bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 2, randomized, open-label study comparing the effects of darolutamide versus enzalutamide monotherapy on serum testosterone levels in patients with hormone-naive prostate cancer: ARAMON study.
Authors: Gao Xin , Smith Matthew Raymond , Scher Howard I. , Verholen Frank , Adorjan Patrick , Dissanayake Manjari , Laccetti Andrew Leonard
Published: June 2023

TPS5111

Background: Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor with low blood–brain barrier penetration. In the phase 3 ARAMIS study (NCT02200614) of patients with nonmetastatic castration-resistant prostate cancer, treatment with darolutamide significantly improved metastasis-free survival and overall survival versus placebo, with a favorable safety profile. The incidences of central nervous system adverse events (AEs; e.g. falls, memory impairment, and depression) showed a ≤2% difference between the darolutamide and placebo groups. Fatigue was the only AE with an incidence of > 10% for darolutamide (13.2% vs 8.3% for placebo). In a separate neuroimaging study of healthy volunteers, cerebral blood flow was not altered in patients treated with darolutamide but was significantly reduced in brain areas related to cognition in patients treated with enzalutamide. Furthermore, it is postulated that the low blood–brain barrier penetration of darolutamide may result in lower serum testosterone elevations than those seen with enzalutamide, with the potential of leading to fewer associated feminizing AEs. The objective of ARAMON (NCT05526248) is to compare the effect of darolutamide and enzalutamide monotherapy on post-treatment testosterone levels in patients with hormone-naive prostate cancer experiencing biochemical recurrence after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of patients with histologically or cytologically confirmed adenocarcinoma of the prostate who have biochemical recurrence after radical primary prostatectomy or radiation therapy, with a prostate-specific antigen (PSA) doubling time of ≤20 months, baseline serum testosterone > 150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During a 52-week lead-in phase, 25 patients will receive darolutamide 600 mg twice daily. If criteria based on serum testosterone increase from baseline to Week 12 are met, the study will proceed to a 52-week randomized phase in which the effects of darolutamide (600 mg twice daily, n = 20) will be compared with the effects of enzalutamide (160 mg once daily, n = 20). The primary endpoint of both phases is the change in serum testosterone level from baseline to Week 12. Secondary endpoints of the randomized phase include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of markers for glucose, lipid metabolism, and endocrine function related to sex hormones; safety; and quality of life. Safety will be assessed through AE monitoring. The first of the 25 planned patients in the lead-in phase was enrolled on January 13, 2023. Clinical trial information: NCT05526248 .
Phase 1/2a study of PRL-02, a long-acting intramuscular (IM) depot injection of abiraterone decanoate, in patients (pts) with advanced prostate cancer.
Authors: Shore Neal D. , Avitia Jose W. , Bailen James L. , Nordquist Luke T. , Richardson William , Peer Cody J. , Figg William Douglas , Walling Jacqueline M. , Eisner Joel Robert , Sharp Matthew , Schotzinger Robert J. , Moore William R. , Tutrone Ronald F.
Published: June 2023

TPS5117

Background: PRL-02 is a long-acting IM depot injection of abiraterone decanoate, a novel prodrug of abiraterone delivered through the lymphatic system. PRL-02 potently blocks androgen production with minimal increases in mineralocorticoids or decreases in glucocorticoids through preferential inhibition of Cytochrome P450 (CYP)17 lyase versus CYP17 hydroxylase. Phase 1 is a standard 3+3 design intended to identify a recommended Phase 2 dose (RP2D). PRL-02 is administered every 84 days (1 cycle). As of 9/8/22, 17 pts (6 mCRPC, 11 mCSPC) were treated across 5 dose cohorts (180, 360, 720, 1260, 1800mg). At 720mg and above, 9 of 11 had a 90% reduction in testosterone (T), including 2 pts with T≤ Lower Limit of Quantitation (LLOQ) of 0.1ng/dL. A PSA decline of ≥50% from baseline (PSA50) was observed in 8 of 10pts. PRL-02 was very well tolerated. Only minimal and transient changes in ‘upstream’ steroids (e.g., progesterone) were observed at doses of 1260 mg (the RP2D) and lower. Methods: Phase 2a is an A'Hern single-stage design. Group 1 includes pts with mCSPC divided into 2 groups (1A: previously untreated high-volume disease and 1B: previously untreated, low-volume disease). Group 2 includes pts with mCRPC. Enrollment of 66 pts is planned across 30 sites in the U.S. (NCT04729114). Patient populations, interventions and study design are described below. Clinical trial information: Clinical Trial information: NCT04729114 . [Table: see text]
UP-NEXT (GOG-3049/ENGOT-Ov71-NSGO-CTU): A study of upitifamab rilsodotin (UpRi), a NaPi2b-directed antibody drug conjugate (ADC), in platinum-sensitive recurrent ovarian cancer.
Authors: Richardson Debra L. , Harter Philipp , O'Malley David M. , Gonzalez Martin Antonio , Herzog Thomas J. , Rogalski Caroline , Lemming Rita , Keeton Erika , Burger Robert Allen , Mirza Mansoor Raza
Published: June 2023

