tbuckley/cabot-search huggingface dataset:
GCISAVE: A non-comparative randomized phase II study of combination of gemcitabine cisplatin (GCis) +/- avelumab (A) in 1st line treatment for locally advanced or metastatic urothelial bladder carcinoma (MUBC)—GETUG AFU V07.
Authors: Marine Gross-Goupil, Eric Frison, Guilhem Roubaud, Aude Flechon, Fabien Calcagno, Frederic Rolland, Florence Joly, Anne-Aurelie Raymond, Guillaume Chotard, Philippe Barthelemy, Damien Pouessel, Constance Thibault, Stephane Culine, Claude Linassier, Alain Ravaud
Journal: Journal of Clinical Oncology (2024)

637 Background: GCis is the standard 1 st line of MUBC. Immune Checkpoint Inhibitor (ICI) is indicated as maintenance with avelumab (A), in patients (pts) with objective response or stable disease after chemotherapy, or as 2 nd line with Pembrolizumab, in case of disease progression. Survival improvement of combining ICI to GCis still remains under investigation. GCISAVE evaluates the efficacy and safety of combining avelumab (A) with GCis in 1 st line treatment. Methods: GCISAVE is a prospective multicenter randomized (2:1) non-comparative open-label phase II study, assessing the efficacy and safety of 6 cycles of GCis +/- A on a two-stage Bryant-Day design. Pts fit for cisplatin received GCis (G 1000 mg/m2, D1,D8; Cis 70 mg/m2, D1) +/- A (10 mg/kg, D1), every 3 weeks. Stratification was on centre, Karnofsky and visceral vs. non-visceral metastases. Two co-primary endpoints were the objective response rate (ORR) at week 18 (target≥ 60%) and the incidence of grade ≥3 treatment related adverse events (TRAE) (target&lt;30%). Secondary objectives included: duration of response, 18 month PFS and OS;describing ORR according to the expression of PD-L1, immune infiltrate population and proteomics. Results: Between 11/2017 and 11/2020, 65 pts have been included, 42 (GCis+A) and 23 (GCis). Study was stopped prematurely due to the approval of A as maintenance treatment. Clinical characteristics were well balanced. 20 pts (47.6 %) in GCis + A arm and 7 pts (31.8 %) in GCis arm achieved 6 cycles with cisplatin : male (83.3 and 81.8%), median age (68 (62-71) and 67(56-72) yo), M1 stage for 76.2 and 77.3% respectively. 18 pts (42.9 %) in GCis + A and 13 pts (59.1 %) in GCis crossed to carboplatin. At week 18, ORR was 79.5% in the (GCis+A), including 15% Complete Response (RC) (39 pts evaluable), and 59.1% (GCis) arm (22 pts evaluable) respectively. TRAE were reported in 11 pts (26.2 %) in GCis+A arm. An oncoprot signature was obtained for CR and Partial Response compared to Progressive Disease (PD). Conclusions: GCis+A achieved the predefined target values with ORR ≥60% and ≤30% of SAE in 1 st line treatment of MUBC. An oncoprot panel seemed to be correlated to PR, CR vs. PD. Clinical trial information: NCT03324282 .
Validity of renal function eligibility criteria for cisplatin-based chemotherapy for patients with urothelial carcinoma.
