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A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222934 | GEO | 2023/03/01

REPOSITORIES: GEO

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A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy.

Project description:PurposeOn the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti-programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy.Patients and methodsWe designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors.ResultsSafety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8-11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients' plasma was associated with short survival.ConclusionsNo RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.

| S-EPMC10233355 | biostudies-literature

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (NGS)

Project description:We designed a Phase II clinical trial testing the combination of guadecitabine (DNMTi) and atezolizumab (anti-PD-L1) with the goal to re-stimulate the immune mediated anticancer effects of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma patients who were resistant to prior ICI treatment. No RECIST criteria responses were observed, however, patients could be separated into those with either progressive or stable disease outcomes. Analysis of the tumors did not show substantial DNA hypomethylation in the tumor or the upregulation of viral mimicry after two cycles of combination treatment. We did, however, observe that the therapy associated with immune activation of circulating immune cells and abundance of tumor-infiltrating CD8 T cells within the tumor, which were correlated with a longer survival outcome. Our results suggest that further studies to target the reprogramming of T cells with alternate methodologies may be of benefit in this disease setting.

2023-03-01 | GSE222932 | GEO

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (EPIC)

2023-03-01 | GSE222933 | GEO

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy

Project description:A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy

| PRJNA924046 | ENA

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (EPIC)

Project description:A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (EPIC)

| PRJNA924050 | ENA

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (NGS)

Project description:A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (NGS)

| PRJNA924049 | ENA

Atezolizumab plus platinum-based chemotherapy as first-line therapy for metastatic urothelial cancer: A cost-effectiveness analysis

Project description:Purpose: According to the IMvigor130 trial, adding atezolizumab to platinum-based chemotherapy was effective in the treatment of metastatic urothelial cancer (mUC). Based on the perspective of the United States and China, the current study evaluated cost-effectiveness of atezolizumab plus chemotherapy for mUC patients in the first-line setting. Methods: A partitioned survival model was adopted for mUC patients. The survival data were derived from the IMvigor130 trial. Direct cost values were collected from the Centers for Medicare and Medicaid Services (CMS), Chinese Drug Bidding Database, and published literatures. The utility and toxicity data were gathered from related research studies and IMvigor130 trial. The incremental cost–utility ratios (ICURs) and incremental cost-effectiveness ratios (ICERs) were calculated and analyzed. Scenario analyses and sensitivity analyses were performed to observe the outputs and uncertainties. Results: The base-case analysis showed that the ICUR of atezolizumab plus chemotherapy versus chemotherapy in American and Chinese settings is $ 737,371 /QALY and $ 385,384 /QALY, respectively. One-way sensitivity analyses showed that the ICUR ranged from $ 555,372/QALY to $ 828,205/QALY for the United States. Also, the range was from $ 303,099/QALY to $ 433,849/QALY in the Chinese setting. A probabilistic sensitivity analysis showed the likelihood that atezolizumab plus chemotherapy becoming the preferred strategy was a little low even if the price reduction strategy was applied. Conclusion: Adding atezolizumab to chemotherapy improved survival time, but it is not a cost-saving option compared to chemotherapy for metastatic urothelial cancer patients in the American and Chinese settings.

| S-EPMC9441572 | biostudies-literature

Phase I Trial of Ipatasertib Plus Carboplatin, Carboplatin/Paclitaxel, or Capecitabine and Atezolizumab in Metastatic Triple-Negative Breast Cancer.

Project description:BackgroundThis trial evaluated the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic triple-negative breast cancer (mTNBC).MethodsEligibility criteria were mTNBC, RECIST 1.1 measurable disease, no prior use of platinum for metastatic disease (Arms A and B), and no prior exposure to immune checkpoint inhibitor (Arm C). Primary endpoints were safety and RP2D. Secondary endpoints were progression-free survival (PFS), response rate, and overall survival.ResultsRP2D for Arm A (n = 10) was ipatasertib 300 mg daily, carboplatin AUC2, and paclitaxel 80 mg m-2 days 1, 8, and 15 every 28 days. RP2D for Arm B (n = 12) was ipatasertib 400 mg daily and carboplatin AUC2 days 1, 8, and 15 every 28 days. RP2D for Arm C (n = 6) was likely ipatasertib 300 mg 21 days on 7 days off, capecitabine 750 mg m-2, twice a day, 7 days on 7 days off, and atezolizumab 840 mg days 1 and 15 every 28 days. The most common (≥10%) grade 3-4 AEs at RP2D for Arm A (N = 7 at RP2D) were neutropenia (29%), diarrhea (14%), oral mucositis (14%), and neuropathy (14%); Arm B had diarrhea (17%) and lymphopenia (25%); and Arm C had anemia, fatigue, cognitive disturbance, and maculopapular rash (17% each). Overall responses at RP2D were 29% Arm A, 25% Arm B, and 33% Arm C. PFS was 4.8, 3.9, and 8.2 months for patients on Arms A, B, and C, respectively.ConclusionsContinuous dosing of ipatasertib with chemotherapy was safe and well-tolerated. Further study is warranted in understanding the role of AKT inhibition in treatment of TNBCs.Trial registrationNCT03853707.

| S-EPMC10322142 | biostudies-literature

TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors.

Project description:PurposePatients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2-directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC.MethodsTROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label, phase II, registrational study. Cohort 1 includes patients with locally advanced or unresectable or mUC who had progressed after prior PLT and CPI. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary outcome was centrally reviewed ORR; secondary outcomes were progression-free survival, OS, duration of response, and safety.ResultsCohort 1 included 113 patients (78% men; median age, 66 years; 66.4% visceral metastases; median of three [range, 1-8] prior therapies). At a median follow-up of 9.1 months, the ORR was 27% (31 of 113; 95% CI, 19.5 to 36.6); 77% had decrease in measurable disease. Median duration of response was 7.2 months (95% CI, 4.7 to 8.6 months), with median progression-free survival and OS of 5.4 months (95% CI, 3.5 to 7.2 months) and 10.9 months (95% CI, 9.0 to 13.8 months), respectively. Key grade ≥ 3 treatment-related adverse events included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%), with 6% discontinuing treatment because of treatment-related adverse events.ConclusionSG is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior PLT regimens and CPI. The results from this study supported accelerated approval of SG in this population.

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Clinical outcomes of immune checkpoint inhibitor plus nab-paclitaxel in metastatic upper tract urothelial carcinoma

Project description: Not available

| S-EPMC10560336 | biostudies-literature