7 research outputs found

    A Phase I Study of the Pan-Notch Inhibitor CB-103 for Patients with Advanced Adenoid Cystic Carcinoma and Other Tumors

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    Pan-notch inhibitor CB-103; Advanced adenoid cystic carcinomaInhibidor pan-notch CB-103; Carcinoma adenoide quístic avançatInhibidor pan-notch CB-103; Carcinoma adenoide quístico avanzadoPurpose: CB-103 selectively inhibits the CSL–NICD (Notch intracellular domain) interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose-escalation/expansion study aimed to determine safety, pharmacokinetics, and preliminary antitumor activity. Experimental Design: Patients ≥18 years of age with selected advanced solid tumors [namely, adenoid cystic carcinoma (ACC)] and hematologic malignancies were eligible. CB-103 was dosed orally in cycles of 28 days at escalating doses until disease progression. Notch-activating mutations were required in a dose confirmatory cohort. Endpoints included dose-limiting toxicities (DLT), safety, tumor response, pharmacokinetics, and pharmacodynamics. Exploratory analyses focused on correlates of Notch and target gene expression. Results: Seventy-nine patients (64, 12 dose-escalation cohorts; 15, confirmatory cohort) enrolled with 54% receiving two or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed [elevated gamma-glutamyl transferase (GGT), visual change]; recommended phase II dose was declared as 500 mg twice daily (5 days on, 2 days off weekly). Grade 3–4 treatment-related adverse events occurred in 15 patients (19%), including elevated liver function tests (LFTs), anemia, and visual changes. Five (6%) discontinued drug for toxicity; with no drug-related deaths. There were no objective responses, but 37 (49%) had stable disease; including 23 of 40 (58%) patients with ACC. In the ACC cohort, median progression-free survival was 2.5 months [95% confidence interval (CI), 1.5–3.7] and median overall survival was 18.4 months (95% CI, 6.3–not reached). Conclusions: CB-103 had a manageable safety profile and biological activity but limited clinical antitumor activity as monotherapy in this first-in-human study. Significance: CB-103 is a novel oral pan-Notch inhibitor that selectively blocks the CSL–NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This first-in-human dose-escalation and -confirmation study aimed to determine the safety, pharmacokinetics, and preliminary antitumor efficacy of CB-103. We observed a favorable safety profile with good tolerability and biological activity but limited clinical single-agent antitumor activity. Some disease stabilization was observed among an aggressive NOTCH-mutant ACC type-I subgroup where prognosis is poor and therapies are critically needed. Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs

    Clinical Implications of Extracellular HMGA1 in Breast Cancer

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    The unconventional secretion of proteins is generally caused by cellular stress. During the tumorigenesis, tumor cells experience high levels of stress, and the secretion of some theoretically intracellular proteins is activated. Once in the extracellular space, these proteins play different paracrine and autocrine roles and could represent a vulnerability of cancer. One of these proteins is the high mobility group A1 (HMGA1), which is frequently overexpressed in tumors and presents a low expression in normal adult tissues. We have recently described that HMGA1 establishes an autocrine loop in invasive triple-negative breast cancer (TNBC) cells. The secretion of HMGA1 and its binding to the receptor for advanced glycation end products (RAGE) mediates the migration, invasion, and metastasis of TNBC cells and predicts the onset of metastasis in these patients. In this review, we summarized different strategies to exploit the novel tumorigenic phenotype mediated by extracellular HMGA1. We envisioned future clinical applications where the association between its change in subcellular localization and breast cancer progression could be used to predict tumor aggressiveness and guide treatment decisions. Furthermore, we proposed that targeting extracellular HMGA1 as monotherapy using monoclonal antibodies, or in combination with chemotherapy and other targeted therapies, could bring new therapeutic options for TNBC patients

    Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: the DEBBRAH trial

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    [AHEAD] Data de publicació electrónica: 26-05-2022Background: trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. Methods: this ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n=8; cohort 1), asymptomatic untreated BMs (n=4; cohort 2), or progressing BMs after local therapy (n=9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial overall response rate (ORR-IC) for cohorts 2 and 3. Results: as of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P<.001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P<.001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade≥3), nausea (42.9%; 0% grade≥3), neutropenia (28.6%; 19% grade≥3), and constipation (28.6%; 0% grade≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. Conclusions: T-DXd showed intracranial activity with manageable toxicity and maintained quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts