bluuebunny/crossref_metadata_2025 huggingface dataset:
Interventions for head and neck cancer survivors: A systematic review.
Authors: Margalit Danielle Nina , Salz Talya , Venchiarutti Rebecca L. , Milley Kristi , McNamara Mairead , Chima Sophie , Druce Paige , Nekhlyudov Larissa
Published: June 2022

e24042

Background: Quality survivorship care includes cancer-related and general health care domains, including cancer surveillance and prevention of new cancers, management of psychosocial and physical late effects, health promotion/disease prevention, and management of chronic conditions. Survivors of head and neck cancer (HNC) have particularly complex unmet needs across all of these domains. We systematically reviewed interventions for HNC survivors to identify existing evidence and gaps in HNC survivorship care research. Methods: We performed a systemic review (PROSPERO ID: CRD42021269566) using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We searched MEDLINE, Embase, Emcare and PsycINFO for primary studies published in English between 2000 and 2021 to identify prospective studies for which interventions began after completion of cancer treatment and had a study endpoint ≥1 year after treatment completion. The population included adults treated with for HNC We used Covidence systematic review software to facilitate article screening and study selection. Two reviewers independently screened titles and abstracts followed by full texts for eligibility. Disagreements were resolved by consensus. Two reviewers critically appraised each selected study. Reviewers evaluated risk of bias with the Cochrane RoB 2.0 tool for randomized trials and the ROBINS-I tool for non-randomized studies. Due to the anticipated heterogeneity of included studies, narrative synthesis was used to summarize data. Results: The literature search identified 7395 studies; after applying inclusion and exclusion criteria, 28 studies were identified for critical appraisal: 13 randomized trials and 15 non-randomized studies. Most study interventions (n = 25) focused on surveillance and management of physical effects, including 13 studies that also targeted management of psychosocial effects. Four studies targeted the prevention and surveillance for recurrence and new cancers, and only one study addressed health promotion and disease prevention. Among the 13 randomized studies, 12 had a medium to high risk of bias, and 1 with a low risk of bias. The 15 non-randomized studies included 12 with a high risk and 3 with a medium risk of bias. Common sources of bias included lack of pre-planned sample size and power, lack of blinding of patients or assessors, heterogeneity in population, and attrition with incomplete follow-up. Conclusions: This systematic review and critical appraisal identified gaps in HNC survivorship intervention research targeting under-represented domains of the survivorship framework, and common challenges in study design that introduce risk of bias. To promote quality survivorship care for HNC survivors, scientifically rigorous intervention studies must address broader areas of focus.
LEAD BY EXAMPLE: Evaluation of an NCCN and ASCO guideline-based virtual weight loss and healthy lifestyle intervention on providers and staff members at a comprehensive cancer center.
Authors: Hansra Damien Mikael , Boodhoo Jacqueline , Warren Anya , Avinger Shanetia , Meiri Eyal
Published: June 2022

e24045

Background: Obesity is a leading cause of preventable death in the United States. The incidence of most obesity associated malignancies are increasing. Novel interventions to combat the obesity epidemic are greatly needed. Here we investigate the effect of a virtual clinical intervention on medical providers & other medical staff at a comprehensive cancer center. Methods: Physicians (MD), nurses (RN), & other medical staff (MS) were enrolled in an IRB approved, prospective single arm clinical trial. We assessed the effect of NCCN & ASCO guideline recommendations for weight loss & healthy lifestyle on overweight (OW) & obese (OB) providers & medical staff. Primary outcome: to assess change in body mass index (BMI) over a 3-month (mo.) intervention. Secondary outcomes: To assess changes in nutrition and exercise habits over time b) evaluate other lifestyle factors over time: stress, self-image, barriers to weight loss. Participants (Pts) filled out two 16 question (Q) pre & post survey (at 1, 90 days) relating to study outcomes. The virtual intervention consisted of giving information & advice over 3 months: A comprehensive handout e-mailed on day 1 + Motivational/info e-mails q 2 weeks/3 mo. Statistical analysis: students' paired T test used to compare changes in weight & survey responses day 0-90. P- value α = 0.05. Inclusions: age > 18 yo males & females, MD, RN, ARNP, & MS who are OW (BMI > 25Kg/m2) or OB (BMI > 30Kg/m2). Exclusions: non-OW/OB, Pts with uncontrolled cardiovascular, pulmonary, orthopedic, or cerebrovascular disease, pregnancy. Results: 106 participants enrolled; 26 subjects completed study. Demographics: 6/26 = 23% (MD/ARNP), 12/26 = 46% (RN), 8/26 = 31% (MS). 4/26 = 15% male, 22/26 = 85% female, µ age 45 (25-67). 3/26 = 12% Asian, 5/26 = 19% Black, 18/26 = 69% White. 100% not Hispanic. µ BMI = 33.9 kg/m2 (25.1-44.5). Intervention: 26/26 (100%) Pts lost weight/3 mo., µ Δ kg = -5.2kg (p < 0.0001), µ Δ BMI = - 1.67 kg/m2 (p = 0.002). Survey results: Significant improvements were seen in: self-image (p = 0.0012), physical activity (p < 0.0001), healthy diet (p < 0.0001), days/week exercise (p = 0.0008), µ Δ minutes exercise/week = +65 min/week (p = 0.0046), decreased stress levels (p < 0.0001). Limitations: significant participant drop out seen. Conclusions: All participants who completed the study lost weight & improved healthy lifestyle parameters. To our knowledge this is the first all virtual clinical weight loss & lifestyle intervention executed. Also, this is the first weight loss & lifestyle intervention executed in providers. Our intervention was cost effective, easy to execute, & warrants further study in both medical staff & patient populations. Last, this novel virtual intervention is highly relevant during the covid 19 pandemic due to social distancing requirements.
Symptom profile of head and neck patients initiating care in a survivorship clinic.
Authors: Gilmore Katherine Ramsey , Hutcheson Kate A. , Chapman Patricia Hansberry , Bi Weiqi , Goepfert Ryan , Pytynia Kristen B , Rodriguez Maria Alma
Published: June 2022