TPS5614

Background: UpRi is a first-in-class NaPi2b-targeting ADC with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in high-grade serous ovarian cancer (HGSOC) with limited expression in healthy tissues. It is estimated that the majority of HGSOCs have high NaPi2b expression. Studies are being conducted to evaluate UpRi safety and efficacy in platinum-resistant ovarian cancer (PROC), but there remains an unmet need in the maintenance setting for patients with recurrent platinum-sensitive ovarian cancer (PSOC), particularly for patients who have received prior maintenance therapy, are at high-risk of early relapse, and where close monitoring after platinum-based therapy would generally be considered preferable. Methods: UP-NEXT is a Phase 3 study evaluating UpRi monotherapy as post-platinum maintenance treatment in recurrent PSOC, enrolling patients with NaPi2b-positive tumors (defined as TPS ≥75). Patients must have received 2-4 prior lines of platinum containing chemotherapy, achieved a partial or complete response in their penultimate platinum regimen, and progressed >6 months after completion of the last dose of platinum in the penultimate regimen. Patients may be enrolled if their best response to the last line of treatment is no evidence of disease, complete or partial response, or stable disease. Prior PARPi treatment is required for patients with a BRCA mutation. Patients who received bevacizumab in combination with their most recent platinum containing regimen are excluded. Patients are randomized 2:1 to UpRi 30mg/m2 or placebo, given IV Q4W. The primary endpoint is PFS assessed by BICR, with key secondary endpoint of OS. UP-NEXT is conducted in collaboration with GOG(3049) and ENGOT(Ov71-NSGO-CTU). Approximately 350 patients will be enrolled globally. NCT05329545. Clinical trial information: NCT05329545 .
Uncovering mechanisms of response of pembrolizumab and lenvatinib for the treatment of platinum-resistant high grade serous ovarian cancer.
Authors: How Jeffrey , Westin Shannon Neville , Sims Travis T. , Lito Kathryn , Celestino Joseph , Rangel Kelly M. , Peng Weiyi , Wang Linghua , Jazaeri Amir A.
Published: June 2023

TPS5619

Background: Despite initial response to conventional platinum-containing therapies, the majority of high grade serous ovarian cancer (HGSOC) patients will eventually develop treatment resistance. Despite interest for immune checkpoint inhibitor alternatives, pembrolizumab monotherapy is poor with objective response rates (ORR) ranging between 4.1 - 10%. Poor response may be linked to higher expression of immunosuppressive factors (e.g. VEGF, TGF-β) in the tumor microenvironment (TME). In an immunosuppressive TME, monotherapy with PD-1 inhibitors can induce T-cell dysfunction and apoptosis, leading to innate resistance to pembrolizumab. Preclinical studies of other tumors have demonstrated that lenvatinib can improve T-cell activation and reduce the tumor-associated macrophage population and TGF-β/VEGF/FGF-signaling. In HGSOC, mechanisms of resistance to pembrolizumab and whether this resistance can be overcome by the addition of lenvatinib remain unknown. The objective of this investigation is to uncover the immunologic basis and synergistic mechanisms of action underlying clinical efficacy of pembrolizumab and lenvatinib in HGSOC. Specifically, we will evaluate the dynamic changes in proliferative and dysfunctional T-cell populations in the peritoneal TME (p-TME) of HGSOC patients receiving monotherapy with pembrolizumab or lenvatinib followed by combination therapy. Methods: All patients will receive a cycle of monotherapy (pembrolizumab 200 mg IV every 3 weeks or lenvatinib 20 mg po daily) followed by combination therapy (both) up to 35 cycles. Enrolled patients will receive intra-peritoneal port placement for serial peritoneal fluid evaluations (cycle 0 day 1, cycle 0 day 8, cycle 1 day 8, cycle 2 day 1, cycle 3 day 1, cycle 5 day 1, then day 1 of every 3rd cycle) for multichannel flow cytometry and single-cell RNA sequencing. Our primary translational objective is to estimate both the individual and combined effects of pembrolizumab and lenvatinib on T-cell dysfunction (PD1+ CD38+) and proliferation (ki67+) in the p-TME using multichannel flow cytometry on the peritoneal fluid. Secondary clinical objective is ORR. Secondary translational objectives include individual and synergistic effects of monotherapy and combination therapy on T-cell effector function, T-cell memory, and myeloid cell subpopulations. Exploratory objectives include evaluating the dynamic changes in immune and non-immune cells in the p-TME for exceptional responders and non-responders using single cell RNA sequencing. Key eligibility criteria include 1) histologic diagnosis of high grade serous ovarian, peritoneal, or fallopian tube cancer 2) platinum-resistant disease and 3) no prior lenvatinib therapy. The trial is open with 10 patients enrolled at the time of submission. Clinical trial information: NCT05114421 .
Oregovomab and non-platinum chemotherapy in PARP inhibitor-resistant ovarian, fallopian tube, or primary peritoneal cancer patients not candidates for platinum retreatment: A multicenter, two-cohort, single-arm phase 2 trial (OPERA/KGOG 3065/APGOT-OV6).
Authors: LEE JUNG-YUN , Park Junsik , Choi Chel Hun , Cho Hyun Woong , No Jae Hong , Hong Dae Gy
Published: June 2023

