines the N-terminal portion of human SIRPα (the binding domain for CD47) with the Fc region of human IgG1, generating a decoy receptor for CD47 on the surface of tumor cells that both over-rides CD47-mediated inhibition of phagocytosis and provides a pro-phagocytic stimulation. Many solid tumors express high levels of CD47 which is associated with poor prognosis, thought to be the result of CD47-mediated inhibition of macrophage phagocytosis and escape of immune-mediated clearance. Interruption of the CD47-SIRPα signaling pathway using monoclonal antibodies to CD47 has shown anti-tumor activity in animal models and in some early clinical trials. The combination of doxorubicin with CD47-targeted antibodies results in enhanced anti-tumor activity and increased macrophage-mediated cell killing in animal models and macrophage-mediated phagocytosis of cancer cell lines in vitro, suggesting that combining TTI-621 with doxorubicin might be more effective than doxorubicin alone in tumor types that express CD47 and have high numbers of macrophages, such as LMS. Thus, a Phase 1/2 study was initiated to evaluate this combination in patients with advanced soft tissue sarcoma, including LMS. Methods: TTI-621-03 is a Phase 1/2, open-label study of TTI-621 in combination with doxorubicin in patients with anthracycline-naïve disease. The Phase 1 dose escalation evaluates doses of TTI-621 (0.2 to 2.0 mg/kg) in combination with doxorubicin at 75 mg/m2 in patients with high-grade soft tissue sarcomas. Expansion cohorts will evaluate TTI-621 (0.2 and 2.0 mg/kg) with doxorubicin in patients with LMS, with pathology confirmed at a central laboratory. The primary goals of this study are evaluation of safety of TTI-621 administered in combination with standard-of-care doxorubicin and to further evaluate clinical activity (ORR, PFS, OS), safety, PK and patient-reported quality of life in the LMS subpopulation. The dose escalation portion of the study has been completed without DLT. Enrollment to the expansion portion of the study is underway. Clinical trial information: NCT04996004.
Nurse AMIE: Addressing symptoms in rural patients with advanced cancer.
Authors: Truica Cristina I. , Schmitz Kathryn , Doerksen Shawna , Calo William , Stout Nicole Lynn , Wang Ming , Lengerich Eugene , Moss Jennifer , Vanness David J.
Published: June 2022

TPS12148

Background: Prior research has shown that monitoring symptoms in advanced cancer patients may provide a survival benefit. Monitoring is a labor-intensive process that requires nursing staff response and visiting a medical office. This may be more challenging in rural areas, given staffing challenges and distances traveled for care. Lower density of supportive care services has been documented in rural as compared to urban settings in Pennsylvania and West Virginia. We have developed a computer tablet-based supportive care program, called Nurse AMIE, and are investigating its use in symptom management among cancer survivors. Our hypothesis is that a tablet-based supportive care program can improve overall survival of advanced cancer patients in rural Pennsylvania and West Virginia. Methods: This randomized controlled trial will recruit 344 patients residing in a rural county or zip code (RUCC 4-9 or RUCA 4-10) in Pennsylvania or West Virginia, who receive treatment for stage III-IV cancer, are 18 years or older, ECOG 0-3, are fluent in written and spoken English, have sufficient vision/hearing to interact with a computer tablet and staff, and have a clinician-defined life expectancy of 6 months or more. Exclusion criteria: patients on active treatment or behavioral or supportive care trials, or with medical or psychiatric conditions that would impair ability to test study hypotheses. Patients will be randomized on a 1:1 basis to receive either Nurse AMIE or a binder with written supportive care materials. Intervention participants will be asked to log into Nurse AMIE daily, where they will interact with a nurse avatar and answer symptom questions (focusing on sleep, fatigue, pain, and distress). They will receive an empathic response to symptoms and be offered evidence based, guideline concordant self-care interventions to address symptoms (including exercise, nutrition, guided meditation, cognitive behavioral therapy videos, and soothing music). Once weekly, patients will answer 21 questions from the Pro-CTCAE survey. All symptom data will be loaded into a dashboard reviewed daily by study staff. Pain or distress scores of 7+ (out of 10) will be communicated to the care team through the EMR. The trial is powered to detect a 19% difference in overall survival at 2 years follow-up (based on Denis et al JAMA 2019). Secondary outcomes include incidence of chemotherapy toxicities, patient reported outcomes, and cost effectiveness. Enrollment is anticipated to start in March 2022. A community advisory board of 12 cancer patients and stakeholders meet on a quarterly basis to provide feedback on study activities (e.g., usability testing, adaptations, overall implementation) and ensure the project responds to the needs and preferences of rural cancer patients in Pennsylvania and West Virginia. NIH R01-CA254659. Clinical trial information: NCT05221606.
Olanzapine versus fosaprepitant for prevention of chemotherapy induced nausea and vomiting in patients receiving carboplatin (AUC ≥ 4) containing chemotherapy regimen: A phase 3 randomized, double-blind, placebo-controlled trial.
Authors: Bhargave Sneh , kumar akash , Sharma Vinod , Kataria Babita , Pushpam Deepam , Batra Atul , Pramanik Raja , Khurana Sachin , Sahoo Ranjit Kumar , Malik Prabhat Singh , Bakhshi Sameer , Sharma Atul , Kumar Lalit
Published: June 2022