Authors: Sai Hi, Yushi Naito, Kyosuke Hattori
Journal: Journal of Clinical Oncology (2024)

638 Background: The eligibility criteria of renal function in cisplatin (CDDP) -based chemotherapy for urothelial carcinoma has generally been a creatinine clearance (CCr) ≥ 60 (mL/min) without adjusting for body surface area (BSA). While CDDP dosage is determined by body surface area, the use of CCr (mL/min) without correction for body surface area as a criterion for cisplatin eligibility may lead to CDDP overdose, especially in obese patients with borderline renal function. CCr with BSA modification (CCr mL/min/1.73 ㎡) may be more appropriate than without BSA modification for assessing renal function in patients with nonstandard body mass. Methods: This retrospective analysis included 82 patients who received CDDP-based chemotherapy as primary systemic treatment for urothelial carcinoma at Nagoya University in the past 10 years. For all patients, CDDP eligibility was determined by CCr mL/min by 24-hour urine collection, and the inclusion criteria for this study were CCr &lt; 80 mL/min. To identify the possibility of a gap between CCr mL/min and CCr mL/min/1.73 ㎡ resulting in cisplatin overdose unit organ function, ΔCCr (difference between CCr mL/min and CCr mL/min/1.73 ㎡) and CDDP/CCr (actual dose of CDDP mg per unit CCr mL/min) were calculated and compared between the obese and standard-body groups. In addition, we compared the incidence of CTCAE Grade ≥3 adverse events (AEs) and the objective response rate (ORR) to chemotherapy in the two groups. In accordance with Japanese standards, BMI ≥ 25 was defined as obese patients. Results: There were no significant differences in patient background between the obese and standard groups in terms of age, gender, cancer type and status, and CDDP dose per unit BSA. CCr mL/min/1.73m2 was similar between the two groups, whereas CCr mL/min was significantly higher in the obese group, which resulted in a significantly higher ΔCCr in the obese group. In addition, CDDP/CCr was also greater in the obese group. Conclusions: The results of the current study suggest that the application of CCr mL/min to the assessment of renal function for CDDP eligibility may lead to CDDP overdosing, especially in obese patients with borderline renal function. Further larger studies are warranted to clarify whether or BSA correction should be applied to assess renal function for CDDP eligibility, since the method for assessing renal function may affect the occurrence of AEs and the efficacy of chemotherapy.
Interim results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager, in patients (pts) with neuroendocrine prostate cancer (NEPC) and other neuroendocrine neoplasms (NEN).
Authors: Himisha Beltran, Afshin Dowlati, Prantesh Jain, Melissa Lynne Johnson, Rachel E. Sanborn, Jonathan Robert Thompson, Hirva Mamdani, Erin L. Schenk, Rahul Raj Aggarwal, Kamya Sankar, Ann W. Gramza, Banmeet S Anand, Noura J. Choudhury
Journal: Journal of Clinical Oncology (2024)

121 Background: HPN328 is a delta-like canonical Notch ligand 3 (DLL3)-targeting T-cell engager. HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for T1/2 extension, and anti-CD3 for T cell engagement and activation. HPN328 treatment resulted in robust and specific anti-tumor activity in preclinical in vitro and in vivo DLL3-expressing NEPC models. Methods: Patients (pts) with relapsed/refractory, metastatic NEPC, small cell lung cancer (SCLC) and other NEN associated with DLL3 expression are eligible. Verification of DLL3 expression is required for NEN other than SCLC or NEPC for eligibility. Primary objectives are safety, maximum tolerated dose (MTD), recommended dose(s) for expansion (RDE) determination, and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. HPN328 is administered IV weekly or biweekly with a priming dose preceding the target dose in higher dose cohorts. Adverse events (AEs) are graded (G) by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Results: As of 21Aug23, 66 pts received HPN328 as a single agent at target doses of 0.015-24 mg across 14 dose escalation cohorts. Ten (10) pts had NEPC and 2 had small cell bladder cancer (SCBC). The remainder were SCLC or other NEN. Median number of prior regimens for all patients was 2 (1-6). Treatment is ongoing in 29 pts, with 3 from early escalation cohorts on study for more than a year. Treatment-related AEs in &gt;10% of pts included CRS (52%), fatigue (35%), dysgeusia (33%), nausea (17%), vomiting and diarrhea (14% each), decreased appetite (12%), and pyrexia (11%). Nearly all CRS occurred after the initial priming dose and not with subsequent infusions. The most common ≥ G3 events were neutropenia (9%) and pneumonia and anemia (5% each). G3 CRS was a dose-limiting toxicity (DLT) in 2 pts at a priming dose of 2 mg; subsequent target dose escalation continued to 24 mg with a priming dose of 1 mg and no further DLTs of CRS; MTD at the target dose has not been reached. The 2 SCBC patients had confirmed partial responses (PR). Of the 10 NEPC patients, 3 of 6 with at least one imaging study had unconfirmed PRs. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. Conclusions: HPN328 is well tolerated and clinically active. MTD determination, dose escalation, and dose optimization are ongoing. Updated safety and efficacy results including recently enrolled NEPC and SCBC pts will be presented. Clinical trial information: NCT04471727 .
