tbuckley/cabot-search huggingface dataset:
A phase IIA clinical trial to evaluate a reversible Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).
Authors: Ning Lee, Yingfu Li, Yong Mao, Guanfeng Liu, Jiang Li, Qingchun Liu
Journal: Journal of Clinical Oncology (2024)

e19042 Background: This clinical study is to evaluate HBW-3220, a novel BTKi with an improved in vitro profile than the existing non-covalent drugs pirtobrutinib (approved) and nemtabrutinib (Phase III). HBW-3220 shows superior inhibition against BTK wild-type and several common mutants, such as C481S, C481R, T474I, T316A, and L528W (enriched in pirtobrutinib resistance), and hematopoietic cell kinase (HCK, a key contributor to BTKi resistance due to kinase-defective BTK). Methods: This phase IIA clinical study is conducted in R/R B-NHL patients who had received two or more prior lines of treatment. The dose escalation study adopts accelerated titration and a "3+3" design, with a daily single dose of 15, 30, 60, 90, 120, or 150 mg. During the dose escalation phase, the sponsor and investigators determine whether to expand the cohort of the previous dose based on the existing data. Adverse events (AEs) are assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment is based on iwCLL 2018 guidelines for chronic lymphocytic leukemia (CLL), IWWM-7 consensus for Waldenstrom macroglobulinemia (WM), and Lugano 2014 guidelines for all other lymphomas, including small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and follicular lymphoma (FL). Results: 29 patients have been enrolled, and the dose escalation study has been completed. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. Adverse events (AEs), similar to other BTKis, were mostly Grade 1 or 2, including fever (36%), diarrhea (32%), headache (18%), anemia (39%), infectious pneumonia (18%), decreased neutrophils count (39%), decreased platelet count (29%), increased alanine aminotransferase (21%), etc. Drug-related Grade 3 AEs included decreased neutrophil count (n=3, 11%), increased lymphocyte count (n=2, 7%), and infectious pneumonia (n=2, 7%). 23 patients underwent at least 1 response assessment. The overall response rate (ORR) in CLL/SLL (all with prior irreversible BTKi treatment, and 4 of them with additional BCL2 inhibitor treatment), MZL, MCL, and DLBCL patients were 83% (5/6), 50% (2/4), 40% (2/5) and 33% (1/3), respectively. Among the ORR, 90% (9/10) were in the 90 mg and above dose group, regardless of previous BTKi treatment history or mutation status of p53 and BTK. After oral administration, the drug exposures showed dose-dependent increases. The time to maximum plasma concentration (Tmax) was 2 hours, and the elimination half-life (T1/2) was 19 hours. Conclusions: The current data show that HBW-3220 is well tolerated with no DLT occurred at daily doses up to 150 mg, displaying most promising efficacy in patients with CLL/SLL, MZL, and MCL. Clinical trial information: ChiCTR2200062537.
Efficacy of cytotoxic chemotherapy in recurrent/metastatic adenoid cystic carcinoma (ACC).
