bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant immunotherapy in clinical stage III melanoma: Real life experience in the community setting.
Authors: Mahmoud Fade , Gimbel Mark , Toledo Ryan , Abbott Jordan , Shellenberger Thomas D. , Tomeh Chafeek , Healy Mark Andrew , Dave Vishangi 
Published: July 2024

e21556 Background: There is a paradigm shift in the management of clinical stages IIIB-IIID melanoma. Results from phase II clinical trials revealed higher pathologic response rates in the neoadjuvant versus adjuvant setting. Methods: We conducted a retrospective study of patients with clinical stages IIIB-IIID melanoma who were deemed suitable for surgical resection and treated with neoadjuvant immunotherapy between January 2019 and December 2023. Patients must have had at least one cycle of neoadjuvant immunotherapy with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). The primary objective was to assess pathologic and radiologic response rates and to determine the association of pathologic response with event free survival (EFS). Results: Thirty-one patients were enrolled with a median age of 60 (range: 31-84) years. 61% of patients received two cycles, 3 weeks apart, of intravenous (IV) ipilimumab 1mg/kg and nivolumab 3mg/kg, while 23% received one cycle of IV ipilimumab 1mg/kg and nivolumab 3mg/kg followed by two cycles, 2 weeks apart, of IV nivolumab 240 mg. Twenty-nine patients underwent therapeutic lymph node dissection; of those 66% had a pathologic complete response (pCR) and 79% had an overall pathologic response. Complete radiologic response using RECIST 1.1 was detected in 28% and radiologic partial response in 56%. Next gene sequencing revealed a total of 47 mutations with BRAF V600 mutation being the most frequently encountered (28%) followed by mutations in TERT promoter (21%) and CDKN2A loss (13%). Two patients died during follow up. One patient refused surgery after neoadjuvant immunotherapy and passed away 4 years later due to stage IV melanoma. The second patient died two years after his surgery due to brain metastases despite achieving a complete pathologic response to neoadjuvant immunotherapy. Any grade adverse events (AE) were detected in 76% of patients; 64% grades 1-2 and 12% grades 3-4. Colitis was the most encountered grade 3 and 4 AE. Three-year event-free survival among 23 evaluable patients who had at least 6 months of follow up after surgery was 95%. Conclusions: Neoadjuvant immunotherapy with ipilimumab and nivolumab resulted in a high pathologic response rate of 79%. A discrepancy was detected between pathologic and radiologic responses. Colitis was the most common grade 3 and 4 toxicity. Three-year event free survival was 95%. Two patients died due to development of stage IV melanoma.
Ulcer-related cutaneous squamous cell carcinoma: New kid on the block.
Authors: Miodovnik Mor , Ospovat Inna , Gutfeld Orit , Finkel Inbar , Dolev Yardenna , Leshem Yasmin 
Published: July 2024

e21559 Background: Cutaneous squamous cell carcinoma (cSCC) represents a favorable tumor microenvironment with high tumor mutational burden, and infiltration of immune cells that are highly responsive to immunotherapies. Yet, we encounter tumors arising on non-exposed skin, such as those developing from chronic ulcers in which the response to anti-PD1 is unknown. Methods: The authors reviewed the medical records of consecutive cSCC patients receiving Cemiplimab or Pembrolizumab at a single tertiary center. Results: Of the 84 eligible patients, 9 (11%) had ulcer-related cSCC. six out of the nine (67%) were located on the lower extremities. Only two out of these nine patients (22%) reached partial response (PR) and none reached complete response (CR). In contrast, of the 75 patients with non-ulcer-related cSCC, 40 had PR (53%), and 20 had CR (26%). The difference between the two subtypes was significant (P < 0.001). Interestingly, two of the seven non-responders in the ulcer-related subtype received second-line chemo-immunotherapy and experienced a partial response that continued for 21 and 8 months. Patients with ulcer-related SCC had a significantly shorter median progression-free survival (PFS) (2.1 months vs. non-reached, p < 0.001). Overall survival (OS) was also shorter, but didn't reach significance (17 vs. 30 months, p = 0.02). Multivariate analysis confirmed ulcer-related SCC as an independent risk factor for shorter PFS (hazard ratio [HR], 7.56; 95% confidence interval [CI], 1.26-40.74, p = 0.027). Conclusions: This study suggests immunotherapy is less beneficial in ulcer-related SCC. More work is needed to verify our findings and explore other treatment options including chemoimmunotherapy.
A randomized, multicenter, open-label, phase 2 study of TRK-950 in combination with ramucirumab and paclitaxel as second-line therapy in patients with Caprin-1 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Authors: Kelly Ronan Joseph , Castillo Dani Ran , Yamaguchi Kensei , Kato Ken , Kudo Toshihiro , Wainberg Zev A. , Rha Sun Young , Lee Jeeyun , Ryu Min-Hee , Okano Fumiyoshi , Shitara Kohei 
Published: July 2024

