tbuckley/cabot-search huggingface dataset:
First-in-human, phase I study of CBP-1008, a first-in-class bispecific ligand drug conjugate (Bi-XDC), in patients with advanced solid tumors.
Authors: Ning Li, Jifang Gong, Jian Zhang, Dan Liu, Yaqing Chen, Youzhong Zhang, Yi Huang, Jing Wang, Jie Tang, Guiling Li, Ying Wang, Junyan Wu, Suxia Luo, Ge Lou, Wei Duan, Robert Huang, Mo Xu, Xichun Hu, Lingying Wu, Lin Shen
Journal: Journal of Clinical Oncology (2024)

5556 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload and is administered by intravenous infusion Q2W. Methods: This phase 1 study includes the dose-escalation of Ia and the dose-expansion of Ib. The phase Ia started with accelerated titration (0.015, 0.03mg/kg) and then switched to 3+3 design (0.12, 0.15, 0.17, 0.18, 0.20mg/kg). Phase Ib dose-expansion study includes 4 cohorts, platinum-resistant high-grade serous ovarian cancer (HGSOC), other sub-types of ovarian cancer such as clear cell ovarian cancer (OCCC) and low-grade serous ovarian cancer, metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective is to assess the safety and preliminary efficacy. Results: As of December 8, 2023, 240 patients (phase Ia: n=40; phase Ib: n=200) have been enrolled including 136 HGSOC,17 OCCC, 24 TNBC and 63 other tumor types. Majority of adverse events were mild to moderate. Common (≥50%) treatment-related AEs (TRAEs) were neutropenia, WBC decreased, AST increased, pyrexia, ALT increased and nausea. Grade 3/4 TRAEs (≥5%) were neutropenia (49%), WBC decreased (26.8%), AST increased (5.9%), ALT increased (5.9%), anaemia (5.4%). 41 HGSOC patients at dose of 0.15mg/kg with ≤3 prior treatment regimens, regardless of FRα expression levels were evaluable for efficacy assessment. 13 patients achieved partial response (PR) and 29 patients achieved stable disease (SD). The objective response rate (ORR) and the disease control rate (DCR) were 31.7% and 70.7%, respectively. For 19 patients with FRα expression level 0 to 49%, 6 patients achieved PR and ORR was 31.6%. The longest treatment duration exceeds 13 months. Conclusions: The current result showed that CBP-1008 demonstrated manageable safety profile. Promising antitumor activity was observed in ovarian cancer patients at dose of 0.15mg/kg, especially in platinum-resistant HGSOC patients with ≤3 prior treatment regimens. CBP-1008 has the potential to provide a better treatment option for ovarian cancer patients regardless of FRα expression levels. Clinical trial information: NCT04740398 .
Phase 2, single arm clinical trial to evaluate the safety and activity of oregovomab and niraparib as a combinatorial immune priming strategy in subjects with platinum sensitive recurrent ovarian cancer: FLORA-4 study.