TPS12149

Background: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse effect affecting quality of life of patients of cancer undergoing chemotherapy. Carboplatin alone or in combination with various other chemotherapy drugs is one of the most commonly used drug in solid malignancies. It is categorised as a highly emetogenic drug in doses above AUC≥4 and multiple past studies revealed high CINV incidence. Current international antiemetic guidelines suggest NK1 receptor antagonist based triplet drugs as an effective regimen of CINV control in these patients. However, the nausea control rates are largely inadequate. Olanzapine, an atypical antipsychotic drug, is another drug that has shown significant activity in CINV control and is an integral part of current chemotherapy induced emesis and nausea prevention. However, robust comparative studies of olanzapine based triplets with NK1 based combination have been lacking. Hence we planned this study to compare efficacy of olanzapine containing triplet with NK1 receptor antagonist (fosaprepitant) based triplet drug combination in a phase 3 randomised study. Methods: This study is an investigator initiated phase 3 prospective randomised double blind placebo controlled trial comparing efficacy of olanzapine, 5HT3 receptor antagonist(ondansetron) and dexamethasone (experimental arm) against fosaprepitant, 5HT3 receptor antagonist(ondansetron) and dexamethasone (standard arm) for prevention of CINV among chemo-naïve patients (aged ≥18 years) receiving carboplatin (AUC ≥4) based chemotherapy regimen. Primary objective is to compare the number of patients with no nausea during overall periods (0-120 hours post-chemotherapy). Secondary objectives are to compare complete response (no emetic episodes and no use of rescue medication) in the acute(0-24 hr), delayed(25-120 hr),overall periods(0-120 hr) and to assess the frequency of rescue medication use. The other secondary objective includes assessment of adverse events in both the arms. Statistical Design: Planned accrual is total 214 patients including 10% drop out rate. It is a superiority design with an absolute improvement of 20% in the proportion of patients with no nausea from a baseline prevalence of 40% in the standard arm and two sided alpha of 5% as well as power of 80%. Conduct to date :Study activation : March 2021. Enrolment : 138 subjects. Clinical trial information: CTRI/2021/03/032165.
Addressing Latinx CANcer Care Equity (ALCANCE) randomized controlled trial: Precision medicine and community health workers.
Authors: Rodriguez Gladys M. , Wood Emily H. , Leach Maria , Villicana Gerardo , Murillo Ariana , G. Rosas Lisa , Duron Ysabel , O'Brien Dale G. , Koontz Zach , Patel Manali I.
Published: June 2022

TPS1601

Background: Cancer mortality has declined over the past decade due to clinical advances including precision medicine. Despite these clinical advancements, low-income and racial/ethnic minorities experience worse cancer morbidity and mortality. Specifically, these populations have lower rates of genomic testing and are significantly underrepresented in precision medicine research. Community-based, culturally tailored approaches are needed to address these ongoing disparities. The objective of this randomized controlled trial is to test whether a community health worker (CHW)-led intervention can improve patient understanding of precision medicine topics and delivery of evidence-based cancer care more than usual cancer care alone. Methods: We developed a county-wide cancer care initiative and a community advisory board (CAB) comprised of patient, caregiver, payer, clinician, and governmental stakeholders in Monterey County—comprised of 60% Latinx, non-English speaking, immigrant populations. As guided by the CAB, we developed a CHW-model to provide education on precision medicine and screen for complications of social determinants of health in 1:1 discussions with patients. In collaboration with a local community oncology clinic, we plan to randomize 110 patients with cancer who are receiving active treatment into usual care or usual care plus the CHW-led intervention. Inclusion criteria includes patients who are: 1) 18 years of age or older; 2) racial/ethnic minorities; 3) low-income; 4) uninsured or insured by Medicaid and/or local agricultural employers; and 5) speak English or Spanish. Exclusion criteria includes: 1) lack capacity to consent to study procedures; 2) plan to move from the area within a year. We will measure the effect of the intervention on patient knowledge of precision medicine using a survey adapted from Davies et al. Secondary outcomes include effect on health-related quality of life using the Functional Assessment of Cancer Therapy – General, patient activation using the Patient Activation Measure, satisfaction using the Satisfaction with Decision Scale, prognosis and treatment preferences using an adapted survey by Weeks et al., healthcare utilization, and receipt of evidence-based cancer care. We will administer surveys at baseline, 3-, 6- and 12-months post-enrollment. To date, 67 participants have been enrolled. This study will show if CHW-models increase knowledge of precision medicine in this population. Clinical trial information: NCT04843332.
GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.
Authors: Cloughesy Timothy Francis , Alexander Brian Michael , Berry Donald A. , Colman Howard , de Groot John Frederick , Ellingson Benjamin M. , Gordon Gary B. , Khasraw Mustafa , Lassman Andrew B. , Lee Eudocia Quant , Lim Michael , Mellinghoff Ingo K. , Nelli Apoorva , Perry James R. , Sulman Erik P. , Tanner Kirk , Weller Michael , Wen Patrick Y. , Yung W. K. Alfred ,   GBM AGILE Investigators
Published: June 2022