Authors: Michael Wotman, Camilla Oliveira Hoff, Flavia Bonini, Matthew Sawyer, Kaiwen Wang, Eduardo Andreazza Dal Lago, Luana Guimaraes de Sousa, Renata Ferrarotto
Journal: Journal of Clinical Oncology (2024)

6111 Background: Despite aggressive local therapy, many ACC patients (~50%) develop recurrent and/or metastatic (R/M) disease. However, there is no standard of care or FDA-approved systemic therapy for this population. Based on small phase II trials, mostly including multiple salivary gland histologies, cytotoxic chemotherapy is recommended for symptomatic patients with high tumor burden, but its efficacy and impact on survival in R/M ACC remain unsubstantiated. Methods: A retrospective cohort study was conducted at MD Anderson Cancer Center with an institutional ACC database (N=769). Patients diagnosed with R/M ACC and treated with single-agent or combination palliative-intent chemotherapy were included. The primary endpoints were overall response rate (ORR) and disease control rate (DCR) per RECIST 1.1. Secondary endpoints were median overall survival (mOS) and progression-free survival (mPFS) on chemotherapy for the entire cohort and stratified by growth pattern (solid v non-solid), line of therapy (1 v &gt;2), chemotherapy regimen, and stage at diagnosis (M0 v M1). Results: 48 out of 115 patients who received chemotherapy were evaluated for response per RECIST.Median age at diagnosis was 43.6 years. 56% were male, 79% had M0 stage at diagnosis, 67% had minor salivary gland primary tumors, 52% had solid growth pattern, 31% had non-solid growth pattern, and 54% received first-line chemotherapy. The most common regimens were Platinum/Vinorelbine (38%), Platinum/Taxane (27%) and CAP (15%).The ORR and DCR rates were 12.5% and 56.3% respectively; 6 had partial response, 21 had stable disease, and 21 had progressive disease. The ORR and DCR rates were 20% and 52% for solid and 6.7% and 73.3% for non-solid growth pattern, respectively. The mOS from diagnosis was 7 years (95% CI, 3.5-10.7). The mOS on chemotherapy was 16 months (95% CI, 10.8-24.5). There was a significant difference in mOS between solid and non-solid growth pattern (10.8 v 24.1 months, p=0.015), but not by line of therapy, regimen, or stage at diagnosis. The mPFS on chemotherapy was 4.3 months (95% CI, 2.8-6.3 months). There was a significant difference in mPFS between solid and non-solid growth pattern (4.0 v 7.3 months, p=0.018), but not by line of therapy, regimen, or stage at diagnosis. Conclusions: In this largest to date real-world data on chemotherapy in ACC, response and survival outcomes were lower than historical data. The efficacy of chemotherapy may vary by growth pattern and other patient and tumor factors, which requires further investigation. Given the low ORR and overall slow-growing disease pattern, tumor volumetrics may be better than RECIST to assess treatment benefit.
A randomized, double-blind controlled trial of medicinal cannabis vs placebo for symptom management in patients with advanced cancer receiving palliative care.
Authors: Janet Rea Hardy, Ristan Greer, Taylan Gurgenci, Alison Kearney, Rahul Ladwa, Georgie Huggett, Phillip Good
Journal: Journal of Clinical Oncology (2024)

12020 Background: Medicinal cannabis remains very popular amongst cancer patients. In our previous study (JCO 2023; 41(7):1444-1452), cannabidiol (CBD) did not improve symptom management above that provided by standard palliative care alone. This study utilized the same design to test whether the addition of tetrahydrocannabinol(THC) to CBD resulted in improved symptom control. Methods: Patients with advanced cancer and a total symptom distress score (TSDS) of ≥10/90 as measured by the Edmonton Symptom Assessment Scale (ESAS) who were receiving palliative care were randomised to a 10mg/ml THC:10mg/ml CBD combination oil (MC) or matched placebo. The dose was escalated according to tolerance and perceived efficacy from 2.5 to 30mg/day over 14 days and continued at that dose to day 28. The primary outcome was the change in TSDS from baseline at day 14. Secondary outcomes included change in individual symptoms, patient-selected dose, global impression of change, anxiety/depression, opioid use, quality of life and toxicity. Results: Of the 144 randomized from Sept 2019 to July 2023 (72 to MC, 72 to placebo), 56 and 65 participants reached the primary analysis point at 14 days, and 33 and 50 to day 28. The most common cancers were breast, lung and gynecological. Most participants were of reasonable performance status (AKPS 70%) and were taking opioids at baseline. Mean baseline TSDS scores were 37.6/90 (MC) and 36.5/90 (placebo). Mean TSDS scores fell over time with no difference between arms at day 14 (-6.3 (SD 12.3) MC and -6.98 (SD 12.6), p = 0.76) or day 28 (-9.24 (SD 15.3) and 8.42 (SD 13.6), p = 0.8). Adjusted for baseline, there was a significant improvement in pain score from baseline in favor of MC (-1.41 (2.15) vs -0.46 (2.82), p = 0.04) and in overall wellbeing in favor of placebo (-0.48 (2.78) and -1.29 (2.74), p = 0.02) at day 14. The median (range) patient selected dose of oil at day 14 was 1.5ml (0.5-3.0) (equivalent to a dose of 15mgTHC/15mg CBD) and 3.0ml (0.5-3.0) for placebo. Side-effects were generally mild. More participants on MC reported confusion (26/69 and 12/72, p = 0.005), feeling high (21/69 and 10/72, p = 0.02) and an exaggerated sense of well-being (10/69 and 2/72, p = 0.01) as worse than baseline. Those on MC reported an improved global impression of change over time but this lost significance when considering those who exited early. Conclusions: Although showing no advantage over placebo with respect to improving total symptom distress, a 1:1 THC:CBD medicinal cannabis oil resulted in a statistically significant improvement in cancer-related pain at the expense of increased psychomimetic toxicity. Trial registration: ACTRN 12619000037101. Sponsor: Australian Government Medical Research Future Fund. Clinical trial information: ACTRN12619000037101.