Dose modification in enzalutamide and abiraterone plus prednisolone for castration-resistant prostate cancer: Sub-analysis from ENABLE for PCa, a multicenter, randomized controlled trial.
Authors: Kouji Izumi, Atsushi Mizokami
Journal: Journal of Clinical Oncology (2024)

127 Background: Head-to-head comparison between enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) demonstrated similar survival benefit for castration-resistant prostate cancer (CRPC) in ENABLE study for PCa. As it is previously reported that reduced dose of ENZ and ABI can maintain sufficient inhibitory ability of androgen receptor signaling, we analyzed the efficacy of modified dose in ENABLE study for PCa. Methods: ENABLE study for PCa is an investigator-initiated, multicenter, randomized controlled trial conducted in Japan. We analyzed survivals, prostate-specific antigen (PSA) response rate (≥50% decline from baseline), and safety assessment in patients treated with modified dose (ENZ ≤120 mg/day, ABI ≤750 mg/day) compared to those treated with standard dose (ENZ 160 mg/day, ABI 1000 mg/day) as a starting dose. Results: In total 92 patients in each arm treated and analyzed, the number of modified dose patients in the ENZ and the ABI arm was 16 and 16, respectively. Total 32 modified dose patients showed significantly better time to PSA progression (TTPP) and overall survival than 152 standard dose patients (HR 0.47, 95%CI 0.27-0.83, p=0.0379 and HR 0.35, 95%CI 0.19-0.63, p=0.0162). Although there was significantly longer TTPP in modified ABI group than standard ABI group (HR 0.29, 95%CI 0.14-0.62, p=0.0248), no significant difference was observed in TTPP between modified ENZ group and standard ENZ group (p=0.5366). There was significant difference in PSA response rate between modified ABI and standard ABI group (79% and 53%, respectively; P=0.0036). Similar adverse event rates and grades were observed in each treatment group. Conclusions: Modified ABI showed better outcomes than standard ABI and may be a potential treatment option for CRPC patients; however, all patients were of Japanese and patients in other countries were not included. Further study should be conducted including other ethnic backgrounds and focusing on different constitutions. Clinical trial information: UMIN000015529 .
Safety, tolerability, and dosimetry of <sup>177</sup>Lu-TLX591 with best standard of care in patients with PSMA-expressing metastatic castration-resistant prostate cancer (ProstAct-SELECT).
Authors: Nat Lenzo, Ken O'Byrne, Stanley Ngai, Danielle Meyrick, Neel Patel, Colin Hayward
Journal: Journal of Clinical Oncology (2024)

TPS253 Background: Prostate-specific membrane antigen (PSMA) has proven to be an ideal therapeutic target in prostate cancer (PC) as it is highly expressed by malignant prostate cells. Based on previous clinical evidence of its favorable safety profile and specificity for PC tumors, 177 Lu-DOTA-HuJ591-CHO (hereafter referred to as 177 Lu-TLX591) may be a potential radioimmunotherapy for the treatment of PC. ProstACT-SELECT (NCT04786847) is a phase 1 study designed to evaluate the safety, tolerability, biodistribution and dosimetry of 177 Lu-TLX591 administered with standard of care (SoC) for patients with PSMA-expressing, metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug. We previously reported positive interim results, and primary analysis of safety and dosimetry data is currently underway and expected to be available in mid-October 2023. Methods: Approximately 30 participants were to be enrolled in 2 cohorts. Cohort 1: 5 patients received a single (27 mCi) intravenous infusion of 177 Lu-TLX591. SPECT images and pharmacokinetic blood samples will be acquired at several time points until Day 13 after dosing. Dosimetry analysis and qualitative comparison of biodistribution of tracer level of 177 Lu-TLX591, as demonstrated by SPECT, with 68 Ga-PSMA-11 on PET imaging were performed to ensure equivalent (or improved) radiopharmaceutical tumour targeting. Patients were to receive a second administration of 177 Lu-TLX591, at a full therapeutic dose of 76 mCi, 14 days following the initial dose after safety confirmed by independent review board. SoC was to continue according to standard practice. Cohort 2: Subsequent patients were to receive 2 administrations of 76 mCi 177 Lu-TLX591, with SPECT dosimetry and pharmacokinetics as in cohort 1. The primary endpoints include the absorbed radiation dose of administered 177 Lu-TLX591 to kidneys, liver, lungs, spleen, bone/red marrow, and salivary glands; tumour-to-healthy tissue ratios and residence times; and type, frequency, and severity of TEAEs. Clinical trial information: NCT04786847 .