TPS2078

Background: GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. With its adaptable structure, GBM AGILE has continued trial activation, inclusion of new investigational therapies, and enrollment globally through the challenges of a global pandemic. Methods: The primary objective of GBM AGILE is to identify therapies that effectively improve the overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as new information about promising new drugs is identified while other therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes such as risk-based monitoring and enhanced remote activities. GBM AGILE has screened over 1000 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/sites/month. While enrollment had an initial dip during the early stages of the pandemic (April-May, 2020), with flexible processes including remote based monitoring, minimizing in person visits, and remote provision of IMP, the enrollment rebounded by June, 2020. Through the use of improved and efficient processes allowed within a master protocol/adaptive platform trial infrastructure, GBM AGILE has been seamlessly operating a global trial during a global pandemic. Clinical trial information: NCT03970447.
Design and initiation of an adaptive, randomized, controlled study of berubicin, a topoisomerase 2 poison that crosses the blood brain barrier (BBB), for the treatment of recurrent glioblastoma multiforme (GBM) after first-line therapy.
Authors: Silberman Sandra , Hsu Sigmund H. , Muzyczenko Zena , Picker Donald , Priebe Waldemar
Published: June 2022

TPS2083

Background: Berubicin (also known as WP744) is a patented doxorubicin (Dox) analog with evidence that it crosses the BBB and has significant central nervous system (CNS) uptake. Induction of apoptosis and DNA damage by Berubicin was compared with Dox and showed much greater potency of Berubicin in all tested cancer cells, also significantly and consistently showing higher cytotoxicity than Dox. In models of intracranial orthotopic gliomas, Berubicin prolonged survival when compared to temozolomide, currently a standard of care in GBM. Evaluation of these models also showed that Berubicin had greater infiltration into the tumor compared to normal tissue, providing additional justification for its observed improved efficacy. Based on this data, a Phase 1 dose escalation study was conducted in patients with recurrent primary brain tumors. Berubicin was well tolerated, with myelosuppression (neutropenia and thrombocytopenia) as dose-limiting toxicities. Of 25 patients evaluable for efficacy, there was 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease over 6 weeks for a clinical benefit rate of 44%. Methods: CNS Pharmaceuticals, Inc. (“CNSP”) has licensed Berubicin and initiated a randomized, controlled clinical trial of Berubicin vs. Lomustine in adults with recurrent GBM after first line therapy. The primary endpoint of this study, being conducted in the United States and Europe, is overall survival (OS), with a projected 243 patients enrolled in a 2:1 randomization design (Berubicin:Lomustine). This study has pharmacokinetic (PK) evaluations of all patients enrolled, with at least 15 patients undergoing complete PK assessments throughout the initial dosing period (3 days of IV administration of Berubicin over 2 hours, repeated every 3 weeks). Patients will be stratified on the basis of MGMT methylation, there will be documentation of IDH WT status, and no prior administration of bevacizumab will be allowed. An interim analysis will evaluate the comparative effectiveness of these treatments, an adaptive design intended to demonstrate that Berubicin’s efficacy is at least equal to that of Lomustine such that continuation of the study is in patients' best interests (futility analysis). The overall survival endpoint and sample size have been calculated to be able to show a statistical difference between the two therapies as second line treatment for GBM. Additional studies in malignant diseases of the CNS (e.g., pediatric brain tumors, primary CNS lymphoma, metastatic tumors) are also being explored based on the potential for anthracycline activity in these indications. For the present study posted on clinicaltrials.gov as, additional details and contact information is available. Clinical trial information: NCT04762069.
A phase 1, first-in-human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in participants with HER2 overexpressing solid tumors.
Authors: Reiss Kim Anna , Yuan Yuan , Ueno Naoto T. , Johnson Melissa Lynne , Gill Saar , Dees Elizabeth Claire , Chao Joseph , Angelos Mathew , Shestova Olga , Serody Jonathan Stuart , Priceman Saul , Barton Debora , Swaby Ramona F. , Ronczka Amy , Condamine Thomas , Cushing Daniel , Qureshi Rehman , Kremp Madison , Klichinsky Michael , Abdou Yara
Published: June 2022

