bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of albumin and neutrophil-to-lymphocyte ratio with hormone-mediated depression in prostate cancer.
Authors: Kato Martha M. , Martinez Constanza , Currier Maria
Published: June 2023

e24214

Background: Androgen deprivation therapy (ADT) increases the risk of developing depression which can affect quality of life and adherence to treatment. Depression has been associated to inflammation in patients with cancer. Albumin and neutrophil-to-lymphocyte ratio (NLR) are inflammatory biomarkers that to our knowledge have not been evaluated in hormone mediated depression in prostate cancer (PC). The aim of this study is to evaluate the severity of hormone related depression and its association with inflammatory biomarkers, demographics, and cancer treatment variables and to determine antidepressant treatment response. Methods: A retrospective chart review of consecutive referrals to psycho-oncology of PC patients on ADT with new onset depression was conducted. Demographics, cancer and psychiatric history, and laboratories within 1 week of initial visit were collected. Assessments for depression included clinical interview and patient-rated scale [Beck Depression Inventory (BDI)]. These measures were done at baseline (before starting an antidepressant) and follow-up to determine treatment response. Successful antidepressant treatment response is defined as ≥50% reduction in baseline BDI score. Statistical analysis comparing the association of clinical variables between depression, inflammatory biomarkers, and demographics included Pearson’s correlation, chi-square, ANOVA, t-test, and binary logistic regression was used to determine associations with depression. Data was dichotomized using median split for inflammatory biomarkers due to skewness. Results: A sample of 26 PC patients on leuprolide (mean age 70 years; 13 Hispanic, 13 non-Hispanic) included 13 with mild depression (BDI£20) and 13 with moderate- to-severe depression (BDI>20). Moderate-to-severe depression was associated with higher NLR (≥3, p= .041), stage IV PC (n=15, p= .001), and Hispanics ( p= .033). Lower albumin (£3.9) was associated with higher age ( p= .007), higher NLR ( p= .006), and non-Hispanics ( p= .049) but not depression. Over 54% (13/24) of patients did not respond to antidepressant treatment. In logistic regression only NLR and Stage IV PC remained significantly associated with depression after adjusting for confounding variables. Conclusions: NLR and stage IV PC were both associated with moderate-to-severe depression. These results are likely due to increased level of inflammation in advanced cancer. Inflammation has been associated with treatment resistant depression which could explain why 54% of patients did not respond to antidepressant treatment. NLR is an inexpensive routinely used test in cancer centers that has the potential to be used as a biomarker of severity of depression in PC patients.
Phase 1b/2 study of abemaciclib combined with chemoimmunotherapy in pediatric and young adult patients with relapsed/refractory neuroblastoma (JPCS Part C).
Authors: Greengard Emily Gustava , Bear Melissa , DeNardo Bradley , Federman Noah , Krystal Julie , Saulnier Sholler Giselle Linda , Zhou Yanhong , Knoderer Holly , Nabinger Sarah C , Hoffman Lindsey M.
Published: June 2023