PETRANHA: Phase 1/2 study of AZD5305 + novel hormonal agents in patients with metastatic prostate cancer–Interim safety and pharmacokinetic results.
Authors: Arun Azad, Mark Voskoboynik, Anthony M. Joshua, Andrew James Weickhardt, Peter Sankey, Simon Pacey, Elisabeth I. Heath, Laurence Krieger, Lisa Horvath, Patrick Glen Pilié, Lynsey Womersley, Spiros Linardopoulos, Ganesh Moorthy, TJ Zhou, Jessica Brown, Bruno de Paula, Edit Lukacs, Andrew Hudson
Journal: Journal of Clinical Oncology (2024)

123 Background: The combination of PARP inhibitors (PARPi) with novel hormonal agents (NHAs) has recently demonstrated significant improvement in progression-free survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) compared with NHAs alone. AZD5305, a PARP1-selective inhibitor, has the potential for an improved safety profile and limited drug-drug interactions (DDIs) compared with first-generation PARPi. PETRANHA, an open-label nonrandomized study, is evaluating the safety and DDIs of AZD5305 with physician’s choice of NHA (enzalutamide [enza], abiraterone acetate [abi] or darolutamide [daro]) in pts with metastatic prostate cancer. Methods: Pts were aged ≥18 years with histologically confirmed mCRPC or metastatic castration-sensitive prostate cancer (mCSPC), suitable for NHA treatment, with or without HRR mutations in tumor tissue. Key exclusion criteria were previous PARPi, platinum chemotherapy, or targeted radioligand therapy for pts with mCRPC or mCSPC; and previous NHA or docetaxel in pts with mCSPC. Pts were assigned to receive AZD5305 60 mg once daily (OD; first dose level tested) and either enza 160 mg OD (Arm 1), abi 1000 mg + 5 mg prednisone OD (Arm 2), or daro 600mg twice daily (Arm 3) until disease progression or any intolerable adverse event (AE) occurred. Primary objectives were safety and tolerability. DDIs were evaluated for each combination. Results: At data cutoff (July 10, 2023), 48 pts were included in the interim safety analysis (Arm 1, n=11; Arm 2, n=19; Arm 3, n=18). In total, 32 (66.7%) pts had mCRPC, 16 (33.3%) pts had mCSPC, and 8 (16.7%) pts were pre-exposed to NHAs. Median duration of AZD5305 exposure was 6.3 months (range, 1.05–12.58) across all arms. Safety data are presented in the Table. The most common AEs were anemia (52.1%; Gr ≥3, 16.7%), fatigue (50.0%; Gr ≥3, 2.1%), and neutropenia (33.3%; Gr ≥3, 6.3%). No dose-limiting toxicities or AE-related deaths occurred in any arm; AEs leading to discontinuations were uncommon. No clinically significant DDIs were measured with any of the combinations. Conclusions: Initial safety, tolerability, and DDI data from the PETRANHA study indicates that AZD5305 can be safely combined with three individual NHAs with low rates of dose interruptions or reductions. The study is ongoing in Australia, Italy, UK, and USA. Clinical trial information: NCT05367440 . [Table: see text]
Erectile function in patients with metastatic renal cell carcinoma treated with first-line therapy.