Authors: Linda R. Duska, Angeles Alvarez Secord, Debra L. Richardson, Srinivas Rao Jada, Sunil Gupta
Journal: Journal of Clinical Oncology (2024)

5586 Background: Oregovomab, a murine IgGκ1 MAb, with high affinity binding (1.16 x 10 10 /M −1 ) to the tumor associated antigen CA125 acts as a therapeutic vaccine inducing indirect immunization by cellular and humoral immune responses directed against CA125. We hypothesize that T cells which have been immune sensitized by oregovomab may be further activated in the presence of niraparib mediated induction of STING (STimulator of INterferon Genes). The primary objective was to assess the safety and activity of combination oregovomab and niraparib in platinum sensitive EOC. Methods: An open-label single arm Phase 2 evaluation of the combination of oregovomab and niraparib in subjects previously treated with 1 to 3 lines of platinum-based chemotherapy. All subjects received the niraparib and oregovomab. The daily dose of niraparib was weight based (200-300 mg) taken orally from Day 1 Week 1 to at least the end of Week 12. Oregovomab (2 mg) was administered at Day 1 of Weeks 1, 4, 7, 12, and 20. This study endpoints were disease control rate (DCR) defined as patients that achieved CR, PR and SD; early humoral response; and safety. Results: Between July 2022 and June 2023, 10 eligible patients with a median age was 67.5 years were enrolled, and all patients were included in this analysis. 6 patients had received 2 prior lines and 4 patients had received 1 prior line of chemotherapy. Five patients received prior PARP inhibitors, 1 patient with HRD, and 1 patient with gBRCA mutation. The median number of oregovomab doses administered were 5 (range, 2.0 to 5.0) and median niraparib doses were 118.5 (range, 28.0 to 168.0). Of the 10 patients enrolled, 1 patient (10%) achieved an objective partial response (PR) and 5 patients had disease stabilization (SD), for an overall DCR of 60% at 12 weeks assessment. Of the 5 patients with SD, 2 maintained SD until week 24 assessment while the remaining patients progressed. The duration of response in the 1 patient with objective response was 2.9 months and the median duration of DCR is not evaluable (range 2.9 months - NE). Treatment related all grades adverse events (AEs) to niraparib included anemia (30%), thrombocytopenia (30.0%) and hypertension (30.0%), and oregovomab related all grades AEs included urticaria in 1 patient (10%). Conclusions: Combination oregovomab and niraparib in patients with platinum sensitive EOC was well tolerated with no new safety signals. Translational research is ongoing to assess biomarkers of early humoral response. Clinical trial information: NCT04498117 .
Prospective evaluation of the effect of 3 days of post-chemotherapy dexamethasone on patient reported symptoms in gynecologic oncology patients treated with carboplatin and paclitaxel.
Authors: Hayley Hart, Christopher Morse, Thomas C. Krivak, Eirwen Murray Miller, Sarah Crafton, Alyssa Wield, Alexander Olawaiye, Ali Imran Amjad, Emily Graham, Tammy Li, Heather English, Donna Marie Kinzler, John Nakayama
Journal: Journal of Clinical Oncology (2024)

5618 Background: Chemotherapy is associated with many adverse side effects including nausea, myalgia, and emotional stress. Some providers recommend three days of dexamethasone (supplemental dexamethasone) following chemotherapy in an effort to mitigate these toxicities. This study seeks to determine if supplemental dexamethasone affects patient-reported outcomes in patients receiving carboplatin and paclitaxel. Methods: Patients with gynecologic malignancies receiving carboplatin and paclitaxel every 3 weeks were eligible. In this prospective case-control study, patients receiving (cases) supplemental dexamethasone (8mg once daily x 3 days starting on post-chemotherapy day 1) were compared with those patients that did not receive delayed dexamethasone (controls). Decision for supplemental dexamethasone was based on provider’s discretion. The FACT-G7, a validated survey assessing the impact of chemotherapy on patients’ quality of life, was administered by telephone one week after each chemotherapy cycle for up to 6 cycles. Pain during post-chemotherapy days 1-3 was also assessed with an additional survey question. FACT-G7 composite score was our primary outcome of interest. The student’s t-test was used to compare the FACT-G7 and average pain scores between cases and controls at each survey point. Results: Fifty-two patients were enrolled, 26 received supplemental dexamethasone and 26 did not. At interim analysis, 94% of subjects have completed all 6 survey time points. The initial response rate was 98.0%. FACT-G7 scores (Table) were significantly higher, corresponding to less symptoms, in patients treated with supplemental dexamethasone after cycles 4-6. Pain scores in post-chemotherapy days 1-3 were lower following cycle 3 for the supplemental dexamethasone group (p=.0083). Conclusions: Supplemental dexamethasone after carboplatin and paclitaxel for patients with gynecologic malignancies improves patient-reported outcomes. This improvement was limited to cycles 4-6, suggesting possible mitigation of cumulative chemotherapy toxicities.[Table: see text]
Outcomes of reduced dosing of lenvatinib with pembrolizumab for advanced endometrial cancer.