TPS10068

Background: Survival for high-risk neuroblastoma (NBL) remains poor with over 50% of patients experiencing disease relapse. The addition of dinutuximab (DIN) and granulocyte macrophage colony-stimulating factor (GM-CSF) to irinotecan (IRN) and temozolomide (TMZ) in patients with first relapse achieved an overall response rate of 42% in the study ANBL12211 and is now standard of care. However, there remains a significant unmet need to improve outcomes for children with relapsed/refractory NBL. Deregulation of the Cyclin D/cyclin-dependent kinase (CDK) 4 & 6 pathway has been observed in NBL, rendering CDK4 & 6 inhibition logical to explore. Abemaciclib is an orally administered, selective CDK4 & 6 inhibitor approved to treat breast cancer. JPCS (NCT04238819) is designed to assess the pharmacokinetics, safety, and tolerability of abemaciclib added to standard treatment regimens for relapsed/refractory pediatric solid tumors. Part A defined the recommended phase 2 dose (RP2D) of abemaciclib in combination with IRN and TMZ. In Part C, the addition of DIN + GM-CSF to the JPCS Part A regimen will be evaluated. The co-primary objectives of Part C are to determine the RP2D and to estimate the anti-tumor activity of abemaciclib added to the ANBL1221 chemoimmunotherapy backbone in patients with first relapse/refractory NBL. Methods: JPCS Part C is a two-stage, non-randomized, open-label, Phase 1b/2 study for patients < 21 years of age with first relapse/refractory NBL. Stage 1 aims to identify the maximum tolerated dose (MTD) of abemaciclib at a starting dose of 55 mg/m2 combined with DIN, GM-CSF, IRN and TMZ using a 3+3 design. One dose de-escalation (30 mg/m2) will be possible if the starting dose is not tolerated. Further tolerability and initial anti-tumor activity will be evaluated in an expansion cohort at the MTD. Up to 11 evaluable patients will enroll in Stage 1 at the MTD; the MTD will be declared the RP2D if adequate safety and tolerability are observed and ≥6 patients achieve minimal response or better per International Neuroblastoma Response Criteria (INRC). Following determination of the RP2D, Stage 2 will enroll 35 patients. If ≥26 of 46 total patients achieve an INRC minimum response or better, further investigation of this regimen could be warranted. As of 31 Jan 2023, Part C is open for enrollment at one site (US) and additional sites are being evaluated. References: Mody et al. J Clin Oncol. 2020;38(19):2160-2169. Clinical trial information: NCT04238819 .
A pilot clinical study of oral irinotecan HCl (VAL-413) in patients with recurrent pediatric solid tumors.
Authors: Bacha Jeffrey A. , Brown Dennis , Geller James I. , Oesterheld Javier E. , McManus Meghann , Kanekal Sarath , Leggas Markos , Lopez Lorena , Sankar Neil , Yam Noymi , Wagner Lars M.
Published: June 2023

TPS10073

Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer and also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days, bi-weekly in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of IRN-IV is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed and implemented with favorable tumor response (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the IRN-IV is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. This pilot trial will examine the safety and tolerability of this novel formulation and assess pharmacokinetics compared to current oral regimen. Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day will be studied in combination with fixed-dose temozolomide using a standard 3 + 3 phase I design. In the event the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures:Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intra-patient pharmacokinetics of irinotecan and its metabolites will be assessed. This trial is ongoing (CT.gov: NCT04337177), with no DLT observed to date. Clinical trial information: NCT04337177 .
Connecting Black families in Houston, Texas, to hereditary cancer genetic counseling, genetic testing, and cascade testing by using a simple cancer genetic risk assessment and telegenetics.
Authors: Kizub Darya Aleksandrovna , Shanker Sreejesh , Green Sierra , Vara Autumn , Arun Banu
Published: June 2023

TPS10638

Background: Hereditary breast and colorectal cancers accounts for 5-10% of all cases, but less than half of all eligible patients undergo NCCN guideline-concordant screening. This proportion is even lower among Black patients, who have a higher breast cancer and colorectal incidence and mortality. Recruitment through community organizations has been shown to identify patients who are eligible for genetic testing but have not been offered it by their doctor. Our one-page cancer genetic risk assessment (CGRA) and telegenetics were previously shown to improve adherence to genetic testing guidelines for hereditary breast and ovarian cancer. Our objective is to identify adults eligible for hereditary breast and colorectal cancer syndromes genetic testing using trusted community organizations that serve the Black community as entry points, reach them with our tailored program, and measure impact. Methods: In this prospective single-arm trial, adults of > 18 years old who self-identify as Black or African American are recruited during events put together by community organizations in Houston, Texas. The CGRA was modified to encompass hereditary breast and colorectal cancer syndromes based on NCCN guidelines. To improve convenience, eligible participants can be consented and fill out the CGRA in-person or via QR code link using a smart phone. Study team members attend community events and are also available via phone to help with informed consent, CGRA, etc. Those at high risk for hereditary breast and colorectal cancer syndromes are provided with educational materials and can be sent the saliva-based kit or complete it on-site. When results of genetic testing include a pathogenic mutation (PV) or variant of uncertain significance, individuals receive telegenetic counseling and risk reduction resources, including about cascade genetic testing. Others are notified of negative results. The program includes education for interested community organization members about importance of genetic testing. The program is projected to reach 1,000 participants with 300 completing genetic testing and identification of 11 PV. The study is overseen by a Community Advisory Board. Impact will be evaluated via a multiple methods design using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) Qualitative Evaluation for Systematic Translation (QuEST) framework six months after program start. Quantitative data will be analyzed using descriptive statistics and standard tests of association. Data collected via semi-structured interviews with participants and program implementers will be audio-recorded, transcribed, double-coded, and analyzed via thematic analysis. Enrollment started December of 2022. 15 participants patients enrolled during two community events. Clinical trial information: NCT05694559 .
HER2CLIMB-05: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer.
Authors: Hamilton Erika P. , Martin Miguel , O'Sullivan Ciara Catherine , Curigliano Giuseppe , Sohn Joohyuk , Tsurutani Junji , Tryfonidis Konstantinos , Santarpia Libero , Yang Shan , Diéras Véronique
Published: June 2023