TPS2677

Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but have had less success in those with solid tumors. Macrophages are actively recruited and abundantly present in the solid tumor microenvironment (sTME). Tumor associated macrophages are predominantly immunosuppressive and support tumor growth (M2), while a subset of proinflammatory macrophages enhance anti-tumor immunogenicity (M1). M1 macrophage function can be augmented by CAR expression to selectively recognize and phagocytose antigen overexpressing cancer cells. Moreover, CAR macrophages can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immune memory. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression promotes tumorigenesis in many solid tumors (Table). CT-0508 is a cell product comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and were safe and effective in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Methods: This Phase 1, FIH study is evaluating safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 in 18 participants (pt) with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2. Pt previously treated with available therapies, including anti-HER2 therapies, as indicated, and subsequent progression are permitted. Filgrastim is used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. CT-0508 is manufactured, prepared, and cryopreserved from mobilized peripheral blood monocytes. Group 1 pt (n=9) receive CT-0508 infusion split over D1, 3, and 5. A Safety Review Committee will review dose limiting toxicities. Group 2 pt (n=9) will receive the full CT-0508 infusion on D1. Pre- and post-treatment biopsies and blood samples will be collected to investigate correlates of safety (immunogenicity), trafficking (RNA scope), CT-0508 persistence in blood and in the tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Radiographic imaging is also being conducted to assess preliminary tumor activity. Clinical trial information: NCT04660929. [Table: see text]
Design and rationale of a phase 1 dose-escalation study of AMG 193, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.
Authors: Villalona-Calero Miguel Angel , Patnaik Amita , Maki Robert G , O'Neil Bert , Abbruzzese James L. , Dagogo-Jack Ibiayi , Devarakonda Siddhartha , Wahlroos Sara , Lin Chia-Chi , Fujiwara Yutaka , Terbuch Angelika , Postel-Vinay Sophie , Goebeler Maria-Elisabeth , Addeo Alfredo , Prenen Hans , Arkenau Tobias , Sacher Adrian G. , Liu Chunxu , Kormany William , Rodon Ahnert Jordi
Published: June 2022

TPS3167

Background: Protein arginine methyltransferase 5 (PRMT5) is an emerging target for cancer treatment. MTAP homozygous deletion occurs in 15% of cancers and often coincides with deletion of the tumor suppressor gene CDKN2A, leading to buildup of its substrate MTA. MTA shares close structural similarity to S-adenosyl methionine (SAM), the substrate methyl donor for PRMT5. By competing with SAM, MTA partially inhibits PRMT5. Thus, MTAP-null cancers are susceptible to further PRMT5 inhibition (Kryukov Science 2016). Current direct/indirect PRMT5 inhibitors (PRMT5i) showed preliminary anticancer activity, albeit with considerable toxicities due to their indiscriminate activities. AMG 193 is an MTA-cooperative PRMT5i that preferentially targets the MTA-bound state of PRMT5 that is enriched in MTAP-null tumors and represents a novel strategy to increase the therapeutic margin of this class of inhibitors. AMG 193 potently inhibits MTAP-null cancer cell lines and patient-derived xenografts. Methods: NCT05094336 is a first-in-human (FIH), multicenter, open-label, phase 1/1b/2 trial evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of AMG 193 in patients with advanced MTAP-null solid tumors. Eligible patients (≥ 18 years) with histologically confirmed locally advanced/metastatic solid tumors not amenable to curative treatment with surgery and/or radiation, homozygous MTAP and/or CDKN2A deletion (by local next generation sequencing), or MTAP protein loss in tumors (by central immunohistochemistry), measurable disease, ECOG PS 0‒1, adequate hematopoietic, renal, liver, pulmonary, cardiac, coagulation function and glucose control will be included. The study will be conducted in 3 parts, each with subparts. Here, we describe Part 1a/b (dose exploration). Five dose levels are planned. Treatment continues until progression or withdrawal. The primary objectives are to evaluate the safety and tolerability of AMG 193 monotherapy; endpoints include dose-limiting toxicities, treatment-emergent adverse events, serious adverse events, electrocardiograms, laboratory abnormalities, and vital signs. Secondary objectives include the characterization of the PK parameters of AMG 193 including Cmax, Tmax, and AUC after single or multiple doses. This study is expected to enroll approximately 30 patients in Part 1a/b. This is the first FIH trial open for enrollment for this new class of PRMT5i and enrollment is ongoing. Clinical trial information: NCT05094336.
CoRInTH: A phase Ib/II trial of checkpoint inhibitor, pembrolizumab (PD-1 antibody [Ab]) plus standard intensity modulated chemoradiotherapy (IMCRT) in HPV-induced stage III squamous cell carcinoma (SCC) of the anus.
Authors: Hall Marcia , Adams Richard , Guren Marianne Grønlie , Carucci Margherita , Nixon Lisette , Porter Catharine , Bhuva Neel , Glynne-Jones Robert , Harrison Mark ,   CoRInTH Trials Group
Published: June 2022