Authors: Quang Dang Ta, Connie Do, Kavita Sharma, Hormozan Sorooshian, Merta Cushing, Nina Shah, Michael A. Bookman, Juraj Kavecansky, Fang Niu, Rita L. Hui
Journal: Journal of Clinical Oncology (2024)

5588 Background: The advent of immunotherapy combined with multitargeted tyrosine kinase inhibitors has significantly improved the treatment of platinum-resistant endometrial cancer (EC). The phase three 309–KEYNOTE-775 trial demonstrated a survival benefit with lenvatinib/pembrolizumab in patients with mismatch repair-proficient (pMMR) advanced EC. However, lenvatinib was discontinued in 31% of patients and dose reduced in 67% due to adverse events (AE). Retrospective reports suggest that reduced dosing for lenvatinib may result in fewer dose reductions, longer time to treatment-related toxicity, and better tolerability without compromising effectiveness. Methods: This multisite, retrospective, cohort study evaluated various dosing strategies of lenvatinib in Kaiser Permanente (KP) California patients treated with lenvatinib/pembrolizumab for pMMR advanced EC between September 1, 2019 and June 30, 2023, and followed through end of membership, December 31, 2023, or death, whichever occurred first. Patients were grouped based on their initial lenvatinib dose: 20 mg daily (Group 1), &lt;20 mg daily (Group 2), and 20 mg daily 5 of 7 days per week (Group 3). The primary outcome was 6-month progression-free survival (PFS); secondary outcomes included incidence rate of lenvatinib dose discontinuation or dose reduction due to AE. Primary analysis of outcomes was performed between Groups 1 and 2; Group 3 was described but not compared to other groups due to small sample size. Results: A total of 369 patients were included in this study (Group 1, n=204; Group 2, n=154; Group 3, n=11). Baseline characteristics were similar between all three groups with mean age of 66.6 ± 9 years; mean body mass index of 29.6 ± 8 kg/m 2 ; and median number of prior lines of systemic therapy of 1 (IQR 1-2). There was no difference in PFS at 6 months between Groups 1 and 2 (40.2% and 33.8%, respectively; p=0.26). There was no difference between Groups 1 and 2 in the rate of lenvatinib discontinuation due to AE (7.2 and 6.6, respectively, per 100 person-year; p=0.61). However, a significantly higher incidence in dose reduction was found in Group 1 when compared to Group 2 (28.1 vs 14.3 per 100 person-year; p&lt;0.01). Conclusions: A lower lenvatinib starting dose (&lt;20 mg daily) in combination with pembrolizumab was no different to the FDA-approved daily dose of 20 mg for the treatment of advanced EC with respect to 6-month PFS. In addition, those who received a lower starting dose experienced fewer dose reductions but no difference in dose discontinuation due to AE. Prospective studies of dose and schedule are needed to confirm these findings and define an optimal dosing strategy.
Prognostic analysis of nimotuzumab combined with concurrent chemoradiotherapy in locally advanced cervical cancer: A multicenter real-world study.