TPS1115

Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T + P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T + P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T + P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), PFS by Blinded Independent Central Review (BICR), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, Canada, Brazil, APAC and EU countries with additional sites planned. Clinical trial information: NCT05132582 .
A phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/ HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor (VIKTORIA-1).
Authors: Hurvitz Sara A. , Andre Fabrice , Cristofanilli Massimo , Curigliano Giuseppe , Giordano Antonio , Han Hyo S. , Martin Miguel , Pistilli Barbara , Rugo Hope S. , Wesolowski Robert , Suzuki Samuel , Mutka Sarah , Gorbatchevsky Igor , Loibl Sibylle
Published: June 2023

TPS1118

Background: Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (palbo) and fulvestrant (FUL). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1 (NCT05501886). Methods: This Phase 3 multinational clinical trial will evaluate geda and FULwith or without palboin patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, palbo, and FUL), Arm B (geda and FUL), or Arm C (FUL). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, palbo, and FUL), Arm E (alpelisib and FUL), or Arm F (geda and FUL). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, Akt, or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival, safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. The trial is open for enrollment. Clinical trial information: NCT05501886 .
AIPAC-003: A randomized, double-blind, placebo-controlled phase 3 trial testing eftilagimod alpha (soluble LAG-3) in patients with HER2-neg/low metastatic breast cancer receiving paclitaxel, following an open-label dose optimization.
Authors: Ibrahim Nuhad K. , Papadamitriou Konstantinos , Duhoux Francois P. , Morales Murillo Serafin , Oliveira Mafalda , Doger de Spéville Bernard , Houtsma Danny , Beeker Aart , Peguero Julio Antonio , Marathe Omkar , Triebel Frederic
Published: June 2023

TPS1120

Background: Eftilagimod alpha (efti), a soluble LAG-3 protein, acts as an MHC class II agonist that enhances immunity by mediating antigen presenting cell and CD8 T-cell activation. Data from a randomized, phase 2b trial of efti plus paclitaxel compared to placebo plus paclitaxel in patients (pts) with HR+ HER2– metastatic breast cancer (MBC) (AIPAC; NCT02614833) showed sustained pharmacodynamic activity that was linked to improved overall survival (OS) in the efti arm. AIPAC-003 is a randomized, double-blind, placebo-controlled phase 3 trial testing efti plus paclitaxel in HER2-neg/low MBC pts, including an initial open-label dose optimization lead-in (DOL) component to determine the optimal biological dose (OBD) of efti in this combination. Methods: Enrolment for the DOL will begin in March 2023 in max. 66 pts. Primary endpoints (EP) in the DOL include safety and tolerability of 90 mg vs 30 mg efti and defining the OBD of efti in combination with weekly paclitaxel. Determination of the OBD will be based on the totality of safety and tolerability data together with overall response rate (ORR) and pharmacodynamic marker (CD8+ T cells, absolute lymphocyte count) data. In the Phase 3 component approx. 771 pts are randomized to receive either paclitaxel + efti or paclitaxel + placebo in a double-blinded fashion. The primary EP for the proposed Phase 3 is OS. Key secondary EPs include progression free survival and ORR by RECIST 1.1, quality of life and safety. Pts will receive paclitaxel (80 mg/m2 I.V. on D1, 8 and 15 in a 4-week cycle), followed by efti or placebo (DOL: 30 or 90 mg efti; Phase 3: OBD of efti or placebo) S.C. on D1 and 15 in a 4-week cycle for up to 12 months. Key inclusion criteria: Pts with either a) HR+ and HER2-neg/low and endocrine therapy-resistant MBC or b) TNBC not eligible for anti-PD-1-based therapy. Pts must have measurable disease, ECOG PS 0-1 and no prior chemo for metastatic disease.
TACTIVE-U: Phase 1b/2 umbrella study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer.
Authors: Layman Rachel M. , Jerzak Katarzyna Joanna , Hilton John Frederick , Clifton Katherine , Alkuzweny Baha , Mo Gary , Valota Olga , Perkins Smith Julia , Anderson Sibyl , Ma Cynthia X.
Published: June 2023