TPS3630

Background: SCC of anus (SCCA) are considered rare tumours, but the incidence is increasing. Only 65% patients with later stage T3/T4 +/-N1 SCCA remain disease free at 3 years (Gunderson 2013, James 2013). The cytotoxicity of IMCRT enhances tumour antigen presentation and promotes cytokine release as well as enhancing the MHC (Demaria 2004, Reits 2006). Immune therapy, against PD-1, have been approved for patients with SCC arising from other primary sites eg. head and neck, lung cancer. The addition of such checkpoint inhibitors might also result in improved PFS and OS for higher risk SCCA patients. Methods: A multicentre, single arm, open-label, non-randomised study to evaluate the safety and tolerability of different schedules of exposure to pembrolizumab (P) with standard IMCRT in 50 patients with locally advanced T3/4 anal cancer. The first cohort of 6 patients commenced standard IMCRT and received P 200mg every 21d beginning at Week 5 day 1 of the IMCRT schedule. If this is considered safe and tolerable with not more than 3/6 SAEs within first 6 weeks after completion IMCRT, a second cohort of 6 patients will be recruited where P is introduced on Week 1 Day 1 with standard IMCRT. Pembrolizumab monotherapy will be continued for a total of 6 months. Primary endpoint is safety and tolerability by assessing AEs and protocol adherence. Secondary endpoints include feasibility, clinical response assessment by RECIST (MRI) for ORR at 3, 6 and 12 months, imaging response assessments by TRG MRI using changes in Apparent Diffusion Coefficient (ADC) on diffusion weighted sequences and patient reported outcomes, using EORTC quality of life questionnaires. Patients are being asked to contribute to translational endpoints with the donation of tissue and blood samples. Eligible patients will have Stage IIIA/B (T3/4, any N, M0) SCCA, performance status 0 or 1 and be suitable for IMCRT. Patents with anal tumours of non-epithelial origin, metastatic disease or a diagnosis of immunodeficiency are excluded. Single phase IMRT with a simultaneous integrated boost to achieve 53.2Gy in 28 fractions over 5.5 weeks to PTV_A, according to the UK consensus is mandated. Concomitant chemotherapy can either be cisplatin 60mg/m2/ or mitomycin 12mg/m2 with either 5FU 1000mg/m2 or capecitabine 825mg/m2 at investigator discretion. The first cohort has completed recruitment with Safety Review Committee / IDMC review planned for April 2022. Patients will then be sought to start P on Week 1 Day 1 with IMCRT. Further safety review will be undertaken following the first 6 patients entered into the second cohort but recruitment will continue in an expansion phase to a maximum of 44 patients. Clinical trial information: NCT04046133.
Five- or 10-year colonoscopy for 1-2 non-advanced adenomatous polyps (FORTE) NRG-CC005 study: A randomized phase III non-inferiority trial comparing colorectal cancer incidence in participants with 1-2 non-advanced adenomas randomized to a 5- and 10-year surveillance colonoscopy exam schedule versus a 10-year surveillance colonoscopy exam schedule.
Authors: Schoen Robert E , Bandos Hanna , Corley Douglas , Dueker Jeff , Yothers Greg , Bai Jinbing , Huh Warner King , Bauman Julie E. , Walker Joan L. , Bruner Deborah , Kachnic Lisa A.
Published: June 2022