TPS5621

Background: As PAPR inhibitors (PARPis) are becoming the standard of care option for epithelial ovarian cancer (EOC), PARPi-resistant patients are increasing. Moreover, non-platinum single agent chemotherapy in these patients has been found to elicit poor survival outcomes. Oregovomab, an investigational murine monoclonal antibody directed against CA-125, has shown promising efficacy in the previous phase II study of combinational front-line adjuvant chemotherapy. The aim of the present study is to investigate the efficacy of oregovomab + non-platinum-based chemotherapy in PARPi-resistant EOC patients not suitable for platinum-based therapy. Methods: OEPRA is a multi-centre, investigator-initiated, two-cohort, single-arm phase II trial recruiting PARPi-resistant EOC patients from five sites in South Korea. The trial includes patients with recurrent EOC who have experienced disease progression despite treatment with PARPis and who have either received bevacizumab or are not eligible for bevacizumab treatment. Mucinous histology type is excluded. Patients who have received one to three prior lines of chemotherapy are to be assigned to Cohort 1 (oregovamab 2 mg [C1,2,3,5,7 for five doses] + pegylated liposomal doxorubicin [PLD] 40 mg/m2 q4w, n = 28), while patients who have received more than three prior lines of chemotherapy are to be assigned to Cohort 2 (oregovamab 2 mg [C1,2,3,5,7 for five doses] + weekly paclitaxel 80 mg/m2 [D1,8,15 q4w], n = 28). A total of 56 patients will be recruited and treated with oregovomab + PLD / weekly paclitaxel until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint is objective response rate by RECIST 1.1. Accrual is expected to be completed in 2023, followed by presentation of results in 2024. The study is registered with Clinicaltrials.gov (NCT05407584). Clinical trial information: NCT05407584 .
A phase II, randomized, double-blind study of the use of rucaparib vs placebo maintenance therapy in metastatic and recurrent endometrial cancer.
Authors: Corr Bradley , Haggerty Ashley Ford , Taylor Sarah E. , Gysler Stefan , Morgan Mark Aloysuis , Behbakht Kian , Lefkowits Carolyn , Alldredge Jill , Brubaker Lindsay , Hopp Samantha , Guntupalli Saketh R
Published: June 2023

TPS5626

Background: There are currently no approved maintenance therapies for metastatic and recurrent endometrial cancer, which carries a dismal long-term prognosis. The PARP inhibitor drug class has demonstrated significant clinical benefit as a maintenance therapy for patients with germline/somatic BRCA mutations or homologous recombination deficiency (HRD) in ovarian cancers. However, BRCA mutations are not common in endometrial cancer. Loss of function of the tumor suppressor gene PTEN has been demonstrated in greater than 80% of endometrioid endometrial cancers 1. PTEN loss of function is well known to lead to activation of the PI3K-AKT-mTOR pathway but has also been shown to lead to defects in homologous recombination (HR) DNA repair of double strand breaks 2. Specifically, PTEN silencing leads to decreased RAD51 foci formation. Based on this mechanism, in vitro data on endometrial cancer cell lines has demonstrated sensitivity to PARP inhibitors. Notably, sensitivity of PARP inhibition in PTEN loss of function is independent of microsatellite instability (MSI) 3. Methods: This is a multi-center phase II, placebo controlled, double-blinded study of the use of rucaparib as maintenance therapy in patients with metastatic or recurrent endometrial cancer. A maximum of 138 patients will be randomized 1:1 to receive rucaparib at starting dose of 600mg BID dosing vs. placebo. Standard dose reductions of known toxicities will be followed based on FDA approved indications of rucaparib. Patients will remain on therapy until progression of disease or toxicity induced discontinuation. Eligible patients will have Stage III/IV or recurrent endometrial cancer and must have received one or two prior lines of chemotherapy. All histologic subtypes, including carcinosarcoma will be included. Treatment arms will be stratified on histology, number of lines of prior therapy, and complete vs partial response to prior line of therapy. The primary endpoint is progression free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), and toxicity. To date, 79 patients have been enrolled. 1. Mutter GL, Lin MC, Fitzgerald JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92(11):924-930. 2. Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128(1):157-170. 3. Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75. Clinical trial information: NCT03617679 .
ENGOT-EN20/GOG-3083/xport-EC-042: A phase 3, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with P53 wild-type, advanced or recurrent endometrial carcinoma.
Authors: Vergote Ignace , Mirza Mansoor R. , Coleman Robert L. , Perez-Fidalgo Jose Alejandro , Monk Bradley J. , Valabrega Giorgio , Slomovitz Brian M. , Van Gorp Toon , Moore Kathleen N. , Sehouli Jalid , Cibula David , Levy Tally , Aravantinos Gerasimos , Li Kai , Kalyanapu Pratheek , Makker Vicky
Published: June 2023