e24047

Background: After treatment, and at a time point of low risk of relapse, cancer patients at our institution transition to Survivorship Clinics (SC) that focus on wellness, late effects management, and psychosocial functioning in additional to cancer screening. We describe the self-reported symptoms of Head and Neck (HNC) survivors at the time of transition to SC, and the level to which these symptoms interfered with their function. Methods: Survivors reporting to their first in person SC appointment were assessed using the MD Anderson Symptom Inventory Head and Neck (MDASI–HN). This validated patient-reported outcome (PRO) instrument consists of 28 questions grouped into three subscales (core symptoms, disease specific symptoms, and interference items). Symptom severity is measured using a 0 to 10 scale (0 = not present, 10 = as bad as can be imagined). Descriptive statistics were used to characterize the sample. Percent of patients reporting moderate to severe symptoms (> = 4) are also noted. Results: This sub-analysis consisted of 377 patients seen for their initial transition visit to the survivorship clinic. Patients were mostly male (83%) and Caucasian (89%), with an average age of 63.8 years, and on average 41.5 months from diagnosis. Most common cancers were oropharynx (49%), oral cavity (33.7%), and larynx/hypopharynx (12.5%), nasopharynx (4.5%). Average symptom reports are presented in table. In rank order of prevalence (4% to 31% of patients), the top reported moderate to severe symptoms included dry mouth, swallowing/chewing, mucus, remembering, distress, and shortness of breath associated with moderated to severe interference in general activity in 8% of patients. Conclusions: HNC survivors report multiple persistent symptoms of moderate to high severity in a significant number, most commonly mouth dryness and swallowing and chewing difficulty. PROs can identify patients with high symptom burden, and lead in interventions to support the patients at their SC visit.[Table: see text]
The impact of NSCLC disease evolution and treatment on pre- and post-diagnosis weight loss and cachexia designation.
Authors: Iyengar Puneeth , Gilmore L Anne , Olaechea Santiago , Alvarez Christian , Ahn Chul , Infante Rodney E
Published: June 2022

e24098

Background: While cancer cachexia is associated with increased morbidity/mortality, little is known about longitudinal weight changes and opportunities for intervention pre- and post-diagnosis in this patient population. We therefore aimed to characterize body weight trajectories pre- and post- non-small cell lung cancer (NSCLC) diagnosis in patients without and with cachexia. Methods: Data were retrospectively extracted for each patient pre- and post-diagnosis of NSCLC from inpatient and outpatient visits within the UT Southwestern Medical Center Healthcare System. 3830 participants were screened with a NSCLC diagnosis between May 2005 to December 2019. Of these, 661 patients had a body weight recorded at cancer diagnosis and at least one body weight pre-diagnosis. The primary outcome was weight change over time. Other measures included defining associations between weight change and tumor pathology, stage of disease, and other clinical characteristics. Results: NSCLC patients without cachexia at cancer diagnosis were weight stable up to 12-months pre-diagnosis (+1.0±0.3% body weight; p = 0.01). Weight loss post-diagnosis was driven by stage of disease (stage 1/2: 0.4±0.5% body weight vs. stage 3/4: 4.8±0.9% body weight p = 0.0008) and treatment with chemotherapy (p < 0.0001). NSCLC patients with cachexia at cancer diagnosis lost weight pre-diagnosis (8.8±0.5% body weight; p < 0.0001), with 25% of this weight loss occurring between 6- and 12-months pre-diagnosis. Assessing weight change over 12 months opposed to 6 months resulted in a 32% increase in NSCLC patients with cachexia at cancer diagnosis (p = 0.006). By 12-months post-diagnosis, 62% of surviving late-stage and 45% of early-stage NSCLC patients had met the criteria for cachexia. Patients on average remained free of weight loss for 150±6.4 days or had pre-cachexia for 146±7.2 days prior to transitioning to a more advanced stage of the syndrome. Conclusions: Significant weight loss in NSCLC patients initiated as far back as 12 months prior to a cancer diagnosis as opposed to a shorter 6-month interval currently used to define patients with cachexia. Therefore, detection of earlier weight loss should be prioritized in high-risk NSCLC screening candidates. Finally, advanced NSCLC patients develop cachexia post-diagnosis irrespective of previous weight history, highlighting the impact of treatment iatrogenicity and/or refractory disease on cachexia development.
Phase 2 trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (HER2CLIMB-04, trial in progress).
Authors: Krop Ian E. , Carey Lisa A. , Ramos Jorge , Chen Yiyi , Hamilton Erika P.
Published: June 2022