Updated results from ALTER-S002: A single-arm multicenter trial of the combination of anlotinib with chemotherapy in patients with stage IIB classic osteosarcoma of the extremity.
Authors: Fan Tang, Yong Zhou, Jie Ma, Dong Wang, Bing Zhang, Yi Luo, Longqing Li, Cuizhen Liu, Yuan Nie, Li Min, Chongqi Tu
Journal: Journal of Clinical Oncology (2024)

11529 Background: The overexpression of multiple tyrosine kinase receptors in osteosarcoma indicated a promising therapy targeting these receptors. Anlotinib is a multi-targeted tyrosine kinase inhibitor that potentially inhibits tumor angiogenesis. The combination of anti-angiogenic drugs with chemotherapeutic agents is proposed to act synergistically to achieve favorable tumor control, especially as the neoadjuvant therapy. We had reported the neoadjuvant therapy data of anlotinib in combination with chemotherapy for treatment-naive stage IIB classical osteosarcoma of the extremity in the 2023 ESMO congress. Here we report an update on the effectiveness and safety of the follow-up. Methods: In this open-label, single-arm, multicenter phase II clinical trial. Eligible patients(pts) were aged 12-40 years with histologically confirmed primary localized extremity classic osteosarcoma, stage IIB, operable. Pts received anlotinib (10mg, po, d1-14, q3w), doxorubicin (A) (20-25mg/m 2 iv, d1-3, q3w) and cisplatin (P) (70-90mg/m 2 , iv, d1, q3w) for the first nine weeks. Pts underwent radical surgery after the exclusion of contraindications at week 10. After surgery, pts received A+P at weeks 12-14, and anlotinib plus A+P at weeks 15-20 with the drug dose unchanged. Since week 21, anlotinib (12mg, po, d1-14, q3w) monotherapy was maintained until week 104 or the occurrence of an EFS event. The primary endpoint was 24-month EFS rate, secondary endpoints were 36-month EFS rate, local recurrence rate, lung metastasis rate, 3-year OS rate and safety. Results: From May 2020 to Apr 2022, 52 eligible pts were enrolled, while 51 pts underwent surgery after 3 cycles of neoadjuvant therapy. At the data cut-off date (Oct. 2023), the median EFS was not reached, 12 and 24-month EFS rates were 84.18% (95% CI :70.82, 91.77) and 73.43% (95% CI :57.40, 84.21), respectively. The stratified analysis of EFS showed that the length and diameter of the target lesion are independent prognostic factors. The median OS was not reached, the 24-month OS rate was 95.92% (95% CI :84.65, 98.96). Among the 51 pts who underwent surgical treatment, 12(23.53%, 95% CI: 12.79, 37.49) pts experienced recurrence or metastasis. Most treatment-related adverse events (TRAEs) were grade 1-2. Grade 3/4 TRAEs (≥20%) included neutropenia (51.92%), leukopenia (38.46%), thrombocytopenia (36.54%) and anemia (32.69%). Conclusions: The updated results suggested that anlotinib combined with doxorubicin and cisplatin in the perioperative period showed favorable efficiency and manageable adverse events in Stage IIB classic osteosarcoma of the extremity. Clinical trial information: ChiCTR 2000033298.