TPS5627

Background: Patients (pts) with first-line metastatic or recurrent endometrial cancer (EC) have a poor prognosis. Selinexor is an oral XPO1 inhibitor, which leads to nuclear accumulation of tumor suppressor proteins, including p53. Selinexor is FDA-approved for use in multiple myeloma and diffuse large B-cell lymphoma, and has shown clinical activity in previously treated, advanced EC. Molecular characterization of EC is critical in directing treatment for advanced and recurrent disease. Of the EC molecular subtypes, TP53 wild type (wt) tumors represent 50% of advanced and recurrent tumors. A recent phase 3 study in maintenance after chemotherapy found that, despite the primary endpoint (PFS) not reaching statistical significance, prolonged PFS of oral once-weekly selinexor versus placebo (13.7 months and 3.7 months, respectively) was observed in a prespecified exploratory subgroup analysis of patients with advanced or recurrent TP53wt EC. Methods: XPORT-EC-042 (NCT05611931) is a Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of selinexor as maintenance therapy in pts with TP53wt advanced or recurrent EC, who have achieved a partial response or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 after completing at least 12 weeks of platinum combination chemotherapy ±immunotherapy for primary stage IV or recurrent disease. Eligible pts must be ≥18 years of age, have histologically confirmed EC, and TP53 wt disease based on NGS sequencing assessed by Foundation Medicine. Pts will be randomized 1:1 with either selinexor 60 mg or placebo once weekly in 28-day cycles until progressive disease, toxicity, or 3 years if in complete response. A total of 220 pts will be enrolled at sites across the United States, Canada, Europe, and Israel. The primary objective is to compare PFS in pts treated with selinexor compared to placebo based on RECIST v1.1 criteria as assessed by the Investigator. Key secondary objective is overall survival. Other secondary objectives are safety, time to first subsequent therapy, time to second subsequent therapy, time from randomization until the second progression event (PFS2), and PFS by a blinded independent central review. Patient enrollment is ongoing. Clinical trial information: NCT05611931 .
RT-PACE: Phase I/II study of adjuvant whole pelvic hypofractionated radiotherapy for non-metastatic cervical and endometrial cancer.
Authors: Son Christina H. , Suneja Gita , Chipman Jonathan , Cursio John , Al-Hallaq Hania A , Gaffney David K. , Hasan Yasmin
Published: June 2023

TPS5631

Background: Whole pelvic radiation therapy (WPRT) improves locoregional control in women with high-intermediate and high-risk endometrial cancer. The standard treatment course consists of 25-28 fractions (5-5.5 weeks) of 1.8-2 Gy/fraction, and is delivered using intensity-modulated radiation therapy (IMRT), which allows for superior sparing of normal tissue with a subsequent lower rate of acute and late toxicity compared to less conformal treatment techniques. Moderate hypofractionation (HF, >2 Gy/fraction) has been studied in other disease sites, such as breast and prostate cancer, and is associated with lower or comparable toxicity, improved patient convenience, and greater cost savings compared to standard fractionation. However, HF has not been well-studied in the setting of WPRT for gynecologic cancers. Methods: This phase I/II multi-institutional study evaluates the feasibility, safety, and toxicity profile of HF-WPRT in women with non-metastatic cervical or endometrial cancers who have undergone curative hysterectomy and are recommended adjuvant WPRT by their treating physician. Concurrent chemotherapy is not allowed, but can be administered sequentially prior to or after WPRT. Para-aortic radiation or nodal boosts are not allowed, however vaginal brachytherapy boost is permissible. Phase I is a safety study of increasing dose-per-fraction. All treatment regimens have an approximate biologic effective dose of 53 Gy (α/β =10). A keyboard design is utilized to identify the maximum tolerated dose-per-fraction (MTD), defined in this study as the regimen that is associated with a CTCAE grade 3+ gastrointestinal/genitourinary toxicity rate of ≤10% on the last day of WPRT. There are 3 dose cohorts of increasing dose-per-fraction. Phase II will accrue 64 evaluable patients to HF-WPRT using the MTD determined in phase I. The primary endpoint is to evaluate the change in patient-reported gastrointestinal toxicity from baseline to the last day of WPRT using the EPIC bowel score. The study is powered to compare results to the RTOG 1203 IMRT standard fractionation arm. The phase 1 portion of the study completed accrual; the phase II portion opened in April 2022 with a fractionation of 42.56 Gy in 16 fractions. Secondary endpoints include genitourinary toxicity (EPIC, CTCAE), quality of life (FACT-Cx, PRO-CTCAE), financial toxicity (FACIT-COST), and decision-making (Decision Regret Scale). Pelvic control at 2 years is an exploratory endpoint. Clinical trial information: NCT04683653 .
The RAINBO MMRd-GREEN trial (GCIG/DGOG/ENGOT-EN142): A phase III trial on the addition of adjuvant durvalumab to radiotherapy in patients with high-risk MMRd endometrial cancer.
Authors: Kaya Merve , Horeweg Nanda , Leary Alexandra , Welch Stephen , Kommoss Stefan , Weidner Nicola , Fanfani Francesco , Lorusso Domenica , McGrane John , Van Gorp Toon , Boere Ingrid , Westermann Anneke M. , Heijns Joan B. , Putter Hein , Verhoeven-Adema Karen , Smit Vincent T.H.B.M. , Creutzberg Carien L. , Bosse Tjalling , Kroep Judith R.
Published: June 2023