TPS1111

Background: Tucatinib is an oral reversible small-molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2). Tucatinib is approved in the US for use in combination with trastuzumab and capecitabine in adult patients with HER2+ metastatic breast cancer (MBC), with and without brain metastases, who have received ≥1 prior anti–HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) comprising a HER2-directed monoclonal antibody conjugated to a topoisomerase I inhibitor payload, is also approved in the US for patients with HER2+ MBC. In HER2+ breast cancer (BC) xenograft models, tucatinib increased the antitumor activity of a HER2-directed ADC comprising a HER2-directed monoclonal antibody conjugated with 8 exatecan moieties (T-Ex) when compared to T-Ex alone (Kulukian et al 2019). While significant advances have been made in the treatment of patients with HER2+ BC, treatment of metastatic disease remains a clinical challenge due to limited treatment options. Methods: HER2CLIMB-04 (NCT04539938) is a single-arm, open-label, multicenter, phase 2 study evaluating the efficacy and safety of tucatinib plus T-DXd in previously treated patients aged ≥18 years with unresectable, locally advanced, or metastatic (LA/M) HER2+ BC. Patients must have prior treatment with a taxane and trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab). Patients with brain metastases, including active brain metastases, may be enrolled. A safety lead-in portion of the study with 10 patients who were followed for at least 1 cycle has been completed. This portion of the study demonstrated a manageable safety profile so the trial will enroll approximately 60 response-evaluable patients (including the 10 patients from the safety lead-in), evenly distributed between patients with and without brain metastases. The primary endpoint is confirmed objective response rate (cORR) by investigator assessment per RECIST 1.1. Secondary endpoints are progression-free survival (PFS), duration of response (DOR), disease control rate (DCR) by investigator assessment per RECIST 1.1, overall survival, and safety. Exploratory endpoints will include cORR, PFS, DCR, and DOR by independent central review per RECIST 1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes. Efficacy and safety will be summarized with descriptive statistics. Enrollment in the US began in late 2020. Clinical trial information: NCT04539938.
A phase I trial of T-cell receptor gene therapy targeting KK-LC-1 for gastric, breast, cervical, lung and other KK-LC-1 positive epithelial cancers.
Authors: Norberg Scott , Von Euw Erika Maria , Parry Gordon , Highfill Steven , Franco Zulmarie , Gulley James L. , Hinrichs Christian S.
Published: June 2022

TPS2678

Background: T cell receptor (TCR)-T cell therapy is an emerging cancer treatment strategy. Thus far, demonstration of clinical activity has been limited to a subset of solid tumors including melanoma, synovial cell sarcoma and HPV-associated cancer. It is estimated that metastatic epithelial cancers are responsible for approximately 90% of cancer deaths in the United States. The estimated 600,000 cancer deaths each year is driven largely by lung adeno- and squamous cell carcinoma and invasive breast cancer, which account for approximately 30% of all cancer-related deaths. Kita-Kyushu Lung Cancer Antigen 1 (KK-LC-1) is a cancer germline antigen with expression restricted to germ cells in adults and certain epithelial cancers including lung, breast, gastric and cervical. We identified a KK-LC-1 TCR from the tumor-infiltrating lymphocytes (TIL) of a patient with cervical cancer who had a complete tumor response to TIL therapy. The KK-LC-1 TCR was the most dominate clonotype in the infused TIL product and persisted in the peripheral blood following infusion, suggesting that it may have contributed to cancer regression in this patient. Methods: We are conducting a phase I cell dose escalation trial to test the safety and efficacy of KK-LC-1 TCR-T cell therapy in patients with metastatic KK-LC-1 positive epithelial cancer. Patients receive a lymphocyte depleting conditioning regimen followed by a one-time infusion of genetically engineered T cells expressing the KK-LC-1 TCR (KK-LC-1 TCR-T cells) and high-dose systemic aldesleukin. KK-LC-1 positivity is determined by RNAscope assay measuring the percentage of cancer cells expressing CT83 (gene encoding KK-LC-1) with a percentage of 25 or greater considered positive. Main inclusion criteria include HLA-A*01:01 allele, prior first-line therapy, ECOG of 0 or 1 and adequate organ and hematologic function. Main exclusion criteria include active major medical illness of the cardiovascular, respiratory or immune system, primary or secondary immunodeficiency and autoimmune disease. Participants will be entered in sequential dose levels and receive escalating doses of cells beginning at 1x108 and ending with 6x1010. Dose-limiting toxicities will be assessed during the first 30 days of cell infusion. The primary objective is to determine the maximally tolerated dose of KK-LC-1 TCR-T cells. Exploratory objectives include assessing the safety and efficacy of KK-LC-1 TCR-T cells and to conduct immunologic studies to understand and improve the administered treatment. Clinical trial information: NCT05035407.
A phase 1/2 study of RTX-224, an engineered red blood cell expressing 4-1BB ligand and membrane-bound IL-12, for the treatment of patients with select advanced solid tumors.
Authors: Spira Alexander I. , Johnson Melissa Lynne , Ren Ai , Sundaresan Varsha , Verdon Ines , Turka Laurence , Elloul Sivan
Published: June 2022

