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A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors.

ABSTRACT: This open-label, phase I, dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors.Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous daily dosing (CDD schedule). Capecitabine (825, 1,000, or 1,250 mg/m(2)) was administered orally twice daily on days 1 to 14 every 3 weeks for all patients. Sunitinib and capecitabine doses were escalated in serial patient cohorts.Seventy-three patients were treated. Grade 3 adverse events included abdominal pain, mucosal inflammation, fatigue, neutropenia, and hand-foot syndrome. The MTD for Schedule 4/2 and the CDD schedule was sunitinib 37.5 mg/d plus capecitabine 1,000 mg/m(2) twice per day; the MTD for Schedule 2/1 was sunitinib 50 mg/d plus capecitabine 1,000 mg/m(2) twice per day. There were no clinically significant pharmacokinetic drug-drug interactions. Nine partial responses were confirmed in patients with pancreatic cancer (n = 3) and breast, thyroid, neuroendocrine, bladder, and colorectal cancer, and cholangiocarcinoma (each n = 1).The combination of sunitinib and capecitabine resulted in an acceptable safety profile in patients with advanced solid tumors. Further evaluation of sunitinib in combination with capecitabine may be undertaken using the MTD for any of the three treatment schedules.

SUBMITTER: Sweeney CJ

PROVIDER: S-EPMC2988641 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors.

Sweeney Christopher J CJ Chiorean E Gabriela EG Verschraegen Claire F CF Lee Fa Chyi FC Jones Suzanne S Royce Melanie M Tye Lesley L Liau Katherine F KF Bello Akintunde A Chao Richard R Burris Howard A HA

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100913 29

<h4>Purpose</h4>This open-label, phase I, dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors.<h4>Patients and methods</h4>Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous dai ...[more]

PMID: 20837944

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Project description:BackgroundThe combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors.Main bodyImmunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8+ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8+ and granzyme B+ cells were observed.ConclusionsAlthough efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME.Trial registration numberNCT02671435.

Project description:BackgroundThe anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsPhase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME).ResultsOverall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME.ConclusionsIsa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

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A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors.

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A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors.

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