TPS5633

Background: The molecular class of endometrial cancer (EC) is both prognostic and predictive in high-risk EC (HREC). The TransPORTEC research consortium showed that patients with MMRd HREC did not benefit from adjuvant chemotherapy added to radiotherapy. MMRd tumors are particularly sensitive to immunotherapy. We hypothesize that adjuvant durvalumab added to standard radiotherapy will increase recurrence-free survival (RFS) in patients with MMRd HREC. Methods: MMRd-GREEN is an international, open-label, randomized phase III trial and part of the RAINBO program (NCT05255653). Eligible patients will be allocated (1:1) to adjuvant durvalumab 1500 mg once every 4 weeks for 1 year combined with radiotherapy or standard radiotherapy alone. The primary endpoint is RFS at 3 years. Secondary endpoints are pelvic, vaginal and distant RFS, EC-specific survival, overall survival, treatment-related toxicity, health-related quality of life and exploratory translational research . Main inclusion criteria include histologically confirmed stage IB/II with (substantial) lymph-vascular space invasion (LVSI) or stage IIIA-C MMRd EC, after hysterectomy and bilateral salpingo-oophorectomy (regardless of lymphadenectomy or sentinel lymph node biopsy) without macroscopic residual disease. Molecular classification must be performed according to the WHO 2020 algorithm. The target accrual is 316 patients, accounting for a total drop-out rate of 12%. This sample size yields 80% power to detect a 13% increase in the 3-year RFS (hazard ratio 0.58) as a result of the addition of durvalumab, with an accrual duration of 48 months and follow-up period of 30 months. No interim analysis is planned; an independent data monitoring committee will routinely monitor recurrences and adverse events. Enrollment: Since August 2022, the trial is open for recruitment in the Netherlands and per February 10th 2023, the first 3 patients have been enrolled. Activation of more international centers is ongoing. Clinical trial information: NCT05255653 .
Phase 2 trial of retifanlimab (anti–PD-1) in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti–TIM-3) as first-line treatment in patients with PD-L1–positive recurrent/metastatic squamous cell carcinoma of the head and neck.
Authors: Cohen Ezra E.W. , Le Tourneau Christophe , Schaub Richard , Bartenstein Matthias , Cheng Lulu , Licitra Lisa F.
Published: June 2023

TPS6104

Background: Anti–PD-(L)1 therapies have improved clinical outcomes in PD-L1+ squamous cell carcinoma of the head and neck (SCCHN). However, many patients either do not respond or develop resistance, partly due to additional immune checkpoint receptors including LAG-3 and TIM-3, which are frequently coexpressed with PD-1 on tumor-infiltrating lymphocytes. In preclinical studies, LAG-3 and TIM-3 blockade showed synergistic activity with PD-1 inhibition, and triple blockade improves T-cell reinvigoration and antitumor efficacy over single/double combinations. Emerging clinical evidence also supports blockade of PD-1, LAG-3, and TIM-3 as a promising combination approach in checkpoint inhibitor–naive patients. This study aims to assess the efficacy and safety of the anti–PD-1 antibody, retifanlimab, in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti–TIM-3) antibodies as first-line treatment in PD-L1+ recurrent or metastatic SCCHN. Methods: This randomized, double-blind, multicenter, phase 2 study (NCT05287113) includes patients with previously untreated, recurrent or metastatic, PD-L1+ (combined positive score [CPS] ≥1%) SCCHN and ECOG status of 0 or 1. Approximately 162 patients will be randomized 1:1:1 to receive (1) intravenous (IV) retifanlimab 500 mg every 4 weeks (Q4W) plus placebo controls, (2) retifanlimab plus IV INCAGN02385 350 mg Q2W plus placebo, or (3) retifanlimab plus INCAGN02385 plus IV INCAGN02390 400 mg Q2W. Patients will be stratified at randomization by LAG-3 expression (tumor proportion score ≥5% vs < 5%), PD-L1 CPS (1%-19% vs ≥20%), and human papillomavirus p16 status (positive vs negative; oropharyngeal tumors only). Treatment will be administered in 4-week cycles for up to 2 years. The primary endpoint is progression-free survival (PFS; defined per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). Secondary endpoints are objective response rate per RECIST v1.1, duration of response, disease control, overall survival, and safety. Sample size calculation is based on a median PFS of 3 months, based on historical data for anti–PD-1 monotherapy in the first-line treatment setting for PD-(L)1+ advanced/metastatic SCCHN. PFS, overall survival, and duration of response data will be analyzed by the Kaplan-Meier method. Patient enrollment is ongoing. Clinical trial information: NCT05287113 .
CCTG HN11: SPECT-CT guided elective contralateral neck treatment (SELECT) for patients with lateralized oropharyngeal cancer—A phase III randomized controlled trial.
Authors: de Almeida John R. , Parulekar Wendy R. , Christopoulos Apostolos , Gauthier Isabelle C , Martino Rosemary , McNiven Andrea , Nichols Anthony C. , Parmar Ambika , Prisman Eitan , Ringash Jolie , Smoragiewicz Martin , Subramaniam Rathan M. , Waldron John , Chinn Steven B. , Bates James Edward , Whelan Kate , Tu Wei , Hosni Ali
Published: June 2023