A phase 2 trial of the CDK4 inhibitor dalpiciclib in well-differentiated or dedifferentiated liposarcoma.
Authors: Zengjun Liu, Mengyao Liu, Jing Xu, Wenyu Hu, Hui Zhang, Rongjie Tao, Xinyu Li, Lichao Cha, Jinfang Cui, Junkai Zhao, Heng Fu, Chunxiang Fan, Lantian Tian, Fabo Qiu, Dongyuan Zhu
Journal: Journal of Clinical Oncology (2024)

11547 Background: The oncogene cyclin-dependent kinase 4 (CDK4) is amplified in &gt; 90% of well-differentiated liposarcomas (WDLS) and dedifferentiated liposarcomas (DDLS). Previous studies have already demonstrated the clinical benefit of CDK4 inhibitors in the treatment of WDLS and DDLS. Dalpiciclib is a more potent and novel CDK4 inhibitor. We designed a multi-center phase 2 study to evaluate the safety and efficacy of dalpiciclib in patients with advanced WDLS/DDLS. Methods: Eligible patients were adults aged 18 years and older, with a confirmed diagnosis of advanced WDLS/DDLS, measurable lesions according to RECIST 1.1, any (or no) priory therapy, and a history of progression by RECIST 1.1 in the 6 months prior to enrollment. All patients were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma (RB) protein expression by immunohistochemistry. All patients were treated with dalpiciclib 150 mg orally once per day for 21 consecutive days within a 28-day treatment cycle. The primary endpoint was progression free survival (PFS) at 12 weeks. Secondary end points included objective response rate and adverse events. Results: From August 2022 to October 2023, a total of 32 patients were enrolled, and 30 were evaluable for the primary end point. Median (range) age was 59 (40-76) years; 22 patients (69%) were male. At 12 weeks, PFS was 61.3% (95% CI, 44-78.5%). The median PFS was 17.4 weeks (95% CI, 10.65-24.15 weeks). Only one patient had a partial response to the treatment. Grade 3 to 4 events included neutropenia (37.5%), anemia (6.25%), thrombocytopenia (6.25%), and nausea (3.13%). Conclusions: Treatment with the CDK4 inhibitor dalpiciclib was associated with a favorable PFS rate in patients with advanced CDK4-amplified and RB-expressing WDLS/DDLS. Clinical trial information: ChiCTR2200062868.
Results of a phase 1/2 study of MHB088C: A novel B7H3 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in recurrent or metastatic solid tumors.
Authors: Lin Shen, Caicun Zhou, Xue Meng, Yuping Sun, Yinghua Ji, Haihua Yang, Fangling Ning, Liang Han, Ou Jiang, Meili Sun, Qing Wen, Xinmin Yu, Yuming Jia, Hai Huang, Yanqiu Zhao, Zhiye Zhang, Chuntao Tian, Zhen Zhang, Junwei Shi, Guoqing Cao
Journal: Journal of Clinical Oncology (2024)

3012 Background: MHB088C is an investigational B7H3-directed ADC, created by coupling a humanized anti-B7H3 monoclonal antibody with a highly potent DNA topoisomerase I inhibitor (5~10 times more potent than DXd). Preclinical studies demonstrated robust binding affinity, superior internalization rates, powerful tumor killing activities (3~10 times more potent than the DS-7300a analog in CDX models) and a favorable safety profile with no unique toxicities observed in the GLP study as compared to other B7H3 ADCs and no occurrences of interstitial lung disease (ILD). We here present the safety and efficacy results from a first-in-human phase 1/2 study of MHB088C. Methods: The study enrolled patients (pts) with recurrent or metastatic solid tumor across two segments: dose-escalation (D-esc) and dose-expansion (D-exp). In the D-esc phase, MHB088C was administrated intravenously at doses of 0.8, 1.6, 3.0mg/kg Q2W; 3.0, 4.0 mg/kg Q3W. Results: As of the data cutoff on Dec 31, 2023, 60 pts were enrolled and received at least one dose of MHB088C (D-esc, n=14; D-exp, n=46). 