TPS3631

Background: Adenomatous polyps are the acknowledged precursors of colorectal cancer (CRC). Identification and removal of adenomas is the mechanism by which screening is effective in reducing CRC incidence and mortality. Patients with 1-2 non-advanced adenomas ( < 1 cm with neither villous components nor high grade dysplasia) are recommended to return at a timing ranging from 5-10 yrs. However, evidence for the benefit, optimal timing, and recommended frequency of surveillance colonoscopy is not available. A randomized, clinical trial to demonstrate the difference in results between 5- or 10-yr surveillance for participants with non-advanced adenoma can guide clinical practice. Methods: NRG-CC005/FORTE is a prospective, randomized, non-blinded, Phase III, non-inferiority clinical trial comparing CRC incidence in participants randomized to recommendation for a 5- and 10-yr vs. a 10-yr only surveillance colonoscopy exam schedule. Other pre-defined exploratory endpoints include incidence of advanced adenomas, CRC mortality, and incidence of stage III-IV CRCs. Stratification factors include age, gender, and time from qualifying colonoscopy to randomization. Participants ≥50 and < 70 yrs of age at the time of randomization with a first-time diagnosis of 1-2 non-advanced tubular adenomas from the qualifying colonoscopy within 4 yrs prior to randomization will be eligible. Participants with a clinical diagnosis of a significant genetic risk for CRC or with a family history of CRC diagnosed at ≤60 yrs in a first degree relative or in two first degree relatives diagnosed at any age are ineligible. Other ineligibility criteria include prior history of CRC or colorectal adenomas, a hyperplastic polyp measuring ≥1 cm or traditional serrated adenomas, or life expectancy < 10 yrs due to comorbid conditions. Collection of blood, stool, and tissue samples is planned. Statistics: The primary endpoint for the trial is CRC incidence. The trial is focused on CRCs diagnosed between year 5 and year 10. By incorporating a window of +/- 1 yr to allow for somewhat earlier and later procedures, as typically occurs in clinical medicine, the primary endpoint will include incident cancers identified in years 4 through 11. A crude 4- to 11-yr incidence rate of 0.387% is assumed for the 5- and 10-yr schedule arm. The study is powered at 90% to detect a non-inferiority margin difference of 0.387% at alpha 5% in CRC incidence rate between two schedules. 9,500 participants are to be enrolled. Support: U10CA180868, -180822, UG1CA189867, U24CA196067 Clinical trial information: NCT05080673.
Myopenia and mechanisms of toxicity in older adults with colorectal cancer (CRC): The M&M study (WF-1806).
Authors: Williams Grant Richard , Bhatia Smita , Klepin Heidi D. , Sanoff Hanna Kelly , Muss Hyman B. , Al-Obaidi Mustafa , Harmon Christian , Richman Joshua , Dressler Emily Van Meter , O'Rourke Mark Allen , Weaver Kathryn E. , Lesser Glenn Jay
Published: June 2022

TPS3640

Background: CRC is the 2nd most common cause of cancer death in the US, and nearly 60% of CRC cases occur among older adults. There is a critical unmet need to understand the underlying cause(s) of observed variability in chemotherapy toxicity (chemotoxicity) outcomes to minimize adverse outcomes and appropriately personalize therapy for older adults. Low muscle mass, known as myopenia, is prevalent in older adults with CRC (̃60%) and is associated with chemotoxicity and decreased overall survival (OS). However, little is known about trajectories of myopenia and underlying mechanisms of increased toxicities and decreased survival in myopenic patients. We address these gaps in a prospective cohort study, with the central goal of examining the role of myopenia in chemotoxicity in older adults with metastatic CRC undergoing 5-Fluouracil (5FU) based chemotherapy, and to explore the mediating influence of germline genetic variants and pharmacokinetics (PKs) in the association between myopenia and chemotherapy toxicity. Methods: This prospective cohort study is accruing through the Wake Forest NCI Community Oncology Research Program Research Base (WF NCORP) and funded by the NCI grants 2UG1CA189824 and K08CA234225. The study examines the impact of myopenia on chemotoxicity and OS in older adults with newly diagnosed metastatic CRC planning to receive systemic 5FU-based chemotherapy (either as monotherapy or in combination with oxaliplatin and/or irinotecan +/- biologics) (NCT03998202). All patients undergo the Cancer & Aging Resilience Evaluation and Life-Space Evaluation at baseline, 3 and 6 months. Standard of care Computed Tomography (CT) images will be obtained to assess muscle measures (skeletal muscle area/density) at the L3 cross-section. The primary outcome is grades 3 to 5 chemotoxicity measured up to 6 months after initiation of chemotherapy using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. We will assess the association of baseline myopenia and trajectories of myopenia with severe chemotherapy toxicities. Secondary outcome measures include OS at 1 year and chemotoxicities using the Patient Reported Outcomes (PRO) version of the CTCAE. The study also explores the mediating/moderating influence of genetic variation and altered PKs (n = 60) in the association between myopenia and chemotherapy toxicity. To date, the study has accrued 73 of the 300 targeted patients from 110 NCORP practices. Clinical trial information: NCT03998202.
ACCRU-GI-2008: A phase II randomized study of atezolizumab (Atezo) plus a multi-kinase inhibitor (MKI) versus MKI alone in patients with unresectable advanced hepatocellular carcinoma (aHCC) who previously received atezolizumab plus bevacizumab (Bev).
Authors: Ma Wen Wee , Ou Fang-Shu , Li Jenny Jing , Tran Nguyen H. , Babiker Hani M. , Revzin Alexander , Dong Haidong , Nelson Garth D. , Ness Andrew , Schuster Carissa E. , Jia Jingquan , Bekaii-Saab Tanios S. ,   Academic and Community Cancer Research United (ACCRU)
Published: June 2022