TPS6114

Background: Lymphatic mapping identifies neck lymph nodes at risk for cancer spread in patients with lateralized oropharyngeal (OPC) squamous cell carcinoma. We hypothesize that a lymphatic mapping guided approach to radiotherapy (RT) treatment of the contralateral neck will enable safe de-escalation of therapy with acceptable disease control with potential benefits in RT related toxicity, QOL, swallowing function and economics. Methods: HN.11 is a Canadian Cancer Trials Group international multi-centre, non-inferiority randomized phase III trial comparing a lymphatic mapping-guided approach for management of the contralateral neck (experimental) vs. bilateral neck radiation therapy (RT) (control). The primary objective is to determine if a lymphatic mapping-guided approach for management of the contralateral neck has a non-inferior disease-free survival (DFS) compared to bilateral neck RT. Secondary objectives: To compare swallowing related QOL, xerostomia, isolated contralateral neck failure, overall survival, loco-regional failure, distant metastases, RT-related toxicities, patient reported adverse events (PRO CTCAE), gastrostomy tube usage, and economics indicators (resource utilization, lost productivity, financial toxicity, EQ5D). Exploratory objectives: Swallowing function using video fluoroscopic swallow studies, head and neck-cancer specific QOL, patterns of lymphatic drainage, radiomic prediction of contralateral lymphatic drainage, correlation of tumour somatic mutations and ctDNA with disease recurrence. Statistical Design: The target sample size is 510 patients. The experimental arm will be considered non-inferior if the upper limit of the one sided 95% confidence interval (CI) of the estimated hazard ratio (HR) does not exceed 1.46 (non-inferiority margin of 6.5% for 2-year DFS). In the primary intention-to-treat (ITT) analysis, the study has 81% power, with a one-sided type I error rate of 5%, assuming 5 years of accrual, 3-years of follow up to observe 178 DFS events, and a 5% loss to follow up. If non-inferiority is demonstrated in the ITT analysis, a secondary per-protocol analysis will be performed, analyzing those patients treated as per their allocation, with 80% power to detect non-inferiority of the experimental arm assuming a conservative 10% cross-over from the experimental to the control arm (i.e. failed lymphatic mapping). Conduct to Date: Study activation September 29, 2022. First enrollment was February 10, 2023. Supported by Canadian Cancer Society, Canadian Institutes of Health Research, National Cancer Trials Network (NCTN). Clinical trial information: NCT05451004 .
Phase 2 study of bintrafusp alfa in recurrent/metastatic olfactory neuroblastoma.
Authors: Bracken-Clarke Dara Mark , London Nyall R , Mallek Marissa , Cordes Lisa M. , Steinberg Seth M. , Marte Jenn , Strauss Julius , Redman Jason M. , Pastor Danielle M. , Schlom Jeffrey , Gulley James L. , Floudas Charalampos S.
Published: June 2023

TPS6116

Background: Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a rare malignant tumor of the nasal cavity, believed to arise from the basal cells of the olfactory neurosensory epithelium. ONB is often locally advanced at diagnosis with high rates of spread both locoregionally and systemically. Current therapy for locoregional disease is local resection with adjuvant (chemo-) radiotherapy. Actionable mutations are rare, and treatment options for recurrent or advanced, non-resectable, disease are limited and include off-label combination chemotherapy (most frequently platinum-containing) and somatostatin-directed therapies (ONB expresses somatostatin receptors). These are based on limited data, with response rates poorly characterized. Bintrafusp alfa is a first-in-class, bifunctional TGF-β “trap”/anti-PD-L1 fusion protein. Analysis of ONB has demonstrated both PD-1/PD-L1 (London et al, 2018) and TGF-β ligand expression (Romani et al, 2021). Pre-clinical and clinical data in advanced solid tumors demonstrate enhanced antitumor activity with combination PD-L1/TGF-β blockade, with responses observed independently of high PD-L1 levels (Strauss et al, 2020). Thus, combination PD-L1/TGF-β blockade in ONB is a rational approach in a setting of unmet clinical need. Methods: This study is a Phase 2 single-site, single-arm clinical trial of bintrafusp alfa (1200mg IV every 2 weeks for up to 26 doses) for patients with recurrent or metastatic ONB. Participants must co-enroll to the ONB Natural History study at the NCI (NCT4755205). Patients must not be candidates for local therapy, have received at least 1 line of systemic therapy (including a platinum salt), have RECIST 1.1 measurable disease and have adequate organ function. Prior checkpoint inhibitor therapy is permitted with patients cohorted according to checkpoint exposure; up to 21 checkpoint-naïve and 8 checkpoint-resistant patients will be enrolled. The primary objective is objective response rate by RECIST 1.1 with secondary endpoints including safety and tolerability, duration of response and overall survival; exploratory endpoints include pharmacokinetic analyses, PD-L1 and immune cell correlative analyses. The trial follows a Simon two-stage design, requiring ≥1 response in the first 12 patients. Tumor biopsy at enrollment is optional. Imaging for response assessment is planned for 8-week intervals and PET scan (preferably 68Ga-DOTATATE) will be obtained for all patients at baseline and first restaging, then on an individualized basis per radiology advice. This study is presently open at the NCI with 5 patients enrolled as of January 2023. Clinical trial registry:NCT05012098. Clinical trial information: NCT05012098 .
Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neoadjuvant and postoperative adjuvant anti-HER2 therapy: Flamingo-01.
Authors: Patel Snehal , Thompson Jaye , Patel Mira , Daugherty F. Joseph , Rimawi Mothaffar F.
Published: June 2023