TPS4181 Background: Caprin-1 is strongly expressed on the cell membrane of many cancer types including G/GEJ and on cancer stem cells. High expression is associated with enhanced in vitro colony-forming activity and in vivo tumorigenicity. TRK-950 is a first in class humanized antibody targeting CAPRIN-11). In the phase I study (NCT02990481), TRK-950 was well tolerated as monotherapy with no DLTs and MTD not reached at doses of 3-30mg/kg IV weekly. Subsequently the Phase 1b study demonstrated that TRK-950 was well tolerated with a high potential for synergistic anti-tumor activity when used in combination with standard of care treatment(s) in selected advanced solid tumors (NCT03872947). Specifically, Regimen D which evaluated TRK-950 in combination with Ramucirumab and Paclitaxel in G/GEJ showed a DCR of 100% in all nine patients receiving 10 mg/kg and partial responses were seen in 5/9 (55%) patients. Caprin-1 strong expression was observed in 4/9 patients and an ORR of 100% was seen in those patients2). A Phase II clinical trial in gastric/GEJ cancer patients with strong Caprin-1 expressions is now enrolling patients. Methods: The phase II study is a multi-national, open-label, randomized, multicenter study evaluating the efficacy of TRK-950 in combination with ramucirumab (Ram) + paclitaxel (PTX ) as compared with Ram + PTX treatment alone in patients with previously treated metastatic G/GEJ adenocarcinoma (NCT06038578). Patients enrolled across 10 sites in Japan, South Korea and the United States are randomized 1:1:1 by the permuted block method to (arm A) TRK-950 5mg/kg plus Ram + PTX, (arm B) TRK-950 10mg/kg plus Ram + PTX or (arm C) Ram + PTX alone. Inclusion criteria include patients with Caprin-1 positive (cutoff; 30% at ≥ 2+ staining) advanced/metastatic G/GEJ adenocarcinoma who have received first line therapy. Key exclusion criteria include HER2 positive disease. The primary endpoint is progression free survival (PFS) based on Independent Central Review (ICR) assessment per RECIST v1.1. Key secondary and exploratory endpoints include overall survival (OS), ORR, DoR, and biomarker evaluation. An interim analysis will be performed after 105 patients are randomized in stage 1 to determine the optimal dose of TRK-950 (5mg/kg or 10mg/kg) that will be evaluated in arm stage 2. In total 146 patients will be enrolled (40 patients in one arm and each 53 patients in two arms). This study opened in September 2023. 1. Okano F, et al. Cancer Res Commun. 2023 Apr 18;3(4):640-658. 2. Cassier P, et al. J Clin Oncol. 2023 Vol. 41, No. 4, suppl. Clinical trial information: NCT06038578 .
Phase 1/2 randomized, open-label, multicenter, Simon two-stage study of pelareorep combined with modified FOLFIRINOX +/- atezolizumab in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Arnold Dirk , Loghmani Houra , Cheetham Karol , Trauger Richard , Heineman Thomas Charles 
Published: July 2024