TPS1121

Background: ARV-471, an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in a phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. The CDK4/6 inhibitors abemaciclib and ribociclib are approved in combination with endocrine therapy as first- and second-line treatment for ER+/HER2- advanced or metastatic breast cancer; abemaciclib is also approved as monotherapy and in combination with other agents in additional breast cancer settings. ARV-471 combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Here we describe the first sub-studies of the open-label, phase 1b/2 TACTIVE-U umbrella study, which evaluate the safety and clinical activity of ARV-471 plus abemaciclib (sub-study A; NCT05548127) and ribociclib (sub-study B; NCT05573555) in patients with ER+/HER2- advanced or metastatic breast cancer. Future combination sub-studies will be included in TACTIVE-U. Methods: Patients eligible for sub-studies A and B are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection with ≥1 measurable lesion by RECIST 1.1, and have received ≤2 lines of prior therapy for advanced or metastatic disease and 1 line of any CDK4/6 inhibitor–based regimen in any setting. In sub-studies A and B, patients will receive ARV-471 orally once daily (QD) continuously in a dose escalation/de-escalation approach. In sub-study A, abemaciclib will be given orally twice daily continuously, and in sub-study B, ribociclib will be given orally QD for 21 days followed by 7 days off treatment. For both sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of ARV-471 in combination with abemaciclib or ribociclib. Secondary endpoints of phase 1b are antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), progression free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. Phase 2 further evaluates the antitumor activity of the combinations; the primary endpoint is ORR and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Clinical trial information: NCT05548127 , NCT05573555 .
Phase I/II study of stereotactic radiosurgery with concurrent olaparib followed by adjuvant durvalumab and physician’s choice systemic therapy in patients with breast cancer brain metastases.
Authors: Shen Colette , Abdou Yara , Chen Linda , Tan Xianming , Gupta Gaorav P. , Lynce Filipa , Lobbous Mina , Stringer-Reasor Erica Michelle , Anders Carey K.
Published: June 2023

TPS1133

Background: Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Current standard of care consists of local therapies, including surgery and radiotherapy, followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other breast cancer subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites via potentiation of the immune response. Methods: We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II) of this treatment combination. Secondary objectives include determining clinical activity via intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study (n=5) will evaluate olaparib concentration/distribution in resected brain metastases. As of January 2023, cohort 1 of phase I has been completed without dose-limiting toxicity. Clinical trial information: NCT04711824 .
A randomized, open-label, phase 2 study evaluating abemaciclib in combination with irinotecan and temozolomide in participants with relapsed or refractory Ewing sarcoma.
Authors: VAN HAL Gertjan , Rubio-San-Simón Alba , Ogawa Chitose , Juan-Ribelles Antonio , Knoderer Holly , Lewin Jeremy Howard
Published: June 2023

TPS11580

Background: Ewing’s sarcoma (ES) is the second most common malignant bone tumor affecting children and young adults. Patients with relapsed disease have a poor prognosis and need effective therapies. EWS-FLI1, the most common ES fusion gene (90-95% of cases), is an oncogenic transcription factor that downregulates intrinsic cyclin-dependent kinase (CDK) inhibitors, CDKN1A and CDKN1C, which promote cell cycle arrest and upregulates CDK4, which drives entry into the cell cycle. This provides a biological rationale for the clinical evaluation of CDK4/6 inhibitors in ES. Abemaciclib is a selective CDK4/6 inhibitor approved for the treatment of breast cancer. It is approximately 14 times more potent against CDK4/cyclin D1 than CDK6/cyclin D3 in enzymatic assays and has the advantage of continuous dosing schedule without breaks for neutrophil recovery. Abemaciclib is currently also in clinical development for paediatric patients with relapse/refractory solid tumors in combination with irinotecan and temozolomide (JPCS study, NCT04238819). This study, NCT05440786, will evaluate the potential benefit of adding abemaciclib to irinotecan plus temozolomide for the treatment of relapsed/refractory ES. Methods: This randomized, open-label, Phase 2 study is part of the CAMPFIRE master protocol. It is enrolling paediatric and young adult patients (1–39 years) with relapsed/refractory ES or ES-like tumors. Approximately 45 patients will be randomized 2:1 between 2 arms: irinotecan and temozolomide with or without abemaciclib. Stratification factors include age, pulmonary/non-pulmonary site of metastases, and time to recurrence from initial diagnosis. Patients will receive irinotecan (50 mg/m2/day intravenously) and temozolomide (100 mg/m2/day orally) on days 1-5. Abemaciclib will be administered orally twice-daily on a continuous 21-day cycle. The abemaciclib dose will be 55mg/m2 BID for patients < 18 years and 100mg BID for those ≥18 years. Besides 25 and 50mg tablets, abemaciclib will be available as 2.5mg granules allowing administration of doses as low as 10mg to patients with a body surface area lower than 0.2m2. Treatment continues until disease progression or other discontinuation criteria are met. The primary endpoint is progression-free survival (PFS) determined by a blinded independent review committee using Response Evaluation Criteria in Solid Tumors, Version 1.1. Key secondary endpoints include overall survival, objective response rate, duration of response, disease control rate, PFS determined by investigator assessment, safety, and pharmacokinetics. Additional analysis includes exploratory biomarker testing. This study is open and actively enrolling in Australia, Europe, Japan, and United States. Clinical trial information: NCT05440786 .
ENLIGHten-01: A phase 1 study of fluorescein-specific (FITC-E2)-CAR T cells in combination with folate-fluorescein (UB-TT170) for osteosarcoma.
Authors: Albert Catherine Michelle , Pinto Navin R. , Taylor Mallory , Wilson Ashley , Rawlings-Rhea Stephanie , Huang Wenjun , Seidel Kristy , Narayanaswamy, Prabha , Mgebroff Stephanie , Brown Christopher , Garcia Jacob , Teoh Jeffrey , Gardner Rebecca Alice , Orentas Rimas , Jensen Michael C. , Park Julie R.
Published: June 2023

TPS11581

Background: Outcomes for relapsed osteosarcoma (OS) remain poor and there are no systemic therapies that have been shown to provide a survival benefit. Chimeric Antigen Receptor (CAR) T cell immunotherapy involves the adoptive transfer of T-lymphocytes that have been engineered to recognize tumor-specific antigens, resulting in targeted lysis of malignant cells. Folate receptors (FR) are membrane-bound surface proteins that bind folates with high affinity. FRs are overexpressed in OS and have very limited expression in normal tissue. UB-TT170 (Umoja Biopharma) is a small molecule bispecific “adapter” consisting of folate conjugated to fluorescein (FL). It penetrates tumors in minutes and is retained for long periods of time due to high affinity for the FR, while unbound UB-TT170 rapidly clears from the blood and from FR- tissues. We hypothesize that administration of fixed dosing anti-FL(FITC-E2) CAR T cells followed by escalating doses of UB-TT170 will deliver personalized immunotherapy to OS patients. In addition, this approach offers an attractive safety mechanism since administration of NaFL should reverse CAR T cell reactivity. Methods: We designed a Phase I study for young adult (15-30 yr) patients with recurrent/refractory OS to examine the safety and feasibility of administering autologous, peripheral blood-derived T cells that have been genetically modified to express a 2nd generation FL-specific CAR in combination with intra-subject dose escalation of UB-TT170. The primary objective is to identify a recommended dose escalation sequence of UB-TT170 to move forward in clinical development. A 3+3 design will be used to investigate 3 possible dosing sequences. The trial opened in July 2022. As of January 5, 2023, 5 subjects have enrolled and one subject has been treated on dose regimen 1.T cell products have been successfully manufactured for all enrolled subjects. The trial remains open to enrollment. Clinical trial information: NCT05312411 .
PEMBROCABOSARC: Combination of pembrolizumab and cabozantinib in patients with advanced sarcomas.
Authors: Sellan-Albert Sabrina , Toulmonde Maud , Spalato Mariella , Bertucci Francois , Bompas Emmanuelle , Desmoulins Isabelle , Duffaud Florence , Cousin Sophie , Auzanneau Celine , Lortal Barbara , Pulido Marina , Le Loarer François , Italiano Antoine
Published: June 2023