TPS2680

Background: RTX-224 is a genetically engineered off-the-shelf, allogeneic red blood cell that expresses the costimulatory molecule 4-1BB ligand (4-1BBL) and cytokine interleukin-12 (IL-12) on the cell surface. The use of 4-1BB and IL-12 agonists for cancer immunotherapy has been limited due to systemic toxicities. Unlike agonist antibodies and recombinant cytokines, which are distributed systemically, Red Cell Therapeutics, such as RTX-224, are restricted to the vasculature and spleen, which may limit toxicities previously observed with agonist 4-1BB monoclonal antibodies and recombinant IL-12. RTX-224 is designed to be a broad immune agonist of both adaptive and innate responses that activates and expands effector and memory CD8+ and CD4+ T cells, cytotoxic natural killer (NK) cells and produces inflammatory cytokines and chemokines, leading to enhanced antigen presentation. In preclinical studies, the combined activation of both adaptive and innate immune responses by the murine surrogate of RTX-224 led to antitumor activity while the restricted biodistribution improved the safety profile. Methods: The RTX-224-01 study is a Phase 1/2, first-in-human, multi-center, dose-escalation and expansion study of RTX-224 in patients with relapsed or refractory urothelial cancer, squamous cell carcinoma of the head and neck, non-small cell lung cancer, triple negative breast cancer and cutaneous melanoma. Safety, tolerability, pharmacokinetics and pharmacodynamics and anti-tumor activity of RTX-224 will be assessed. Approximately 28 patients will be enrolled across dose level cohorts to identify the recommended Phase 2 dose (RP2D). The starting dose is 100 million (1x108) cells administered intravenously every 3 weeks (Q3W) and the dose will be escalated by half-log increments following a Bayesian logarithmic regression model (BLRM) with overdose control. Following RP2D selection, each of the 5 expansion cohorts will enroll approximately 20 patients. Pharmacodynamic and exploratory biomarker studies correlative to clinical response will be evaluated on peripheral blood and paired tumor biopsies. Multiple technologies will be employed to profile the innate and adaptive responses following RTX-224 treatment. The study is open and enrolling patients in Phase 1. Clinical trial information: NCT05219578.
A multicenter, open-label, phase 1a/b study of HC-7366, a modulator of integrated stress response (ISR) kinase GCN2 in subjects with advanced solid tumors.
Authors: Pelster Meredith , Torre Marcio , Kannan Geoffrey Sumithran , Gargano Michele Anne , Mattson Paulette , Rathmann Blaine , Bose Nandita , Iglesias Jose Luis
Published: June 2022

TPS3179

Background: To survive harsh tumor microenvironments, cancer cells actively utilize ISR as an adaptive stress response and survival mechanism. General control nonderepressible 2 (GCN2), a serine-threonine kinase is essential for maintaining cellular homeostasis in amino acid stress conditions. HC-7366 is a novel, highly selective, and potent GCN2 kinase modulator. Single agent HC-7366 has demonstrated potent anti-tumor activity resulting in regression and complete responses in several pre-clinical tumor models. Methods: This is a first in human, multicenter, open label, Phase 1a/b dose escalation and expansion study to establish the maximum tolerated dose, evaluate safety and tolerability, and determine the recommended Phase 2 dose of daily oral dosing of HC-7366 in patients (pts) with advanced solid tumors. Up to 36 pts with squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or transitional cell carcinoma of the bladder (TCC) will be enrolled into Phase 1a; other solid tumors are eligible if selection criteria are met (capped at 50%). A 3+3 design will be employed and dose escalation determined by occurrence of dose limiting toxicities (DLT) within Cycle 1 (21 days). A Safety Monitoring Committee will review each cohort when the planned number of pts complete the DLT period. Six dose levels (10, 20, 40, 75, 125, 150 mg) of HC-7366 will be evaluated. Phase 1b will be an expansion of up to two Phase 1a dose levels and enroll 15 pts per cohort. Secondary endpoints include ORR, DOR, TTF, PFS, and OS. Pharmacokinetic data will be profiled. Exploratory objectives include evaluation of pharmacodynamic markers in tumor biopsies and immunophenotyping in blood samples. Main inclusion criteria include: SCCHN, CRC, NSCLC, TCC or other solid tumors; >1 radiologically measurable lesion per RECISTv1.1; >1 biopsiable lesion at baseline; no immune checkpoint inhibitor within 4 weeks (wks) of 1st dose; ECOG 0 or 1; <10% body weight loss in 4 wks before 1st dose & serum albumin >3 g/dL; and normal/adequately controlled pan-endocrine function. Main exclusion criteria include: autoimmune disease, organ transplant, retinitis or photosensitive skin disorders; history of interstitial lung disease or pneumonitis within 1yr; and overt or latent disorders of the exocrine pancreas. Formal hypothesis testing will not be performed. Descriptive statistics of parameters of interest will be presented by dose level and safety parameters will be summarized. The trial is sponsored by HiberCell, Inc. Approximately 9 US sites will participate. Clinical trial information: NCT05121948.
Trial in progress: Phase 1b/3 study of bemarituzumab + mFOLFOX6 + nivolumab versus mFOLFOX6 + nivolumab in previously untreated advanced gastric and gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-102).
Authors: Wainberg Zev A. , Van Cutsem Eric , Moehler Markus H. , Kang Yoon-Koo , Yen Priscilla , Finger Elizabeth , Keegan Alissa , Shitara Kohei
Published: June 2022