TPS4203 Background: Immune therapies benefit only the small subset of metastatic pancreatic ductal adenocarcinoma (mPDAC) patients who have microsatellite instability-high (MSI-H) tumors (approximately 1%). Most PDAC tumors are microsatellite stable (MSS) and have an immunologically “cold” phenotype with fewer genetic mutations, reduced immune cell infiltration, and downregulated immune checkpoint proteins. These attributes make most mPDAC tumors resistant to conventional immunotherapy including checkpoint inhibitors. Pelareorep is a naturally occurring, non-genetically modified reovirus that selectively infects cancer cells following intravenous administration. Upon infection, pelareorep’s double-stranded RNA genome stimulates a pro-inflammatory response that primes tumors for immunologic killing. This includes increased T cell infiltration into tumors, expansion of tumor-infiltrating lymphocyte clones, increased PD-L1 expression, and stimulation of tumor-directed innate and adaptive immune responses. Pelareorep combined with chemotherapy, checkpoint inhibitors, or both has shown promising efficacy in several malignancies, including mPDAC. This study is designed to evaluate pelareorep plus modified FOLFIRINOX with or without the PD-L1 inhibitor atezolizumab as first-line therapy in patients with mPDAC. Methods: This trial represents a new cohort within the ongoing GOBLET signal finding platform study in gastrointestinal cancers. This is a phase 1/2 randomized, open-label study that uses a screened selection design within a Simon two-stage approach. Eligible patients must be 18 years or older and have newly diagnosed, radiologically evaluable mPDAC with no prior chemotherapy and an ECOG performance status of 0 or 1. Patients are randomized 1:1 to receive either pelareorep + mFOLFIRINOX orpelareorep + mFOLFIRINOX + atezolizumab. The first stage enrolls 15 evaluable patients into each arm. If pre-specified efficacy criteria are met in Stage 1, one or both arms may be expanded to Stage 2 and enroll 17 additional evaluable patients per arm. The first 3-6 patients enrolled into both arms comprise a safety run-in that must be successfully concluded prior to enrolling additional patients. The treatment period consists of 4-week treatment cycles. The primary objectives are 1) safety and tolerability of pelareorep + mFOLFIRINOX with or without atezolizumab and 2) efficacy based on objective response rate per RECIST v1.1. Secondary objectives include duration of response, progression-free survival, and overall survival. In addition, tumor and blood samples are being collected to evaluate the immunological effects of treatment and to explore potential biomarkers of response. Clinical trial information: Eudra-CT: 2020-003996-16.
Targeting replication stress in pancreatic cancer: A phase II trial investigating azenosertib in combination with gemcitabine in second-line advanced pancreatic cancer.
Authors: Huffman Brandon , Horick Nora K. , Bird Alexandra , Gibson Caroline , Brais Lauren K. , Graham Christopher , Schlechter Benjamin L. , Wolpin Brian M. , Aguirre Andrew , D'Andrea Alan D. , Shapiro Geoffrey Ira , Cleary James M. 
Published: July 2024

TPS4211 Background: A major unmet need in pancreatic cancer (PDAC) is molecularly targeted treatment options for patients who develop resistance to first-line platinum chemotherapy. While combined gemcitabine and nab-paclitaxel is commonly used after progression with first-line therapy, the efficacy in the second-line setting is fair, with recent phase clinical trial data demonstrating a median progression-free survival (PFS) of 2.7 months and a median overall survival of 6.6 months (1). In recent years, preclinical work has identified that replication stress is a potential PDAC vulnerability. The WEE1 kinase regulates the checkpoint governing the G2/M transition of the cell cycle to compensate for replication stress. The G2/M checkpoint is critically important in malignancies like PDAC where over 75% of tumors have p53 pathway deficits. Therapies that inhibit cancer cells’ ability to compensate for replication stress are particularly attractive in cancers that have genomic alterations that generate replication stress. It has been demonstrated that in vitro and in vivo PDAC models were exquisitely sensitive to WEE1 inhibition in combination with gemcitabine. Azenosertib (Zn-c3) is an orally available, highly selective, nanomolar inhibitor of the WEE1 kinase and when combined with gemcitabine in PDAC cell lines, synergistic cytotoxicity is observed. Methods: NCT06015659 is an ongoing phase II clinical trial with safety lead-in that is testing the azenosertib WEE1 inhibitor combined with gemcitabine in patients with advanced pancreatic cancer after progression or intolerance with FOLFIRINOX. Subjects are dosed once daily, days 1-5, 8-12, and 15-19 with azenosertib and receive gemcitabine 800 mg/m2 on days 1 and 8 of 21-day cycles. Up to 12 subjects are expected to enroll in the safety lead-in portion based on a typical 3 + 3 design. Once the recommended phase 2 dose is confirmed, we will use a Simon two-stage minimax design to evaluate efficacy where the null hypothesis is that the true 6-month PFS rate is ≤ 24% (unacceptable historical control data) and the alternative hypothesis is that the true 6-month PFS is ≥ 44%. Pretreatment and on-treatment tumor biopsies are incorporated into the trial to identify potential biomarkers of treatment response. Subjects must be able to swallow oral tablets and have measurable disease by RECIST v1.1; prior exposure to gemcitabine is not allowed. Enrollment began November 21, 2023, and is ongoing. 1. Huffman BM, Basu Mallick A, Horick NK, et al. JAMA Netw Open. 2023;6(1):e2249720. Clinical trial information: NCT06015659 .
A randomized, multicenter, open-label phase III trial of hyperthermic intraperitoneal chemotherapy in platinum-resistant recurrent ovarian cancer (KOV-HIPEC-02).
Authors: Lim Myong Cheol , Kim Ji Hyun , Park Eun Young , Jeong Dae Hoon , Lee Yoo-Young , Choi Chel Hun , Lee Sungjong , Lee Shin-Wha , Park Jeong-Yeol , Kim Se Ik , Baek Jong Chul , Ha Hyeong In , Song Yong Jung , Jeon Seob , Lee Taek Sang , Jeon Hye won , Kim Ki Hyung , Park Sang-Yoon 
Published: July 2024