TPS11586

Background: Despite optimal treatment, up to 40% of patients with sarcomas will develop locoregional and/or distant relapse and median survival in this setting is less than two years. There are very few options in the treatment of undifferentiated pleomorphic sarcomas whereas there is no specific treatment regimen established for recurrent osteosarcoma (OSS) and Ewing sarcoma (ES). Innovative strategies are therefore urgently needed in these settings. In preclinical studies, while immune checkpoint inhibitors were insufficient in controlling tumour growth, combining them with M2 macrophage or angiogenesis targeting resulted in superior tumour control (Mao et al, Clin Cancer Res 2016; Zhu et al, Cancer Res 2014). Combining both antiangiogenic and MET inhibition properties, cabozantinib has shown both preclinical and clinical activity, notably in osteosarcoma and Ewing sarcoma (Italiano et al. ESMO 2018). Interestingly, cabozantinib has also recently been shown to trigger an innate immune response in a preclinical model (Patnaik et al, Cancer Discov 2017). Altogether, these findings pave the way for studies assessing the impact of targeting angiogenesis, MET and immune response in soft-tissue and bone sarcomas. Methods: PEMBROCABOSARC (NCT05182164) is a multi-stratum, three single-arm phase 2, multicenter, open-label study investigating pembrolizumab combined with cabozantinib in patients with advanced selected sarcomas: undifferentiated pleomorphic sarcoma (stratum 1), osteosarcoma (stratum 2), Ewing sarcoma (stratum 3). Strata 1 and 2 will enroll ~32 patients and stratum 3 ~55 patients, respectively. Each stratum phase II will be conducted using a Simon's optimal two-stage design. Eligible and consented patients must be ECOG PS 0–1, have measurable and progressive disease according to RECIST 1.1 and have received less than 3 previous lines of systemic therapy for advanced disease and consent also to baseline and per treatment biopsies. Cabozantinib will be administered orally, once daily at a fixed dose of 40 mg, continuously. Pembrolizumab will be administered by intravenous infusion every 3 weeks on Day 1 of each cycle, at a fixed dose of 200 mg. Both treatments will start on Day 1 (of cycle 1). The primary endpoint is 6-months non progression rate as per RECIST 1.1. Secondary endpoints include adverse events (AEs)/serious AEs, best overall response, and progression-free survival. Pharmacodynamic and other biomarkers will be explored on blood and tumor tissue. The first patient received study drug on May, 31, 2022; 8 of planned 119 patients have been enrolled and 5 sites across France among the planned 10, are currently enrolling patients. Clinical trial information: NCT05182164 .
SARC041: A phase 3 randomized double-blind study of abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma.
Authors: Dickson Mark Andrew , Ballman Karla V. , Weiss Mia C. , Attia Steven , Wagner Michael J , Pollack Seth , Choy Edwin , Wagner Andrew J. , Wilky Breelyn A. , Davis Lara E. , Riedel Richard F. , Tap William D.
Published: June 2023