Authors: Jiwei Li, Tao Wu, Manbo Cai, Changjun Xie, Sijuan Ding, Wen Zou, Jingjing Wang
Journal: Journal of Clinical Oncology (2024)

5532 Background: Nimotuzumab is a monoclonal antibody against EGFR, which can improve the radiotherapy efficacy of nasopharyngeal carcinoma with EGFR positive. Most cervical cancers are induced by virus and express EGFR. Therefore, this study explores the efficacy and safety of Nimotuzumab combined with concurrent chemoradiotherapy (CCRT) in locally advanced cervical cancer (LACC). Methods: Information on patients with stage IIB-IVa cervical cancer who received CCRT combined with Nimotuzumab or CCRT alone at five cancer centers from January 2021 to December 2022 were collected. Nimotuzumab was administered 200mg once a week for a total of 6 weeks, starting on the same day as CCRT. The imaging examination was carried out 2 months after the end of radiotherapy. The reduction rate of lesions = (pre-treatment diameter - post-treatment diameter)/pre-treatment diameter. Patients were classified into the Nimotuzumab group and No-Nimotuzumab group. Categorical variables were compared using the χ2 test or Fisher’s exact test. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. Results: There are 224 patients enrolled, median age 57 years (32–90 years). The median follow-up time was 20 months (12–36months). The 2-year overall survival (OS) and progression-free survival (PFS) rates were 93% and 89.5%, respectively. The objective response rate (ORR) was 91.96%. There were 64 patients in Nimotuzumab group and 160 patients in No-Nimotuzumab group. The number of patients in Nimotuzumab group with stage IIIC and IVa, as well as those without chemotherapy, is higher than that in No-Nimotuzumab group. There was no significant difference between the Nimotuzumab and No-Nimotuzumab groups in terms of 2-year OS rate (93.2% vs.93%, p = 0.895), and PFS rate (96.2% vs.90.4%, p = 0.645). However, The Nimotuzumab group has a better CR rate (53.13% vs. 35%, P=0.012), ORR (98.44% vs. 89.38%, p=0.024), and reduction rate of cervical lesions (79.26% vs.70.94%, p=0.046) compared to the No-Nimotuzumab group (Table). Also, there was no significant difference between the Nimotuzumab and No-Nimotuzumab groups in terms of hematological toxicity (89.83% vs. 94.48%, p=0.730), nausea and vomiting (35.59% vs. 38.19, p=0.865), radiation proctitis (45% vs. 33.1%, p=0.371), radiation cystitis (8.47% vs. 7.64%, p=0.761), and grade 3-4 toxicities. Conclusions: The combination of Nimotuzumab and CCRT for LACC has a better reduction rate of lesions and ORR, without increasing side effects. [Table: see text]
Standing out: an atypical salience account of creativity
Authors: Madeleine E. Gross, Jonathan W. Schooler
Journal: Trends in Cognitive Sciences (2024)

Creativity often entails gaining a novel perspective, yet it remains uncertain how this is accomplished. Atypical salience processing may foster creative thinking by prioritizing putatively irrelevant information, thereby broadening the material accessible for idea generation and inhibiting attentional fixedness; in essence, motivating creative individuals to incorporate information that others overlook.
Final safety results from ATHENA–MONO (GOG-3020/ENGOT-ov45), a randomized, placebo-controlled, double-blind, phase 3 trial evaluating rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer.
Authors: David M. O'Malley, Bradley J. Monk, Myong Cheol Lim, Jose Fuentes Pradera, Joseph Buscema, Michelle K. Wilson, Rocco De Vivo, Thomas J. Herzog, Flora Zagouri, Amit M. Oza, Olga N. Mikheeva, John Paul Diaz, Alla Sergeevna Lisyanskaya, Robert Morris, Ilan Bruchim, Marcia Craib, Christy Connor, Danny Shih, Keiichi Fujiwara, Rebecca Kristeleit
Journal: Journal of Clinical Oncology (2024)