TPS5635 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreductive surgery has emerged to achieve a higher concentration of chemotherapeutic agents and treat micro-metastases on peritoneal surfaces. At advanced staged ovarian cancer treated with neoadjuvant chemotherapy, HIPEC during interval cytoreductive surgery with cisplatin 75-100mg/m2 increases progression-free survival and overall survival (OV-HIPEC-01 and KOV-HIPEC-01). In chemotherapy-naïve ovarian cancer patients, survival benefit is not identified with HIPEC (KOV-HIPEC-01). And the meta-analysis revealed the survival benefit after recent exposure of chemotherapy. In ovarian cancer, HIPEC is thought to overcome chemotherapy resistance. Methods: This trial (KOV-02) is currently actively enrolling, a multicenter, open-label, 1:1 randomized, phase III trial that will enroll 140 patients in platinum-resistant recurrent epithelial ovarian cancer. The trial is registered on ClinicalTrials.gov (NCT05316181). Institutional review board approval was obtained. The first patient was enrolled on April 07, 2022. The experimental arm will receive cytoreductive surgery and HIPEC (Doxorubicin 35mg/m2 and mitomycin 15mg/m2, 41.5-42.0°C) followed by physician-choice chemotherapy, and the control arm will receive physician-choice chemotherapy until disease progression or intolerable toxicity. The primary objective of the trial is to evaluate progression-free survival (PFS) between the HIPEC group and the control group. Secondary objectives are overall survival (OS), cancer-specific survival, safety, and quality of life. Assuming that the enrollment period is three years and the follow-up period is two years, the total number of events required is 121. Based on the log-rank test, the total number of subjects required to prove HR 0.6 with a two-sided alpha of 0.05 and 80% power is 126. Considering 10% drop-out, 140 patients are finally studied. Clinical trial information: NCT05316181 .
Rationale and study design of the KOV-HIPEC-04: A phase III randomized controlled trial in primary stage III and IV ovarian cancer after interval cytoreductive surgery (FOCUS).
Authors: Lim Myong Cheol , Kim Ji Hyun , Park Boram , Lee Jung-Yun , Chang Suk-Joon , Lee Yoo-Young , Choi Chel Hun , Park Jeong-Yeol , Kim Dae-Yeon , Hong Dae Gy , Cho Hyun-Woong , Song Jae-Yun , Kim Yun Hwan , Kim Ki Hyung , Park Sang-Yoon , You Benoit , Jeon Seob 
Published: July 2024

TPS5636 Background: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) during interval cytoreductive surgery increases progression-free and overall survival for patients with stage III ovarian cancer in two randomized controlled trials (OV-HIPEC-01 and KOV-HIPEC-01) in the era of platinum. The aim of this trial is to identify the survival benefit of HIPEC in stage III & IV ovarian cancer with maintenance therapy of bevacizumab and/or PARP inhibitor. Methods: The KOV-HIPEC-04 trial is the international, multicenter, 1:1 randomized, phase III trial that will enroll 520 patients with stage III & IV ovarian cancer who received neoadjuvant chemotherapy. Patients with residual tumor < 2.5mm after interval cytoreductive surgery will be randomized to the trial arm (HIPEC, 41.0-42.0°C cisplatin 75mg/m2, 90 minutes) or control arm. After recovery from surgery, patients will receive postoperative platinum-based adjuvant chemotherapy followed by maintenance therapy with PARP inhibitor or bevacizumab by the institutional guideline based on BRCA/HRD status. The primary endpoint is to evaluate overall survival (OS); secondary objectives are progression-free survival (PFS), cancer-specific survival, time to the first subsequent therapy, safety, and quality of life. Assuming that the enrollment period is 5 years and the follow-up period is 3 years, the total number of events required is 263. Based on the log-rank test, the total number of subjects required to prove HR 0.67 with a two-sided alpha of 0.05 and 90% power is 494. Considering 5% drop-out, 520 patients are finally enrolled. ClinicalTrials.gov (NCT05827523). Clinical trial information: NCT05827523 .
GOG 3088: A randomized phase II study of letrozole versus observation in patients with newly diagnosed uterine leiomyosarcoma.
Authors: Corr Bradley , Sill Michael , Klein Jennifer , Herzog Thomas J. , Coleman Robert L. , Slomovitz Brian M. 
Published: July 2024