TPS4165

Background: Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in approximately 30% of non-human epidermal growth factor receptor 2 (non-HER2) positive gastric cancer (Wainberg, 2021). Bemarituzumab is a first-in-class monoclonal antibody that specifically blocks FGFR2b, inhibiting downstream tumor proliferation and enhancing antibody dependent cellular cytotoxicity (Catenacci, 2020; Xiang, 2021). In the phase 2 FIGHT study (Wainberg, 2021; Catenacci, 2021), progression-free survival (PFS) was improved (HR, 0.68; 95% CI, 0.44-1.04; p = 0.07) and a 5.7 month longer median overall survival (OS) was observed (19.2 months vs 13.5 months; HR, 0.60; 95% CI, 0.38-0.94) with bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6. Preclinical studies indicate that bemarituzumab modulates the tumor microenvironment to sensitize tumors to anti-PD1 monoclonal antibodies (Powers, 2016; Xiang, 2021) providing rationale for combination with nivolumab. Methods: FORTITUDE-102 (NCT05111626) is a phase 1b/3 study in patients (pts) with unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Part 1 is an open-label safety lead-in; Part 2 is a double-blind, placebo-controlled study to evaluate efficacy and safety. Approximately 702 pts ≥18 years will be enrolled (Part 1, ̃20; Part 2, ̃682). Key eligibility criteria include Eastern Cooperative Oncology Group performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and organ function, and no contraindication to receive mFOLFOX6 chemotherapy or nivolumab; for part 2, IHC-confirmed FGFR2b overexpression by central testing is required and no prior treatment for metastatic or unresectable disease allowed except 1 dose of mFOLFOX6 ± nivolumab. Key exclusion criteria include positive HER2 status and untreated or symptomatic CNS metastasis and leptomeningeal disease. Pts on bemarituzumab will receive 15 mg/kg every 2 weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8. mFOLFOX6 + nivolumab will be at a fixed dose Q2W. The dose-limiting toxicity (DLT) period is 28 days; observed safety data will influence additional enrollment to Part 1, de-escalation of bemarituzumab, or the recommended phase 3 dose (RP3D). For Part 1, primary endpoints are DLTs and adverse events; secondary endpoints include OS, PFS, and objective response (OR). For Part 2, pts will be randomized 1:1 to mFOLFOX6 + nivolumab Q2W plus either bemarituzumab at RP3D or placebo. Primary endpoint for Part 2 is OS; secondary endpoints include PFS, OR, and safety. The concurrent phase 3 FORTITUDE-101 study (NCT05052801) will evaluate bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6. Clinical trial information: NCT05111626.
PROOF 301: A multicenter, open-label, randomized, phase 3 trial of infigratinib versus gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma with an FGFR2 gene fusion/rearrangement.
Authors: Abou-Alfa Ghassan K. , Borbath Ivan , Goyal Lipika , Lamarca Angela , Macarulla Teresa , Oh Do-Youn , Roychowdhury Sameek , Sadeghi Saeed , Shroff Rachna T. , Li Ai , Soto Jose , Avogadri Francesca , Dambkowski Carl L. , Javle Milind M.
Published: June 2022

TPS4171

Background: First-line treatment options are limited for patients with advanced cholangiocarcinoma (CCA). Genetic alterations in the fibroblast growth factor receptor ( FGFR) gene play an important role in CCA. FGFR gene fusions/rearrangements are present in 10–16% of intrahepatic CCA and may predict tumor sensitivity to FGFR inhibitors. Infigratinib (BGJ398) is a potent, orally bioavailable, selective, ATP-competitive, small-molecule tyrosine kinase inhibitor of FGFRs that showed promising clinical activity and a manageable adverse event profile in a phase 2 study in patients with previously treated, unresectable locally advanced/metastatic CCA with an FGFR2 gene fusion/rearrangement. The multicenter, open-label, randomized, controlled phase 3 PROOF 301 trial is evaluating infigratinib vs standard-of-care gemcitabine + cisplatin as first-line treatment for patients with advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/rearrangement. Methods: Approximately 300 patients ≥18 years of age with histologically or cytologically confirmed, advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/rearrangement (confirmed by central laboratory) are randomized 2:1 to oral infigratinib 125 mg once daily for the first 21 days of a 28-day treatment cycle vs intravenous standard gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. Randomization will be stratified by unresectable locally advanced vs metastatic disease, geographic region, prior neoadjuvant/adjuvant treatment vs none, and receipt of up to 1 cycle of gemcitabine-based chemotherapy for unresectable locally advanced/metastatic disease prior to randomization vs none. Treatment will continue until confirmed progressive disease by blinded independent central review (BICR), intolerance, withdrawal of informed consent, or death. Patients on the gemcitabine + cisplatin arm who develop disease progression, confirmed by BICR, can cross-over to receive infigratinib. The primary endpoint is progression-free survival (PFS, RECIST v1.1), confirmed by BICR. Secondary endpoints include overall survival, PFS (investigator determined), overall response rate, best overall response, disease control rate, duration of response (BICR and investigator determined), and the type, frequency, and severity of adverse events (AEs) and serious AEs. PFS after subsequent therapy (PFS2), quality of life, pharmacokinetics and other exploratory genetic alterations/biomarkers will also be evaluated. Trial enrollment is ongoing in the US, EU, and APAC (including Australia). The Data Monitoring Committee last reviewed the trial in December 2021. Clinical trial information: NCT03773302.
A phase I trial to evaluate the biologic effect of CBM588 (Clostridium butyricum) in combination with cabozantinib plus nivolumab for patients with metastatic renal cell carcinoma (mRCC).
Authors: Meza Luis A , Malhotra Jasnoor , Zengin Zeynep Busra , Dizman Nazli , Hsu Joann , Chawla Neal Shiv , Chehrazi-Raffle Alex , Muddasani Ramya , Govindarajan Ameish , Castro Daniela V. , Dorff Tanya B. , Lyou Yung , Frankel Paul Henry , Pal Sumanta K.
Published: June 2022