TPS4170

Background: IMbrave150 is the first study demonstrating the benefit of anti-PDL1 in the frontline treatment of aHCC, and established Atezo/Bev as a new 1st line standard for aHCC. There is currently limited evidence to guide subsequent therapy for aHCC patients progressing on Atezo/Bev. ACCRU-GI-2008 is designed to determine the benefit of continuing Atezo into 2nd line and the safety of Atezo plus a MKI in patients with aHCC who previously received Atezo/Bev. The study is being conducted across 12 centers in the United States (ClincalTrials.gov#: NCT05168163). Methods: This study utilizes a 2:1 randomized phase II design where eligible patients will receive either Atezo/MKI (experimental arm) or MKI alone (control). Patients will be stratified according to the MKI choice (cabozantinib or lenvatinib, per physician’s decision), etiology of HCC (viral vs. non-viral) and alpha-fetoprotein level ( < 400 vs. > = 400 ng/mL). The major eligibility criteria are histological/cytological diagnosis or clinical diagnosis of HCC per the AASLD or WASL 2018 guidelines, has advanced disease not amendable to curative treatment, previously received and progressed on Atezo/Bev, has received only 1 previous line of systemic therapy (2nd line only), ECOG PS 0-1, Child Pugh Class A, adequate organ reserves and RECIST v1.1 measurable disease; previous MKI for advanced disease is excluded. The primary endpoints are overall survival (OS) and progression free survival (PFS). A total sample size of 122, with 89 PFS events, we will have 80% power to detect an improvement in median PFS from 4 to 7 months, assuming a one-sided significance level of 0.05. With approximately 84 deaths, we will have 80% power to detect an improvement in median OS from 10 to 18 months, assuming a one-sided significance level of 0.05. The overall one-sided significance level, for the study, is 0.1. An OS interim analysis will be conducted at 89 PFS events. Secondary endpoints include objective response, duration of response, and adverse events. Archival tumor and serial blood samples will be collected to evaluate for potential prediction biomarkers and mechanisms of sensitivity/resistance. Baseline and on-treatment tumor biopsy specimens will also be collected from the initial 10 patients of each arm. The study is approved by the ethics committee and enrollment to the study will be underway by Q2/3 2022. Clinical trial information: NCT05168163.
Trial in progress: Durvalumab and olaparib for the treatment of prostate cancer in men predicted to have a high neoantigen load.
Authors: Sokolova Alexandra , Gulati Roman , Cheng Heather H. , Beer Tomasz M. , Graff Julie N , Amador Melanie , Toulouse Andrea , Taylor Kamilah , Bailey Shawna , Smith Steven , Tabatabaei Shaadi , Sinit Ryan , Slottke Rachel , Vuky Jacqueline , Yezefski Todd , Grivas Petros , Yu Evan Y. , Schweizer Michael Thomas
Published: June 2022

TPS5099

Background: Approximately 30% of patients (pts) treated with definitive surgical and/or radiation therapy for localized prostate adenocarcinoma develop biochemical recurrence (BCR). The optimal time to initiate androgen deprivation therapy (ADT) for such patients is controversial and depends on patient and provider preference, absolute PSA value, and PSA doubling time (PSADT), which has been associated with time to metastasis. Because the time from BCR to metastasis can be long in many cases, strategies allowing pts to avoid ADT while extending metastasis-free survival are desirable. Prior studies have shown that a high tumor neoantigen load correlates with response to anti-PD(L)1. We hypothesized that PARP inhibitor-induced genomic instability may sensitize tumors to anti-PD(L)1 through: i) increasing mutational burden and subsequent tumor neoantigen formation, and/or ii) through activation of other immunogenic pathways (e.g. the STING pathway). This trial investigates an ADT-sparing approach for men predicted to have high neoantigen load and who have BCR prostate cancer. Methods: This is a phase 2 clinical trial testing durvalumab (1500 mg IV every 4 weeks) and olaparib (300 mg PO twice a day) (one cycle = 4 weeks) in men with BCR (PSADT≤10 months) whose tumors are predicted to have high neoantigen load based on: biallelic CDK12 mutations (Cohort A), mismatch repair deficiency (MMRd)/high microsatellite instability (MSI-H) (Cohort B), or loss of function mutations in homologous recombination repair (HRR) genes (Cohort C). Cohorts A and B will receive 3 cycles of durvalumab followed by 3 cycles of the combination of durvalumab and olaparib. Given the proven efficacy of olaparib in prostate cancer patient whose tumors posses an HRR gene mutation, Cohort C will receive 6 full cycles of the combination. Ten patients will be enrolled in each cohort (total n = 30) at two collaborating sites. This study was designed to provide preliminary efficacy data across eligible cohorts, with a primary objective of estimating the proportion of pts with an undetectable PSA at 12 months within each cohort. Secondary objectives include safety, proportion of patients with ≥50% decline in PSA from baseline and quality of life measures. Correlative studies will assess blood and tissue molecular biomarkers for association with outcomes. The study is open with two patients enrolled at the time of abstract submission. Clinical trial information: NCT04336943.
DASL-HiCaP: Darolutamide augments standard therapy for localized very high-risk cancer of the prostate (ANZUP1801)—A randomized phase 3, double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation.
Authors: Niazi Tamim , McBride Sean Matthew , Williams Scott , Davis Ian D. , Stockler Martin R. , Martin Andrew James , Bracken Karen , Roncolato Felicia , Horvath Lisa , Sengupta Shomik , Martin Jarad , Lim Tee , Hughes Simon , McDermott Raymond S. , Catto James W.F. , Kelly Paul J. , Parulekar Wendy R. , Morgan Scott Carlyle , Rendon Ricardo A. , Sweeney Christopher ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2022