TPS11587

Background: Recurrent or metastatic dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat. Available agents such as doxorubicin, eribulin, trabectedin, ifosfamide, dacarbazine, or gemcitabine-based regimens are associated with low response rates and only modest improvements in progression free or overall survival. The oncogene CDK4 is ubiquitously amplified in this disease and represents a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in clinical benefit (12-week progression-free survival (PFS) of 57% with palbociclib and 74% with abemaciclib). We hypothesize that treatment with abemaciclib will improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: This is a phase 3 randomized double-blind study of abemaciclib versus placebo. Eligible patients have recurrent or metastatic dedifferentiated liposarcoma (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Patients are stratified by number of prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day and matching placebo. Patients are followed with scans every 6 weeks (every 12w after 36w) and those with progression of disease on placebo may cross over to open label abemaciclib. The primary endpoint is PFS. Target enrollment is 108 evaluable patients which provides 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6. Secondary endpoints include response rate, PFS and response rate after crossover, and overall survival. Archival tissue will be collected to explore potential biomarkers. As of Feb 1, 2023, 43 patients have been accrued at 9 participating centers. Clinical trial information: NCT04967521 .
Phase 1 dose-expansion study of oral TP-1287, a cyclin-dependent kinase 9 (CDK9) inhibitor, in patients with Ewing sarcoma (EWS).
Authors: Cote Gregory Michael , Wagner Andrew J. , Charlson John A. , Hu James S , Dickson Mark Andrew , D'Amato Gina Z. , Kabir Sujan , Xu Bo , Lebedinsky Claudia , von Mehren Margaret
Published: June 2023

TPS11589

Background: Cyclin-dependent kinase 9 (CDK9) blockade inhibits tumor growth and progression by impairing the transcription of key oncogenes, such as myeloid cell leukemia-1 (MCL-1) and c-MYC. CDK9 overexpression has been observed in sarcoma patients (pts), and CDK9 has emerged as a potential therapeutic target in pts with sarcoma. TP-1287 is an investigational orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. In preclinical studies, TP-1287 has been shown to decrease MCL-1 expression and phosphorylation of RNA polymerase II (RPB1), and inhibit tumor growth in an Ewing sarcoma (EWS) mouse model. Phase 1 dose-escalation in solid tumors has completed and TP-1287 is being investigated in a dose expansion cohort in pts with EWS (NCT03604783). The design of the expansion part of the trial in pts with EWS is herein described. Methods: Up to thirty pts with EWS will be enrolled in this dose expansion cohort. Key eligibility criteria are age ≥18 years (≥12 years, if weight ≥40 kg); histologically confirmed locally advanced or metastatic unresectable EWS; received 1 to 5 prior lines of treatment including an anthracycline; one or more measurable tumors per the RECIST v1.1; ECOG performance status of ≤1; acceptable liver and renal function, and acceptable hematologic and coagulation status; no treatment with surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives. Eligible pts will be treated with oral TP-1287 monotherapy RP2D established from the dose escalation part (11 mg BID, continuous dosing in a 28-day treatment cycle) and will continue treatment until treatment-related adverse event or disease progression. Assessments will be performed on Day 1 and Day 15 of each cycle. Tumor response assessment will be done after Cycle 2 and at the end of every other cycle thereafter. The primary objectives are objective response rate (ORR) and clinical benefit rate (CBR) ; secondary objectives are median progression-free survival (PFS), PFS rate at 16-weeks and 24-weeks and safety; and exploratory objectives include evaluation of systemic exposure and pharmacodynamics. Safety data will be reviewed on an ongoing basis and a Bayesian approach will be used to assess the efficacy data. Statistical analysis for safety and efficacy parameters will be primarily descriptive in nature. EWS dose expansion cohort is currently recruiting in the United States. Clinical trial information: NCT03604783 .
The FARGO study: Frailty assessment for risk prediction in gynecologic oncology.
Authors: Nguyen Julie My Van , Vicus Danielle , Hogen Liat Frida , Zigras Tiffany , Roldanbenitez Yetiani , Marcucci Maura
Published: June 2023