55 pts remain on the treatment and 12 pts had at least one tumor assessment according to RECIST 1.1. Dose-limiting toxicities (DLTs) were platelet count decreased and febrile neutropenia at 4.0 mg/kg Q3W. The MTD was determined to be 3.0 mg/kg Q3W. The most common TRAEs overall in ≥25% of pts were neutrophil count decreased, lymphocyte count decreased, and white blood cell (WBC) count decreased. The most common Grade ≥3 TRAEs (≥5% of pts) were neutrophil count decreased (33.3%), lymphocyte count decreased (30.0%), WBC count decreased (26.7%), platelet count decreased (23.3%), and anemia (15.0%). No ILD was reported. Of12 response-evaluable pts, 5 partial responses (PRs) were observed (ORR: 41.7%). The disease control rate was 91.7% (11/12). In the subset of 3 SCLC pts, all 3 showed PRs (ORR: 100.0%), with one case demonstrating complete response of the target lesion and another with close to 80% tumor volume reduction. The efficacy of 2 SCLC pts was achieved in 1.6 mg/kg Q2W group without major hematologic side effects. All responses among SCLC pts occurred at the first tumor assessment. Conclusions: MHB088C exhibited a manageable safety profile, with striking efficacy in SCLC pts. The dose optimization and expansion study is continuing to establish the RP2D for MHB088C. Clinical trial information: CTR20231298.
Treatment discontinuation due to toxicity for patients with acute myeloid leukemia (AML) treated on SWOG S1203.
Authors: Suravi Raychaudhuri, Megan Othus, Mary-Elizabeth M. Percival, Guillermo Garcia-Manero, Frederick R. Appelbaum, Harry Paul Erba, Jacob Appelbaum
Journal: Journal of Clinical Oncology (2024)

6529 Background: Curative-intent therapy for patients with newly diagnosed AML centers on the use of cytarabine as part of an intensive multi-drug induction regimen. Treatment-related toxicity may lead to patients stopping treatment, despite the considerable risk of inadequately treated AML. We compared rates of protocol therapy discontinuation due to adverse events (AEs) in either of two standard induction regimens (7+3 or high dose cytarabine + idarubicin, IA) on the S1203 study (Garcia-Manero; Leukemia 2023). Methods: S1203 was a randomized study of patients &lt;60 years old with newly diagnosed AML. Patients were required to have performance status (PS) &lt;3, ejection fraction &gt;45%, and no prolonged QTc interval or known cardiac disease. There were no exclusion criteria for kidney or liver function. On the 7+3 induction arm, subjects received daunorubicin 90 mg/m 2 IV daily days 1-3 with continuous infusion cytarabine 100 mg/m 2 daily days 1-7. On the IA arm, subjects received idarubicin 12 mg/m 2 daily days 1-3 with continuous infusion cytarabine 1.5 g/m 2 daily days 1-4. Toxicities were assessed per the Common Terminology Criteria for Adverse Events version 4.0. Rates of discontinuation were compared using Fisher’s exact test. Results: From 4/2013-11/2015, 522 subjects were randomized (261 to each arm). Treatment discontinuation due to either death or toxicity occurred in 8 vs 22 patients on 7+3 vs IA respectively (p=0.014). During induction, 0 patients on the 7+3 arm discontinued treatment due to toxicity versus 4 patients on the IA arm (0% vs 2%; p=0.12). Toxicities leading to treatment discontinuation on the IA arm included congestive heart failure (n=2, one with concurrent arrhythmia), acute kidney injury (n=1), and hypotension complicated by stroke and cardiac arrest (n=1). Two of the 4 patients who discontinued treatment due to toxicity on IA achieved a complete remission after their first cycle. For patients with PS 2-3 (n=40 on 7+3, n=27 on IA), rates of grade 3-5 AEs were 85% vs 86% and rates of grade 5 AEs were 0% vs 11% (p=0.065). Conclusions: 7+3 was well tolerated. Excluding patients from S1203 with PS 2-3 or decreased hepatic/renal function would not have prevented treatment-related toxicity. The low rate of protocol therapy discontinuation due to toxicity suggests that eligibility criteria for clinical trials could be further broadened to improve patient access. Clinical trial information: NCT0180233 . [Table: see text]
Results of a phase 1/2 study of MHB036C: A potential best-in-class TROP2 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in locally advanced or metastatic solid tumors.