TPS4606

Background: Combination therapy with the immune checkpoint inhibitor (ICI) nivolumab (nivo) and the tyrosine kinase inhibitor cabozantinib (cabo) is a new standard of care for first line treatment of patients with clear cell mRCC. However, despite the improved clinical benefit obtained with this regimen, a subgroup of patients still presents with progressive disease as best response (Choueiri et al NEJM 2021). There is now evidence supporting the role of the gut microbiome in mediating ICI activity (Routy et al Science 2018) and certain bacterial species, such as Bifidobacterium spp. in predisposing clinical response in patients with mRCC receiving ICIs (Salgia et al Eur Urol 2020). Moreover, recent evidence from a phase I clinical trial suggests that the addition of CBM588, a live probiotic comprised primarily of Clostridium butyricum, can enhance clinical response in patients with mRCC receiving nivolumab plus ipilimumab without incurring added toxicity (Meza et al ASCO, 2021). Herein we present the study design of an ongoing phase I study evaluating the biological effect of CBM588 in combination with cabozantinib plus nivolumab in patients with mRCC. Methods: This is an open label, randomized, single institution phase 1 trial for patients with confirmed mRCC with clear cell, papillary, or sarcomatoid components, who have not received prior systemic therapy for metastatic disease. A total of 30 eligible patient will be randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg PO QD and 480mg IV /4wks, respectively) alone or with CBM588 dosed at 80mg PO bid. The primary objective of the study is to determine the biologic effect of CBM588 with cabo/nivo in the modulation of the gut microbiome. This will be done by assessing the changes in Bifidobacterium spp. abundance and Shannon index (a measure of microbiome diversity) in stool specimens. Stool will be collected for bacteriomic profiling at baseline and after 12 weeks of treatment. Metagenomic sequencing will be performed using previously published methods (Dizman et al Cancer Med 2020). Secondary objectives include determining the effect of CBM588 on (1) clinical efficacy, through overall survival, response rate, and progression-free survival; (2) systemic immunomodulation, through assessment of changes in circulating Tregs, circulating cytokines/chemokines, etc; and (3) toxicities. A two-group t-test with a one-sided type I error of 0.05 will be used to assess the study primary endpoint. Clinical trial information: NCT05122546 .
ANTICIPATE: A phase I/II, open-label, multicenter study to evaluate the safety and efficacy of oral APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy (NAC) in patients with muscle invasive bladder cancer (MIBC).
Authors: Galsky Matt D. , Sfakianos John P. , Ye Ding-Wei , Zhang Mingming
Published: June 2022

TPS4613

Background: Standard treatment for muscle invasive bladder cancer (MIBC) is radical cystectomy (RC) and administration of NAC in patients who are eligible to receive cisplatin. Approximately 50% of patients are ineligible to receive cisplatin as a result of pre-existing contraindications, and some refuse to receive any chemotherapy due to concerns of toxicities. Immune checkpoint inhibitors (ICIs) have been shown to be highly active in metastatic urothelial cancer. APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Synergistic effects of APL-1202 and ICIs have been shown in model systems of bladder cancer. It is hypothesized that APL-1202 in combination with tislelizumab, a humanized IgG4 anti-PD-1 MAb, may be an effective neoadjuvant therapy in MIBC. This trial will evaluate the safety, efficacy, and pharmacodynamic effects of APL-1202 in combination with tislelizumab as neoadjuvant therapy for patients with MIBC who are cisplatin ineligible or refuse cisplatin-based chemotherapy. Methods: ANTICIPATE is an open-label, multi-center clinical trial enrolling 79 patients in two phases: Phase Ⅰ and Phase Ⅱ. Phase I is a dose escalation study to determine MTD (maximum tolerated dose) and/or RP2D. Phase II is an expanded proof-of-concept study to evaluate the safety and efficacy of APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy for MIBC as measured by pathological complete response (pCR). Phase Ⅰ and Phase Ⅱ both are divided into 3 periods: screening period of 4 weeks, neoadjuvant therapy comprising 3 cycles (each 21 days) prior to radical cystectomy; and a follow-up period of up to 90 days after surgery. The phase Ⅰ will determine the RP2D of APL-1202 in combination with tislelizumab as neoadjuvant therapy for MIBC. Eligible patients have newly diagnosed MIBC and are cisplatin ineligible or refuse cisplatin-based NAC and are planned for RC. In phase Ⅰ, a standard 3+3 dose-escalation design will be used. On day 1 of each cycle, a single dose of 200 mg tislelizumab will be administered intravenously. The daily dose APL-1202 will be escalated in successive cohorts (375 mg à 750 mg à 1,125 mg). The DLT observation window for any dose level will be treatment cycle 1. There will be no intra-patient dose escalation. In phase II patients will be randomly assigned to group 1 (APL-1202 + tislelizumab) or group 2 (tislelizumab only), stratified by PD-L1 expression. The IND has been approved by FDA and NMPA, and the study execution is under preparation both in US and China. Clinical trial information: NCT04813107.
A phase 2 study of cabozantinib in combination with atezolizumab as neoadjuvant treatment for muscle-invasive bladder cancer (HCRN GU18-343) ABATE study.
Authors: Kilari Deepak , Szabo Aniko , Tripathi Abhishek , Paul Asit K. , Alter Robert S. , Bylow Kathryn A. , Nelson Ariel Ann , Hall William A. , Langenstroer Peter , Jacobsohn Kenneth , Rini Brian I. , Van Veldhuizen Peter J. , Johnson Scott , Davis Nancy B. , Fung Chunkit , Milowsky Matthew I.
Published: June 2022