TPS617

Background: GP2 is a biologic nine amino acid peptide of the HER2/ neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient was treated with GLSI-100, survived, and was followed for more than 6 months ( p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events observed were considered related to the immunotherapy. Methods: This Phase III trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. The patient population is defined by these key eligibility criteria: HER2/neu positive and HLA-A*02; residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy; exclude stage IV; completed at least 90% of planned trastuzumab-based therapy. Trial objectives were to determine if GP2 therapy increases IBCFS, to assess the safety profile of GP2 and to monitor immunologic responses to treatment and assess relationship to efficacy and safety. The study has been initiated at a number of sites in the US. The study is also expected to be opened in Spain, Germany, and France. Clinical trial information: NCT05232916 .
Selective avoidance of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with HER-2 positive/triple negative breast cancer: Prospective, multi-center, single-arm study (ASLAN).
Authors: Ryu Jai Min , Han Wonshik , Lee Han-Byoel , Ahn Sung Gwe , Kim Hee Jeong , Park Hyung Seok , Choi Ji Soo , Kim Haeyoung , Lee Jeong Eon
Published: June 2023

TPS624

Background: According to advanced neoadjuvant chemotherapy (NACT), which dual HER2 blockage in HER2+ BC and adding carboplatin or immunotherapy in triple-negative breast cancer (TNBC) increased pathologic complete response (ypCR) rates up to 68% and 80%. Because ypCR patients showed better survival, the indications for NACT have expanded to early BC and the expected ypCR rate has increased. Therefore, it may be reasonable to consider omitting surgery in cases with excellent responses to NACT. Several recent retrospective studies and pilot prospective studies have reported axillary pathologic complete response (ApCR) is highly correlated with breast pathologic complete response (BpCR) in HER2+ or TNBC after NACT. The current report describes the design of omission of sentinel lymph node biopsy (SLNB) after NACT in HER2+ or TNBC patients with excellent response. Similarly, EUBREAST-01 (NCT04101851) study is ongoing omission of sentinel lymph node biopsy (SLNB) after NACT in HER2+/TNBC with radiologic complete remission and a BpCR. Methods: The ASLAN trial is a prospective, multicenter, single-arm, clinical study. Five tertiary care hospitals in South Korea are participating. Inclusion criteria: women aged 20-69; cT1-3N0-1M0; HER2+ or TNBC (defined by ER-negative (< 10% positive cells in IHC) and PgR-negative (< 10% positive cells in IHC)); expected complete remission at physical examination and radiological expected Tumor size ≤ 2cm or non-mass enhancement ≤ 4cm at breast MRI after standard NACT; planned breast conserving surgery (BCS) with whole-breast irradiation; ECOG performance status 0-1. Exclusion criteria: SLNB before NACT; previous axillary surgery; bilateral BC. Patients who are eligible proceed BCS. After BCS, patients who showed BpCR are enrolled with omission of SLNB. Patients with no BpCR proceed with routine axillary surgery. The assumption for acceptable 5-year RFS ≥84% is based on previous study findings. The calculated total case number for per- protocol analysis is N=178. Primary endpoint: 5-year recurrence free survival. Secondary endpoint: local recurrence free survival, breast cancer specific survival, overall survival, ipsilateral axillary recurrence interval, distant metastasis free survival, contralateral breast free survival, re-operation rate according to breast biopsy after NACT, adverse event, and quality of life. The first patient was enrolled on September 2021. Among 147 patients who screened, 106 patients have been enrolled in January 2022. We plan to complete the target accrual by December 2025. Clinical trial information: NCT04993625 .
Tailored axillary surgery (TAS) in patients with clinically node-positive breast cancer in the upfront surgery setting: A prospective, single-arm, multicenter trial.
Authors: Terata Kaori , Sagara Yasuaki , Shien Tadahiko , Sakai Takehiko , Takayama Shin , Kitagawa Dai , Iwatani Tsuguo , Tsukioki Takahiro , Ogita Mami , Sanuki Naoko , Yoshida Masayuki , Tsuda Hitoshi , Yamamoto Seiichiro , Iwata Hiroji
Published: June 2023