Authors: Shun Lu, Qingyuan Zhang, Xiangjiao Meng, Yuping Sun, Hui Hua Xiong, Dongqing Lv, Xiaojia Wang, Lin Wu, Xiaorong Dong, Yuanyuan Ji, Yinghua Ji, Liang Han, Kaijian Lei, Ou Jiang, Yanqiu Zhao, Zhen Zhang, Junwei Shi, Guoqing Cao
Journal: Journal of Clinical Oncology (2024)

e15007 Background: MHB036C, an investigational ADC, comprises a humanized anti-TROP2 monoclonal antibody engineered to minimize potential toxicities mediated by non-specific uptake, and a highly potent DNA topoisomerase I inhibitor (5~10 times more potent than DXd) conjugated via a stable cleavable linker. In preclinical studies, MHB036C demonstrated superior tumor killing activities (5~10 times more potent than the DS-1062a analog) and a favorable safety profile with no unique toxicities as compared to other TROP2 ADCs and no occurrences of interstitial lung disease (ILD). We here present the safety and efficacy results from a first-in-human phase 1/2 study of MHB036C. Methods: Patients with locally advanced or metastatic solid tumors were enrolled in dose-escalation (D-Esc) and dose-expansion (D-Exp) segments. The D-esc study, utilizing an accelerated titration followed by the traditional 3+3 design, assessed MHB036C at doses ranging from 0.25-2.25 mg/kg administered intravenously (IV) every 3 weeks. Results: At data cutoff (Dec 31, 2023), 26 pts were enrolled and received at least one dose of MHB036C (D-Esc, n=11, D-Exp, n=15). Two pts experienced dose-limiting toxicities (Grade 3 stomatitis) at 2.25 mg/kg. The MTD was determined to be 1.5 mg/kg. The most common TRAEs overall in ≥25% of pts were stomatitis, anemia, decreased appetite, vomiting, white blood cell (WBC) count decreased, fatigue, nausea, and neutrophil count decreased. The most common Grade ≥3 TRAEs (occurred in ≥5% of pts) were stomatitis (34.6%), WBC count decreased (11.5%), neutrophil count decreased (7.7%), and anemia (7.7%). No ILD was reported. Of 21 response-evaluable pts, 7 experienced partial responses. In the subset of 12 NSCLC pts treated with doses ranging from 1.3 to 2.25 mg/kg, the ORR was 33.3% (4/12) and the DCR was 83.3%. In the subset of 5 HER2-negative breast cancer pts encompassing 4 TNBC pts and 1 HR+/HER2- breast cancer patient, the ORR was 60.0% (3/5). Conclusions: MHB036C demonstrated a manageable safety profile without either major hematologic side effects or ILDs and encouraging efficacy in NSCLC and HER2- breast cancer, representing a potential best-in-class TROP2 ADC. The dose optimization and expansion study is ongoing to establish the RP2D for MHB036C. Clinical trial information: CTR20231246.
Impact of respiratory pathogens detection by a rapid multiplex polymerase chain reaction assay on the management of community-acquired pneumonia for children at the paediatric emergency department. A randomized controlled trial, the Optimization of Pneumonia Acute Care (OPTIPAC) study
Authors: Aymeric Cantais, Sylvie Pillet, Josselin Rigaill, François Angoulvant, Christele Gras-Le-Guen, Pierrick Cros, Charlotte Thuiller, Claudine Molly, Louise Tripodi, Aurélie Desbree, Nadine Annino, Paul Verhoeven, Anne Carricajo, Thomas Bourlet, Céline Chapelle, Isabelle Claudet, Arnauld Garcin, Jacques Izopet, Olivier Mory, Bruno Pozzetto
Journal: Clinical Microbiology and Infection (2024)