TPS4618

Background: ABACUS and PURE-01 trials demonstrated the activity of single agent atezolizumab and pembrolizumab respectively as neoadjuvant therapy for muscle invasive bladder carcinoma (MIBC). However, downstaging to non-muscle invasive disease was noted in only 50 percent of patients. Resistance to programmed death (PD)- 1/L1 antibodies is likely to include factors such as impaired dendritic cell maturation/function, infiltration of T-Regs and myeloid derived suppressor cells, impaired T-cell priming and T-cell trafficking in tumors. Cabozantinib is a tyrosine kinase inhibitor which targets MET, AXL, MER, Tyro3 and VEGFR2. Cabozantinib has a unique immunomodulatory profile and has demonstrated clinical activity as monotherapy and in combination with PD-1/L1 antibodies in various solid tumors including urothelial cancer (UC), renal cell, castrate- resistant prostate and non-small cell lung cancer. We hypothesize that the combination of cabozantinib and atezolizumab as neoadjuvant therapy for MIBC would improve rates of pathologic downstaging compared to single-agent checkpoint inhibitors. Methods: ABATE is an open-label, single arm, multi-center study to assess the efficacy and safety of cabozantinib with atezolizumab as neoadjuvant therapy for cT2-T4aN0/xM0 MIBC. An estimated 42 patients will be enrolled to obtain 38 evaluable patients, and the study will have over 80% power to declare the investigational combination to be successful using a Bayesian evaluation at 90% posterior probability cutoff, if the response probability is 59%, i.e., 20% higher than the 39% response rate with the single agent atezolizumab. Eligible patients will receive cabozantinib 40 mg PO daily with atezolizumab 1200mg every 3 weeks for a total duration of 9 weeks (3 cycles) followed by radical cystectomy. Adults (≥18 years) with resectable MIBC who are either cisplatin-ineligible or decline cisplatin-based chemotherapy are eligible. Patients are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 expression analysis. UC should be predominant component (≥ 50%). Previous systemic anticancer therapies for MIBC are not permitted. CT/MRI will be performed before investigational therapy and cystectomy. Primary endpoint is pathologic response rate defined as the absence of residual muscle-invasive cancer in the surgical specimen (< pT2). Secondary endpoints are safety and toxicity, pathologic complete response rate and event-free survival. Exploratory end points include patient-reported outcomes and outcome associations with biomarkers. Accrual began May 2020. Clinical trial information: NCT04289779.
CCTG BL13 a randomized phase II trial assessing trimodality therapy with or without adjuvant durvalumab to treat patients with muscle-invasive bladder cancer (NCT03768570).
Authors: Kassouf Wassim , Crabb Simon J. , Duran Ignacio , Brundage Michael Donald , Reaume M. Neil , Dragomir Alice , Wyatt Alexander William , Vera Badillo Francisco Emilio , Lukka Himu , Niazi Tamim , Souhami Luis , Sridhar Srikala S. , Griffiths Gareth Owen , Howell Doris , Richardson Harriet , Djurfeldt Marina , Ding Keyue , Parulekar Wendy R.
Published: June 2022

TPS4619

Background: Immunotherapy improves outcomes in the advanced (Bellmunt 2019; Powles 2020) as well as in the adjuvant setting post cystectomy (Bajorin 2021) for muscle invasive bladder cancer (MIBC) patients. Trimodality treatment (TMT) consisting of transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy (CRT) may be considered an alternative to radical cystectomy in MIBC. The role of radiotherapy and chemotherapy as immune system stimulants provides a rationale to evaluate the anticancer activity of checkpoint inhibitors in this patient population. Durvalumab, an anti PDL1 inhibitor, administered after CRT leads to improvement in PFS and OS in patients with locally advanced NSCLC, which further supports the rationale for this study (Antonia 2017, 2018). We hypothesized that durvalumab will improve outcomes in patients with MIBC when administered in the adjuvant setting after completion of trimodality therapy. Methods: CCTG BL13 is a Canadian Cancer Trials Group, randomized phase II trial in patients with stage T2-T4a N0M0, urothelial carcinoma treated with TURBT followed by radiotherapy with concurrent chemotherapy. Treatment arms consist of durvalumab 1500 mg IV q 4 weeks for 12 months versus surveillance. The primary objective: to compare disease free survival (DFS) between arms (RECIST 1.1, investigator assessed). Secondary endpoints include a non muscle-invasive bladder cancer recurrence rate (< T2); locoregional control rate; overall survival; bladder intact DFS, patterns of disease recurrence; metastasis free survival; safety; quality of life ; economics evaluation. A pilot sub study (BL13F) has been activated and will evaluate the feasibility of electronic real-time patient self-reporting of immunotherapy related symptomatic adverse events using the SYMPTOM-IQ Tool on the uMotif Mobile Health Application (APP). Statistical Design: Randomization 1:1 balanced for stratification factors: ECOG PS; neoadjuvant chemotherapy; radiation field extent; T2 vs T3/T4; centre. Assuming a 2-year DFS rate 65% for patients on the control arm and estimated 12% improvement in the 2-year DFS rate (65% to 77% (HR 0.61)) with 80% power using a 1-sided 10% level test requires a sample size of 190 including 5% drop out rate. Conduct to Date: Study activation Dec 2018. Enrollment as of January 31 2022: 49. The DSMC reviewed and recommended trial continuation in November 2021. Clinical trial information: NCT03768570.
TALAPRO-3: A phase 3, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) versus placebo plus ENZA in patients with DDR gene–mutated, metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Agarwal Neeraj , Saad Fred , Azad Arun , Mateo Joaquin , Matsubara Nobuaki , Shore Neal D. , Chakrabarti Jayeta , Chen Hsiang-Chun , Lanzalone Silvana , Niyazov Alexander , Fizazi Karim
Published: June 2022