TPS628

Background: Axillary lymph node dissection (ALND), which can induce lymphedema, has been omitted in clinically node-negative(cN0) patients with positive sentinel lymph nodes (SLNs) if they meet the eligibility criteria of ACOSOG Z0011. Furthermore, the omission of ALND has been attempted through targeted axillary dissection (TAD) in patients whose cN+ status converts to ycN0 after neoadjuvant chemotherapy. However, ALND remains the standard of care in patients with cN+ who undergo upfront surgery. The aims of this trial are to establish a surgical method of tailored axillary surgery (TAS), which combines TAD and SLN biopsy among patients with cN+ who undergo upfront surgery, and to determine the appropriate criteria for a Phase III TAS trial. Methods: We have planned a single-arm Phase II trial to confirm the feasibility and assess patient eligibility for TAS. A total of 300 patients will be enrolled from 33 study sites in Japan. The eligibility criteria are as follows: 1) histologically-proven invasive breast cancer, 2) upfront surgery is planned, 3) pathologically-diagnosed metastatic lymph node (cytology or core needle biopsy), 4) 1-3 LN metastases in level I by imaging, 5) cT1-3, and 6) females aged ≥18 and ≤74 years on the enrollment date. TAS involves removing marking lymph nodes by TAD (clip, wire, or tattoo) and SLNB, and ALND up to Level II are performed after TAS. These LNs are defined as non-TAS LNs. The primary endpoint is the non-TAS LNs positive rate. Clinicopathological factors (the number of suspected metastases by imaging, the number of metastases in LNs resected by TAS, tumor size, and invasive ductal/lobular carcinoma) are analyzed to predict the non-TAS LN metastasis rate (e.g., < 10%). By using these clinicopathological factors, we determine the eligibility of TAS to omit ALND safely. The secondary endpoints are TAS LNs identification rate, labeled LNs identification rate, marked lymph node resection rate, arm edema incidence rate, and QOL (FACT-B, QuickDASH). After this feasibility study, we will conduct a phase III trial that omits ALND using TAS to investigate the regional recurrence rate.
Phase 1 dose-escalation, dose-expansion trial of intratumoral HER2- and HER3-primed dendritic cells injections for the treatment of early-stage TNBC and HR low positive breast cancer: DecipHER trial.
Authors: Costa Ricardo L , Childress Jennifer A , Abraham Edith , Farrell Carly , Mo Qianxing , Jameel Zena , Soyano Muller Aixa Elena , Lee Kimberley T , Hoover Susan , Kiluk John , Weinfurtner Robert J , Lee Marie Catherine , Laronga Christine , Khakpour Nazanin , Han Hyo S. , Khong Hung T. , Soliman Hatem Hussein , Czerniecki Brian J.
Published: June 2023

TPS629

Background: Patients with breast cancers (BCs) harboring low expression of hormone receptors (HRs) and human epidermal growth factor receptor-2 (HER2) have poor outcomes. Results from the KEYNOTE-522 trial showed that activation of the immune system using a PD1/PD-L1-targeted approach improves outcomes of patients with these high-risk tumors. Antigen-presenting cells (eg, dendritic cells [DCs]) are pivotal for robust cytotoxic responses due to broader activation of the adaptive immune system (ie, CD4+ and CD8+ Th1) against tumor-associated antigens (ie, HER2 or HER3) expressed by high-risk BCs. Methods: DecipHER is a dose-escalation, dose-expansion phase 1 trial designed to assess the safety and the preliminary efficacy of autologous, HER2- and HER3-primed DCs in combination with KEYNOTE 522 regimen in 30 patients. Patients with clinical stage cT1cN1/2 or cT2-4cN0-2, HR 20, HER2-negative BCs are eligible. Patients with inflammatory BC cancer and uncontrolled immune mediated diseases are excluded. After collection through aphaeresis, autologous DCs will be primed ex vivo against 6 HER2 and 8 HER3 immunogenic peptides. Participants will receive alternating ultrasound-guided intratumoral HER2 and HER3 DC injections administered twice a week for 8 doses in total starting 2 weeks prior to neoadjuvant therapy with KEYNOTE 522 regimen. The dose-escalation phase of the study has 3 planned cohorts (10-20, 30-50, 80-100 million DCs) and follows a 3+3 design (maximum n=18). The 12 additional patients enrolled will be treated at the maximum tolerated dose (MTD) in the dose-expansion cohort. The MTD will be defined as the highest dose level at which < 2 of 6 patients experience dose-limiting toxicities (grade ≥ 3 non-hematologic, ; grade ≥ 3 hematologic toxicity thought be at least possibly related to DCs ; any grade 4 nausea, vomiting, or diarrhea [or grade 3 if duration > 3 days]) during the 5 weeks following treatment initiation with DCs. Secondary endpoints include the absolute risk of adverse events, clinical and pathological responses, and recurrence free survival. Tumor tissue, blood and stool samples will be collected for correlative analyses. The study is open at H. Lee Moffitt Cancer Center. Clinical trial information: NCT05504707 .
A single-arm phase 2 study of peri-operative immune checkpoint inhibition and cryoablation in women with hormone receptor-negative, HER2-negative, early-stage/resectable breast cancer.
Authors: McArthur Heather L. , Comen Elizabeth Anne , Bryce Yolanda , Solomon Stephen Barnett , Leal Jorge Henrique S. , Abaya Christina DiLauro , Martinez Cristal , Basho Reva K , McAndrew Philomena , Larkin Brigid , Page David B. , Mellinger Staci L. , Fredrich Nicole , Moxon Nicole , Reddy Sangeetha M. , Carter Meredith , Patil Sujata , Dogan Basak , Gatti-Mays Margaret Elena , Norton Larry
Published: June 2023

TPS635

Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with immune checkpoint inhibition (ICI) augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ICI [ipilimumab (ipi) +/- nivolumab (nivo)] was safe in patients (pts) with operable, early stage breast cancer (ESBC) and generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ICI in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible women are ≥18y, with ER <10%, PR <10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. As of 2/14/21, 16/80 pts have been enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and received ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts received 3 additional doses of nivo at 240mg IV Q2 weeks. To reflect the US FDA approval of curative-intent pembrolizumab (pembro) in 2021, the protocol was recently amended to allow standard-of-care pembro as an alternative ICI option. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686 .