Authors: Ilya Tsimafeyeu, Ruslan Zukov, Pavel S. Borisov, Valentina Leonenko, Vladimir Kuznetsov, Anastasia Bondarenko, Yulia Tishova
Journal: Journal of Clinical Oncology (2024)

383 Background: Sexual activity is an important part of social functioning and quality of life. Cancer diagnosis and concomitant treatment has a damaging effect on sexual function. The objective of this prospective study was to evaluate the incidence of erectile dysfunction (ED) in men with metastatic renal cell carcinoma (mRCC) receiving first-line therapy. Methods: All patients were evaluated for erectile function with the 5-item version of the International Index of Erectile Function (IIEF-5) and Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) before first and after four cycles/months of the first-line therapy with nivolumab plus ipilimumab (IO-IO), pembrolizumab plus axitinib/lenvatinib (IO-TKI) or sunitinib, pazopanib and cabozantinib (TKI). Results: Two hundred eighty-two male patients with mRCC were enrolled. Median age was 60.5 years (range 39–71 years) and 164 (58%) patients had at least one cardiovascular risk factor. Sixty-seven (24%) patients had favorable IMDC risk, 208 (74%) had ECOG ≤1, 214 (76%) had ≥2 organs with metastases, and 11 (4%) had non-clear cell mRCC. All patients were treated with IO-IO (32%), IO-TKI (26%), and TKI (42%). At baseline, IIEF-5 mean score was 17 (SD, 2.9) in ITT population. Patients with 2 and more IMDC risk factors had a lower IIEF-5 mean score (13; SD, 1.4). 182 (64.5%) patients reported a negative change in their sexual life since the start of the therapy. 90 (32%) patients had no sexual activity. After four treatment cycles/months IIEF-5 mean score reduced to 9 (SD, 3.5), which was statistically significant (P&lt;0.0001). The IIEF-5 scores were associated with type of anticancer treatment, with the minimal change observed in IO-IO group (P=0.2) and highest change in TKI group (P&lt;0.0001). A correlation was no found between FKSI-19 and IIEF-5 scoring systems. Conclusions: A prospective assessment in a large group of male mRCC patients revealed mild ED (17/25) in previously untreated patients and moderate ED (9/25) after four cycles/months of first-line therapy, especially in patients receiving TKIs. These changes did not correlate with kidney symptom index.
Impact of body mass index (BMI) on clinical and toxicity outcomes in patients with relapsed metastatic germ-cell tumor (GCT) undergoing high-dose chemotherapy (HDCT) with peripheral blood stem cell transplant (PBSCT).
Authors: Ahmed Bilal Khalid, Phillip Pham, Rebecca Hassoun, Sandra K. Althouse, Rafat Abonour, Mohammad Issam Abu Zaid, Nasser H. Hanna, Nabil Adra, Lawrence H. Einhorn, Jennifer King
Journal: Journal of Clinical Oncology (2024)

517 Background: ASCO guidelines recommend full weight-based dosing of cytotoxic chemotherapy for all pts regardless of BMI. The regimen for HDCT in relapsed GCT at our institution uses actual body weight (ABW) dosing for carboplatin and etoposide. There is limited data on the implications of using ABW to dose HDCT in pts with GCT. We describe clinical and toxicity outcomes based on pre-transplant BMI in pts with relapsed metastatic GCT undergoing HDCT with PBSCT. Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with relapsed GCT treated between 1990-2023 with HDCT and PBSCT. Pts were classified by pre-transplant BMI as BMI &lt;25 (normal weight), BMI 25-29.9 (overweight), or BMI ≥30 (obese). Grade 3 or higher (≥G3) toxicities were assessed using CTCAE. Comparisons between groups were done using Chi-square tests for categorical variables or Wilcoxon test for continuous variables. Kaplan-Meier methods were used to analyze progression-free survival (PFS) and overall survival (OS). The log rank test was used to compare groups. Results: 597 pts met inclusion criteria. Median age at initiation of HDCT was 32.4 (range, 16.7-70.1). Primary site was testis in 85%, retroperitoneum in 8%, and mediastinum in 7%. 