5554 Background: Rucaparib provided a sustained progression-free survival benefit in patients (pts) with newly diagnosed advanced ovarian cancer after first-line treatment in the phase 3 ATHENA-MONO study (NCT03522246). We report final safety analyses (data cutoff 09 Mar 2023). Methods: Rucaparib was administered in 28-day cycles. Eligible pts were randomized 4:1 to oral rucaparib 600 mg BID (N=427) or placebo (N=111), with a treatment cap defined as 24 months. The safety population included randomized pts who received at least 1 dose of study drug (rucaparib, n=425; placebo, n=110). Results: All ATHENA-MONO pts discontinued treatment as of 24 Nov 2022 with a median treatment duration of 15 months and 35% of pts reaching the 24-month treatment cap. The median (range) relative dose intensity was 89% (30-110) for rucaparib. The rate of treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, TEAEs leading to interruption, dose reduction, or discontinuation with rucaparib remained consistent with the primary endpoint analysis with some minor changes (see Table below). Most common grade ≥3 TEAEs were anemia/decreased hemoglobin (28.7%), neutropenia/decreased neutrophils (14.6%), increased ALT/AST (10.6%), and thrombocytopenia/decreased platelets (7.3%). The most common TEAEs leading to discontinuation were anemia/decreased hemoglobin (3.5%), asthenia/fatigue (4.9%), and nausea (2.1%). Hypertension continued to be the most common TEAE observed in the placebo group (3.6%) compared with 1.6% in the rucaparib group. There were no changes in the incidence of serious adverse events or TEAEs leading to death since the primary endpoint analysis. Myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) were reported in a total of 3 pts in the rucaparib group (1 MDS during treatment [0.2%] and 1 AML and 1 MDS during long-term follow-up [0.5%]), of which the latter occurred since the primary readout. The initial MDS event that occurred during treatment, included in these incidence numbers, was considered resolved by the investigator since the initial analysis. Conclusions: Long-term maintenance treatment with rucaparib demonstrates a consistent and manageable safety profile in a broad population of pts with newly diagnosed ovarian cancer. No new safety signals were identified. Adverse events were generally manageable and led to discontinuation in a low proportion of pts. Clinical trial information: NCT03522246 . [Table: see text]
Gemcitabine plus cisplatin in recurrent ovarian, fallopian tube, and primary peritoneal cancer.
Authors: Mostafa Eyada, Bryan M. Fellman, Shrina Patel, Victoria Michael, Pamela T. Soliman, Travis T. Sims, Jeffrey Andrew How, Amir A. Jazaeri, Nicole D. Fleming, Lois M. Ramondetta, Shannon Neville Westin
Journal: Journal of Clinical Oncology (2024)

5548 Background: Our objective was to explore safety and efficacy of gemcitabine plus cisplatin for treatment of patients with recurrent ovarian, fallopian tube and primary peritoneal cancer (OC). Methods: This single institution retrospective analysis conducted at MD Anderson Cancer Center, included patients with recurrent platinum sensitive (PSOC) or resistant (PROC) OC treated with gemcitabine plus cisplatin. Treatment doses were cisplatin 30-40 mg/m 2 and gemcitabine 600-800 mg/m 2 . Utilized regimens were as follows: 1) cisplatin Day 1 (D1), gemcitabine D1 on 21-day cycle; 2) cisplatin D1, gemcitabine Day 8 (D8) on 21-day cycle; or 3) cisplatin/gemcitabine every 2 weeks on 28-day cycle. Objective response rate (ORR= complete response (CR) + partial response (PR)) was calculated along with 95% confidence interval (95%CI). Adverse events were collected and graded. Results: One hundred and seventy-six patients were included; 90% had high grade serous OC and 95% were stage III/IV at diagnosis. Subjects received a median of 3 prior lines of therapy (range 1-10). ORR was 44.1% (95% CI: 36.6-51.9) with 12 CR (7%), 64 PR (37%), 42 SD (24%) and 54 PD (31%). One hundred sixteen (66.6%) patients discontinued treatment due to disease progression after median 3 cycles (range 1-19). Among responders, median number of cycles with response was 3 (range 2-13). Twenty-three percent of subjects had PSOC with ORR of 61.5% and 76.1% had PROC with ORR of 39.4% (p =0.014). Number of prior lines of cytotoxic treatment or prior use of bevacizumab wasn’t associated with response to treatment. Median platinum free interval was associated with response to therapy (5 months in responders vs 3 months in non-responders; P=0.007). Forty-four percent of patients had adverse events, with most common being thrombocytopenia (12%), neutropenia (9%), and neurotoxicity (10%). Conclusions: Cisplatin in combination with gemcitabine demonstrates activity regardless of platinum sensitivity status in patients with recurrent ovarian cancer. However, longer platinum-free interval is associated with improved response to this therapy.