TPS5096

Background: TALA is a poly(ADP-ribose) polymerase inhibitor (PARPi) approved as monotherapy for germline BRCA1/2-mutated HER2-negative advanced breast cancer. Clinical efficacy in metastatic castration-resistant prostate cancers (mCRPC) with alterations in DNA damage response (DDR) genes involved directly or indirectly in homologous recombination repair (HRR) has been demonstrated with some PARPi. Phase 3 study findings (de Bono et al. N Engl J Med, 2020;382:2091-2102) resulted in the approval of olaparib for mCRPC. ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. Since PARP activity has been shown to support AR function, PARP inhibition may increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “ BRCAness” phenotype. A Phase 2 study of TALA monotherapy (TALAPRO-1) demonstrated robust antitumor activity in men with heavily pretreated, HRR-mutated mCRPC. The Phase 3, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA vs placebo plus ENZA in men with mCSPC with DDR/HRR alterations. Methods: Approximately 550 patients with mCSPC harboring DDR/HRR alterations will be randomized to TALA (0.5 mg once daily) plus ENZA (160 mg once daily) or placebo (once daily) plus ENZA (160 mg once daily). Patients will be stratified according to de novo mCSPC vs relapsed mCSPC, high-volume disease vs low-volume disease, where high-volume disease is defined as the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis and BRCA vs non-BRCA mutational status. Key eligibility criteria include age ≥18 years; histological diagnosis of prostate cancer; alterations in at least one of 12 DDR/HRR genes known to sensitize patients to PARPi ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is rPFS (time to radiographic progression in soft tissue per RECIST 1.1 or in bone per PCWG3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Patient recruitment is planned at approximately 285 sites in 27 countries, including the US and Europe, South America, South Africa, and Asia-Pacific. This study was approved by an Institutional Review Board. Clinical trial information: NCT04821622.
177Lu-DOTA-TLX591 safety, biodistribution and dosimetry study (ProstACT-SELECT).
Authors: Antonini Paola , Meyrick Danielle , Hayward Colin
Published: June 2022

TPS5109

Background: The cell surface glycoprotein prostate-specific membrane antigen (PSMA) has proven to be an ideal therapeutic target in prostate cancer (PC) as it is highly expressed by malignant prostate cells.1,2 177Lu-DOTA-HuJ591-CHO (TLX591) is a radioimmunoconjugate comprised of the humanized IgG1 mAb rosopatamab, linked to the low energy beta-emitting radioisotope lutetium-177 (177Lu) via the bifunctional chelating agent DOTA-NHS ester. Chinese Hamster Ovary (CHO) cell line has been selected for the manufacture of the recombinant mAb. There is a strong rationale for investigation of TLX591 as a potential radioligand therapy for the treatment of PC, supported by previous clinical evidence of the safety of the antibody, as unconjugated and as a DOTA conjugate, and of the specificity of the antibody for PC tumors. 3,4,5,6. This multicenter Phase 1 radiomics study (ClinicalTrials.gov Identifier: NCT04786847) is designed to evaluate the safety, tolerability, biodistribution and dosimetry of TLX591 administered with best SoC to patients with PSMA-expressing, metastatic castration-resistant prostate cancer (mCRPC) progressing despite prior treatment with a novel androgen axis drug (NAAD). At the time of this abstract the study has commenced recruitment in Australia. This trial is sponsored by Telix Pharmaceuticals. Methods: The study will consist of 2 cohorts: Cohort 1: Five patients will be recruited for evaluation of biodistribution of TLX591 administered in combination with SoC. These patients will receive a single tracer (27 mCi) intravenous (IV) infusion of TLX591, and SPECT images and pharmacokinetic blood samples acquired at several time points until Day 13. A qualitative comparison of biodistribution of tracer level TLX591, as demonstrated by SPECT, with 68Ga-PSMA-11 on PET imaging will be performed to ensure equivalent (or improved) radiopharmaceutical tumour targeting. Dosimetry analysis will also be performed. If safety is confirmed by independent DSMB review, each individual patient in Cohort 1 will proceed 14 days following the initial tracer dose to a second administration of TLX591. SoC therapy will continue according to standard practice. Cohort 2: All further enrolled patients will receive two administrations of 76 mCi TLX591 for further evaluation of safety, tolerability and biodistribution, and efficacy in combination with SoC. 1. Pan M-H et al. 2009 2. Dorff TB et al., 2019 3. Tagawa, Milowsky et al., 2013 4. Tagawa et al., 2019 5. Tagawa, Whang et al., 2014 6. Niaz et al., 2020. Clinical trial information: NCT04786847.