TPS5643 Background: Uterine leiomyosarcomas (uLMS) are rare, accounting for less than five percent of all malignant uterine neoplasms. Approximately 85% of women present with clinical stage I disease (i.e., disease limited to the uterus and cervix). NCCN guidelines for stage I uterine confined disease currently recommend observation; however, recurrence risk of uLMS overall is quite high at 50-70% within the first two years. The estrogen receptor (ER) is expressed in 40-87% of leiomyosarcomas. Because of this high expression, estrogen may act as a growth factor that stimulates cell proliferation and tumor growth. Subsequently, there have been several evaluations for the use of aromatase inhibitors as single agent therapy for uLMS. These trials have each shown varying degrees of clinical activity. We hypothesize that by decreasing systemic estrogen using an aromatase inhibitor we will prolong the time to recurrence for patients with this disease. Methods: This is a GOG Foundation led phase II randomized controlled trial comparing letrozole (2.5mg PO daily) to observation in newly diagnosed patients with uterine confined stage I uLMS. Forty patients will be randomized 1:1. Patients will be eligible post operatively if they have no measurable disease and will be required to be estrogen receptor (ER) positive, as defined by ³ 10% expression by immunohistochemistry (IHC). No stratification methods will be applied. The primary endpoint of the trial is investigator-assessed progression free survival. Exploratory translational evaluation will occur to 1) correlate response to letrozole based on IHC hormone receptor status, 2) evaluate gene expression signatures of hormone receptor activity, tumor biology, and tumor microenvironment in relation to response to letrozole, and 3) evaluate the contribution of single nucleotide polymorphism rs3820282 to tumor biology and response to letrozole. GOG 3088 activated in January of 2024 and expects to enroll across 20 US sites. Clinicaltrials.gov Identifier: NCT05649956. Clinical trial information: NCT05649956 .
Phase II trial assessing safety, efficacy and immune correlates of heterologous prime-boost with pBI-11 (IM) and TA-HPV (IM) plus pembrolizumab for advanced, PD-L1 CPS≥1, hrHPV+ oropharyngeal cancer.
Authors: Gibson Michael K. , Roden Richard , Wu TC , Heimann-Nichols Ellen 
Published: July 2024

TPS6118 Background: HPV-related OPSCC occurs in younger patients, has a significantly better prognosis, and is most often caused by HPV subtype 16. There is a 90% overall survival for HPV+/p16+ OPSCC (40% for HPV-/p16- OPSCC), which can be cured with multimodality care. For patients with R/M disease, treatment with pembrolizumab (P) +/- chemotherapy is palliative, with a median OS of approximately 12 months for patients with PD-L1 combined positive score (cps) >1 treated with P alone. Heterologous prime boost with DNA priming followed by vaccinia-based boosting against HPV16 viral antigens will be studied using pBI-11 [(DNA vaccine pNGVL4a-SigE7 (detox)/HSP70, HPV16 E7(detox)/ HPV18 E7(detox), HPV16 E6(detox), and HPV18 E6(detox)] followed by TA-HPV (recombinant vaccinia-human papillomavirus (denoted TA-HPV) derived from the Wyeth strain of vaccinia which carries modified E6 and E7 genes from HPV types 16 and 18). This study is approved by the Vanderbilt University IRB and is open accrual (NCT NCT05799144). Methods: Patients with R/M, HPV positive OPSCC without prior therapy for R/M disease, without contraindications to immunotherapy and with a PD-L1 cps > 1 will be screened. There is a 6 patient safety run-in. Treatment with pBI-11 vaccine (2 IM injections on weeks 1 and 4) plus one IM administration of TA-HPV on week 7 will be given in combination with P IV on weeks 1, 4, and 7). Following restaging, all patients will continue (including those with PD) with 3 more cycles of P followed by restaging. The primary clinical outcome is RR to addition of vaccine in the 50% of predicted P non-responders (NR) who proceed to Part II (ie conversion to responders). All responders will continue to receive P until progression. Approximately 54 patients with be enrolled. Two research tumor biopsies and blood draws will be obtained pre- and on treatment (week7-9). Tumor tissue cores will be utilized for immunohistochemical and molecular tests (e.g., expression of immune cell and viral markers, TCR sequencing and total transcripts). Blood with be tested for HPV16/18 E6, E7 antibodies and vaccinia virus neutralizing assays; proliferative responses of peripheral blood lymphocytes to stimulation by HPV16/18 E6 and E7; HPV16/18 E6- and E7-Specific T cells; and HPV DNA in plasma. Data from the 1st four patients enrolled will be presented. Clinical trial information: NCT05799144 .