Efficacy of olaparib combined to metronomic cyclophosphamide and metformin in patients with recurrent advanced/metastatic endometrial by molecular subtypes: ENDOLA phase I/II trial.
Authors: Benoit You, Alexandra Leary, Philippe Follana, Cyril Abdeddaim, Florence Joly, Sylvie Bin, Laurent Villeneuve, Marine Alexandre, Maxime Bonjour, Vérane Schwiertz, Anais Boulai, Manuel Rodrigues, Max Piffoux, Gilles Freyer, Celine Callens
Journal: Journal of Clinical Oncology (2024)

5605 Background: In patients with recurrent advanced endometrial carcinomas (EC), innovative treatments are needed after platinum chemotherapy and immunotherapy. EC are characterized by frequent defective DNA repair, along with alterations of PI3K-AKT-mTor, and IGF1R pathways. ENDOLA trial was meant to assess the safety and efficacy of the triplet olaparib (PARP 1-3 inhibitor) + metronomic cyclophosphamide + metformin in patients with advanced recurrent EC. We assessed the outcomes by the 4 molecular EC subtypes (POLE; dMMR/MSI-high; NSMP; P53mutated). Methods: ENDOLA trial (NCT02755844) was an academic French prospective multicenter phase I/II open-label dose-escalation study conducted in 6 French centers. The RP2D was defined as olaparib 300 mg BID combined to metformin 1500 mg/day and metronomic cyclophosphamide 50 mg/day (You et al. Proc AACR 2022). Alterations of POLE, MMR and p53 were assessed using local in-house assays. BRCA &amp; HRD status were centrally defined using shallow Whole Genome Sequencing (sWGS) (HRP/HRD status defined as large genomic alteration (LGA) ≤ 7/≥8). Results: From Sept 2016to Nov 2019, 35 patients enrolled, and 31 were assessable for ITT (median age: 69, IQR: 62-72; endometrioid: n=18 (51.4%); serous: n=11 (35.5%); carcinosarcoma: n=2 (6.5%)). 2 patients (6.5%) were previously treated with immunotherapy. In the whole population, the non-progression rate at 10 weeks (NP10w, primary endpoint) was 61.5%, and median PFS (mPFS) was 5.1 months. The molecular subtype could be defined for 20 patients (64.5%): MSI-high, n=3 (15.0%); NSMP, n= 4 (20.0%); P53mutated, n= 13 (65.0%). The NP10w (&amp; mPFS) were 18.2% (5.1 months), 27.3% (9.0 months), and 54.5% (5.1 months), respectively. The rates of patients with LGA ≤7 (non-HRD)/≥8 (HRD) were 15(48.3%)/8(25.8%). 100% patients with P53wild-type had low LGA≤ 7. No clear impact of LGA score alone was found (LGA≤ 7: NP10w 63.6%, and mPFS 5.1 month; LGA /≥8: NP10w 36.4% and mPFS 5.1 months). By combining LGA and P53, the worse mPFS was for patients with P53mutated &amp; LGA≤ 7 (n=5, 3.1 months), and the best for patients with P53mutated &amp; LGA≥8 (n=10, 8.5 months). Conclusions: In this heavily pre-treated population of patients with advanced EC (55% patients treated with ≥ 4 previous lines; and 50% were &gt; 69 years old), the combination of olaparib + metronomic cyclophosphamide and metformin was highly effective, especially in those with NSMP or with P53mutated &amp; HRD (LGA≥8) subtypes, with mPFS ~8 months. It might a promising therapeutic alternative in recurrent setting. Clinical trial information: NCT02755844 .