A phase I study of the safety, tolerability, pharmacokinetics, and immunoregulatory activity of urelumab (BMS-663513) in subjects with advanced and/or metastatic solid tumors and relapsed/refractory B-cell non-Hodgkin’s lymphoma (B-NHL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3107-TPS3107 ◽  
Author(s):  
Ignacio Melero ◽  
Tara C. Gangadhar ◽  
Holbrook Edwin Kohrt ◽  
Neil Howard Segal ◽  
Theodore Logan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
B Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Advanced Solid Tumors ◽  
Non Hodgkin's Lymphoma

TPS3107 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses in T-cell directed therapy as well as in antibody-dependent cell-mediated cytotoxicity. Urelumab is an agonistic antibody targeting CD137 which has demonstrated antitumor activity against a variety of cancers in pre-clinical and clinical studies. We describe a phase I study to investigate the clinical and biologic effects of treatment with urelumab in patients with advanced solid tumors and B-cell non-Hodgkin’s lymphoma (B-NHL). Methods: This phase I study (n=70) will include dose escalation (Part 1) using a 6+9 design, cohort expansion (Part 2), and tumor-specific cohort expansion (Part 3). In Part 1, successive cohorts of pts with advanced solid tumors will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks). In Part 2, both cohorts (1 +2) will expand to 20 patients with advanced solid tumors. In Part 3, additional tumor-specific cohorts with B-NHL, colorectal cancer, and head and neck cancer (10 subjects each) will be enrolled at the highest tolerated dose. The primary objective of this study is to evaluate the safety and to define the MTD of the respective doses of 0.1 and 0.3 mg/kg administered every 3 weeks with special attention to hepatic toxicity. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity in peripheral blood and paired tumor biopsy specimens and associations with clinical outcome. Part 1 (dose escalation) has been completed without any DLTs. Clinical trial information: NCT01471210.

A Phase I Study of Humanized Anti-CD40 Immunotherapy with SGN-40 in Non-Hodgkin’s Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1504-1504 ◽  
Author(s):  
Ranjana H. Advani ◽  
Richard R. Furman ◽  
Joseph D. Rosenblatt ◽  
Anas Younes ◽  
Andres Forero-Torres ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Ct Scans ◽  
Cytokine Release ◽  
Non Hodgkin's Lymphoma ◽  
Grade 3

Abstract The vast majority of B-cell malignancies express CD40, a member of the TNF receptor family. This receptor, along with the cognate ligand (CD154), mediates cell survival and proliferation of normal B-cells and can regulate apoptosis as well as survival in transformed cells, making this pathway an appealing target for B-cell lymphoma. Both in vitro and in vivo preclinical studies support the development of anti-CD40 immunotherapy for non-Hodgkin’s lymphoma (NHL). Accordingly, a phase I single-arm dose escalation trial was initiated to test the safety, pharmacokinetics, and antitumor activity of SGN-40, a humanized anti-CD40 antibody, in patients with NHL. The protocol was designed to treat patients with follicular, mantle cell, diffuse large B-cell, small lymphocytic, and marginal zone lymphomas in cohorts using SGN-40 infusions at doses of 2, 4, 8, or 16 mg/kg/week for four weeks. We report results for cohort 1 (n = 6) treated at 2 mg/kg/week. Four of 6 patients completed the planned 4 weekly infusions. No grade 4 toxicity was observed. Two grade 3 toxicities were seen, both in the same patient (unilateral conjunctivitis and ipsilateral loss of vision in a patient with pre-existing macular degeneration). Grade 2 loss of balance was also seen in the same patient. Imaging studies with CT and MRI did not reveal a stroke or leptomeningeal disease nor were there inflammatory or malignant cells in the CSF. All these adverse events resolved over six weeks, including vision which returned to baseline acuity. The only other severe adverse event reported was a deep venous thrombosis in the setting of bulky ipsilateral pelvic adenopathy, which was considered to be unrelated to SGN-40. Dose escalation was temporarily suspended to evaluate these unexplained toxicities and the report of severe headaches, attributed to cytokine release reaction, at the next dose level (i.e. 4 mg/kg) in a parallel phase I protocol for multiple myeloma. Although none of the NHL patients in this study developed headaches or clinical symptoms, several patients demonstrated a significant increase in plasma cytokine levels (i.e. TNF-alpha, IL-6) following the first infusion but not subsequent treatments with SGN-40, raising the possibility that a first-dose cytokine release effect may be involved in the grade 3 toxicities observed. Pharmacokinetic samples for the NHL patients were collected and are currently being analyzed. Preliminary antitumor activity at the 2 mg/kg dose is reflected in one patient who had stable disease as determined by serial CT scans and in another patient who had subjective improvement in B symptoms during therapy but was found to have disease progression based on CT scans 4 weeks after completing therapy. An amended protocol is actively accruing patients that will address the concern for first-dose cytokine release and allow continued dose escalation. Clinical and pharmacokinetic data from these additional cohorts will be presented.

scholarly journals A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors

2021 ◽  
Author(s):  
Martina Puglisi ◽  
L Rhoda Molife ◽  
Maja JA de Jonge ◽  
Khurum H Khan ◽  
Leni van Doorn ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Optimal Schedule ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Clinical Trial Registration

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1–5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov)

Phase I Study of the Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-Hodgkin's Lymphoma

2009 ◽  
Vol 27 (26) ◽  
pp. 4371-4377 ◽  
Author(s):  
Ranjana Advani ◽  
Andres Forero-Torres ◽  
Richard R. Furman ◽  
Joseph D. Rosenblatt ◽  
Anas Younes ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Hodgkin’S Lymphoma ◽  
Vision Loss ◽  
Hodgkin's Lymphoma ◽  
Open Label ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Grade 3

PurposeTo evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL).Patients and MethodsIn this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle.ResultsIn the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in ≥ 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade ≥ 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients.ConclusionDacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.

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