TPS12137

Background: Little is known about how to best predict postoperative outcomes and chemotherapy tolerance in an increasingly aging and complex gynecologic oncology (GO) population. Frailty is a multidimensional age-related and disease-related state of vulnerability to stressors due to reduced capacity of different physiological systems. Resource limitations are a barrier to routine adoption of frailty assessments through comprehensive clinical evaluations in daily practice. This highlights the relevance of studying potential biomarkers of frailty, which could complement or replace clinical assessments. Frailty has been associated with worse perioperative and oncologic outcomes in many subspecialties, however the literature in patients with gynecologic malignancies is very limited. Methods: The FARGO study is a multi-centre prospective cohort study of 280 patients aged ≥55 years-old undergoing surgery, with or without chemotherapy for a suspected or confirmed gynecologic malignancy. Patient recruitment will occur over 13 months. The over-arching goal is to evaluate the predictive value of frailty assessments in predicting surgical and chemotherapy outcomes. The two primary objectives are: 1) To evaluate the predictive value of preoperative frailty assessment based on the Frailty Phenotype (FP), compared to a perioperative cardiovascular risk assessment, in predicting the composite of all-cause death or new disability at 6 months after surgery 2) To create of a biobank to explore possible biomarkers of frailty, including mitochondrial DNA levels. Secondary objectives include to evaluate the predictive value of clinical and biomarker frailty assessment for 30-day postoperative complications, for chemotherapy tolerance and 1-year recurrence-free survival. Patients will undergo frailty and cardiovascular risk assessment prior to surgery and/or neoadjuvant chemotherapy. A trained clinical research assistant will measure frailty based on the clinical frailty scale (CFS) and the FP. The cardiovascular risk calculation will be based on the preoperative Revised Cardiac Risk Index, age, and occurrence of myocardial injury after non-cardiac surgery (MINS). Research personnel blinded to the frailty and cardiovascular risk assessment will evaluate study outcomes including death, disability, and clinical events at 30 days, 6 months, and 12 months after surgery. Disability will be measured with the WHODAS 2.0 (World Health Organization Disability Assessment Schedule), a validated patient-reported outcome measure. Pre-specified blood biomarkers will be measured. Our study emphasizes patient-centered outcomes (i.e. loss of independence, short and long-term disability) and system-level outcomes. Our findings may have important implications to assist in risk stratification and planning for oncologic treatments and perioperative care needs. Clinical trial information: will be added later .
A randomized phase III clinical trial of yoga for chemotherapy-induced peripheral neuropathy treatment.
Authors: Saint Kirin , Han Katherine , Piulson Lauren , Seluzicki Christina , Zhi Iris , Bao Ting
Published: June 2023

TPS12143

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, painful, and debilitating side effect of many standard chemotherapy regimens. CIPN symptoms include pain, paresthesia, and muscle weakness, and patients may exhibit functional decline and lower quality of life. Our prior study showed more than half of breast cancer survivors experience persistent CIPN up to a mean duration of 5.6 years, which is associated with a doubled fall risk. Identifying non-pharmacological approaches to reduce CIPN symptoms and improve cancer survivors’ outcomes is urgently needed. Yoga is a meditative movement therapy that includes stretching, and flexibility and balance training. Our pilot study (NCT03292328) demonstrated that yoga reduced CIPN-related symptoms, and improved quality of life and functional reach scores compared to waitlist control. We hypothesize that yoga can reduce CIPN symptoms, improve function, and reduce the risk of falls. Methods: We are conducting a three-arm randomized education and usual care-controlled trial in cancer survivors with chronic CIPN pain at Memorial Sloan Kettering Cancer Center (MSK), New York, NY. Participants in the intervention arm will receive twice-weekly one-hour Hatha yoga classes taught virtually by MSK instructors and practice yoga at home daily for eight weeks. Participants in the education control arm will receive one-hour virtual education classes twice per week taught by an MSK instructor for eight weeks. Participants in the usual care arm will continue their usual care for CIPN for eight weeks. The primary endpoint is the Brief Pain Inventory-Short Form average pain item at weeks 8 and 24. Secondary outcomes include the Neuropathic Pain Scale, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, Patient-Reported Outcomes Measurement Information System Global Health, Brief Fatigue Inventory, Insomnia Severity Index, Hospital Anxiety and Depression Scale, Quality of Life Questionnaire of CIPN twenty-item scale, functional assessments, and quantitative sensory testing at weeks 0, 4, 8, 12, 18, and 24. Eligibility criteria include: 1) Moderate-to-severe CIPN pain, defined by a score of 4 or greater on a 0-10 numerical rating scale; 2) completion of neurotoxic chemotherapy at least three months prior; 3) no changes in anti-neuropathy medications within three months of enrollment; and 4) changes in balance and functionality. As of February 2023, we have accrued 64 of our total target of 268 participants. We anticipate completing accrual in March 2025. We have 35 participants in the yoga intervention, 15 participants in education control, and 14 participants in usual care control. The majority (89%) of participants are female and 11% are male. 78% of our participants are white, 16% are black or African American, 1% are Asian, and 5% identify as more than one race. Clinical trial information: NCT05121558 .