TPS5103

Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analog (LHRHA), is standard of care for men with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT in the setting of either primary definitive therapy, or salvage therapy for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind trial for men planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by: RP; use of adjuvant docetaxel; pelvic nodal involvement. 1100 participants will be randomized to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomization. Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival (ICECaP-validated), with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353.
Phase 1 study of JNJ-69086420, an actinium-225-labeled antibody targeting human kallikrein-2, for advanced prostate cancer.
Authors: Morris Michael J. , Sartor A. Oliver , Wong Jeffrey Y.C. , Max Steven I , Xie Hong , Yu Alex , Divgi Chaitanya R. , Patricia Daniel , Avadhani Anjali Narayan , Pandit-Taskar Neeta , Barata Pedro C. , Nordquist Luke T.
Published: June 2022

TPS5104

Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has been shown to prolong survival, delay disease progression, and improve quality of life, raising hopes that these gains will be amplified with even more cancer-specific targets and more powerful radioligands. Human kallikrein-related peptidase 2 (hK2) is a tumor-associated member of the kallikrein family that shares significant homology to prostate-specific antigen and is minimally expressed in normal non-prostate tissues. JNJ-69086420 (JNJ-420; 225Ac-DOTA-h11B6 [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]), is a first-in-class radioimmunotherapy targeted to hK2 antigen. In a phase 0 study of [111In]-DOTA-h11B6, patients with mCRPC (progressed on standard therapies), treatment with a single dose of [111In]-DOTA-h11B6 (2 mg) with/without 8 mg h11B6, demonstrated safety, good tumor localization, nominal normal-organ uptake, and no difference in pharmacokinetics (PK) between 2 and 10 mg antibody mass (Morris et al. J Clin Oncol. 2021 39:6 suppl, 122). We have initiated the first-in-human study to assess the safety, PK, pharmacodynamic (PD), and clinical activity of Ac-225 radiolabeled JNJ-420, to determine its recommended phase 2 dose (RP2D) in adults with advanced PC. Methods: This open-label, multicenter, phase 1 study will recruit approximately 50 men (aged ≥18 years) with advanced PC across dose escalation (Part 1) and expansion (Part 2) parts. Key eligibility criteria: mCRPC with histologic confirmation of adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function based on hematology and serum chemistry, and 1 or more prior novel androgen receptor-targeted therapies (prior chemotherapy acceptable). Key exclusion criteria: prior treatment with radium/strontium/samarium/radioconjugate therapy, superscan findings as protocol defined, active central nervous system metastases. In Part 1, men will receive intravenous (IV) injection of 50 μCi/ 2 mg JNJ-420 (once every 8 weeks) with one or multiple doses; escalation of dose levels to be based on dose limiting toxicities (DLTs) evaluation, until RP2D identification. In Part 2, JNJ-420 is to be given at one of the RP2D(s) determined in Part 1. Primary endpoint is safety (incidence and severity [grading per NCI-CTCAE V5.0] of AEs including DLTs). Secondary endpoints include prostate specific antigen response rate, overall response rate (PCWG3 modified RECIST 1.1 criteria), PK, PD, immunogenicity, and biomarker analyses. Enrollment began in Dec 2020; as of 10 Feb 2022, 4 sites have been initiated and 23 patients enrolled; currently, dose escalation is ongoing. Clinical trial information: NCT04644770.