76% of patients had non-seminoma. IGCCCG risk was good in 40%, intermediate in 11%, and poor in 48%. HDCT was the 2 nd line treatment for 83% of pts and ≥3 rd line for 17%. 90% of pts completed both cycles of HDCT. 202 pts (34%) had normal BMI, 223 (37%) were overweight and 172 (29%) were obese. Median carboplatin dose was 2100mg/m2 and median etoposide dose 2250mg/m2 for all pts in both cycles. 63% of obese pts experienced at least 1 G≥3 non-hematologic adverse event vs. 43% of overweight pts vs. 44% of pts with normal weight (p=0.0001). The rate of G≥3 renal toxicity was higher in obese pts at 17% vs. 7% in overweight pts vs. 5% in normal weight pts (p= 0.0001). G≥3 GI toxicity was higher in obese pts at 50% compared to 36% in overweight pts and 37% in normal weight pts (p=0.0079). The table lists toxicity and survival outcomes by pre-transplant BMI. Conclusions: Obese pts with relapsed GCT undergoing HDCT had higher incidence of overall G≥3 toxicity specifically renal and GI toxicity. Treatment-related mortality and survival was not impacted by differences in BMI. [Table: see text]
Health-related quality of life (HRQoL) profile and clinical outcomes in first-line (1L) advanced renal cell carcinoma (aRCC): A modelling analysis based on CheckMate 9ER (CM9ER) trial.
Authors: Jens Bedke, Rachel H. Giles, Thomas Powles, Michael Derosa, Lysbeth Floden, Intan Purnajo, Mickael Lothgren, Alessia Ogareva, David Cella
Journal: Journal of Clinical Oncology (2024)

384 Background: Cabozantinib plus nivolumab (CN) is a 1L therapy for aRCC. In the CM9ER trial CN had superior efficacy to sunitinib (SUN) and showed HRQoL benefit. We investigated the relationship between clinical outcomes, treatment and early deterioration in HRQoL dimensions in the CM9ER population. Methods: Using the CM9ER intention-to-treat (ITT) population (median follow-up 32.9 months) we: (a) explored time-to-event outcomes for CN vs SUN (b) identified determinants of HRQoL benefit by performing ordinal regression using the 19-item Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI-19) item scores at week 13 (c) investigated relationships between early (week 13) deterioration in FKSI-19 items and clinical outcomes using a cox proportional modeling framework. First, univariate Cox proportional hazard modeling assessed the predictiveness of early FKSI-19 item deterioration (sig. threshold p ≤ 0.20). Items with significant univariate associations with the outcome were included in multivariate regression modeling (sig. threshold p ≤ 0.10). Treatment and baseline stratification factors (geographic region, baseline IMDC score, PD-L1 status) remained in all models. Results: All CM9ER ITT patients (N = 651; CN, 323; SUN, 328) were included. Compared with SUN, CN patients had a longer median duration of treatment (94.6 wks vs 36.5 wks), time to disease progression (83.1 wks vs 42.1 wks) and time to first grade 3/4 adverse event (16.3 wks vs 12.0 wks). FKSI-19 items with early deterioration favoring CN vs SUN ( p ≤ 0.05) were: lack of energy; pain; fatigue; bone pain; weak all over; nausea; bothered by treatment side effects; able to work. The table reports variables significantly associated with clinical outcomes ( p ≤ 0.05). Conclusions: Early deterioration in bone pain and sleep were associated with increased risk of mortality, and early deterioration in pain with reduced risk of toxicity-related discontinuation. We found no association between early FKSI-19 item deterioration and risk of progression or tumor shrinkage. Controlling for other variables, CN (vs SUN) treatment was positively and significantly associated with increased chance of tumor shrinkage, survival and progression-free survival, independent of early HRQoL deterioration. Clinical trial information: NCT03141177 . [Table: see text]