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Phase Ib study on the humanized anti-CCR4 antibody, KW-0761, in advanced solid tumors.

ABSTRACT: Tregs infiltrate tumors and inhibit antitumor immunity. KW-0761 (Mogamulizumab) is a humanized anti-CCR4 monoclonal antibody that could eliminate activated Tregs with high immunosuppressive activity that express CCR4. In this phase Ib trial, KW-0761 was used as a cancer immunotherapeutic reagent to deplete Tregs in patients with advanced or recurrent solid CCR4-negative tumors. Thirty-nine patients with solid cancer were treated with KW-0761 at a dose of 0.1 or 1.0 mg/kg. The safety, clinical responses, and effects of Treg depletion were analyzed. Any grade and grade 3-4 treatment-related adverse events (AEs) were observed in 36 (92%) and 14 (36%) out of 39 patients, respectively. All treatment-related AEs were manageable. One and 5 patients achieved a partial response and stable disease, respectively, during treatment and were long survivors. The efficient depletion of Treg in peripheral blood was confirmed in both cohorts. Therefore, the administration of KW-0761 was safe, resulting in the depletion of Tregs in peripheral blood and potential immune responses in patients with solid cancer. The combined use of KW-0761 to deplete Tregs and other immunotherapies is a promising approach to augment immune responses.

SUBMITTER: Saito T

PROVIDER: S-EPMC8648528 | biostudies-literature |

REPOSITORIES: biostudies-literature

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First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors.

Project description:BackgroundTransient CD4+ T cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity.MethodsPatients with advanced solid tumors were treated with intravenous IT1208 at doses of 0.1 or 1.0 mg/kg. The first patient in each cohort received a single administration, and the other patients received two administrations of IT1208 on days 1 and 8.ResultsEleven patients were enrolled in the 0.1 mg/kg (n = 4) and 1.0 mg/kg cohorts (n = 7). Grade 1 or 2 infusion-related reactions was observed in all patients. Decreased CD4+ T cells in peripheral blood due to IT1208 were observed in all patients and especially in those receiving two administrations of 1.0 mg/kg. CD8+ T cells increased on day 29 compared with baseline in most patients, resulting in remarkably decreased CD4/8 ratios. One microsatellite-stable colon cancer patient achieved durable partial response showing increased infiltration of both CD4+ and CD8+ T cells into tumors after IT1208 administration. Moreover, transcriptomic profiling of the liver metastasis of the patient revealed upregulation of the expression of interferon-stimulated genes, T cell activation-related genes, and antigen presentation-related genes after IT1208 administration. Two additional patients with gastric or esophageal cancer achieved stable disease lasting at least 3 months.ConclusionsIT1208 monotherapy successfully depleted CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combination with immune checkpoint inhibitors.

| S-EPMC6657210 | biostudies-literature

First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors.

Project description:Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.

| S-EPMC5346770 | biostudies-literature

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

Project description:PurposeRC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer.Patients and methodsThis was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48.ResultsFifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20).ConclusionRC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status.Clinical trial informationNCT02881190.

| S-EPMC8205919 | biostudies-literature

Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors.

Project description:Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies. Identified effects of sex, baseline Eastern Cooperative Oncology Group performance status, measures of renal and hepatic function, tumor type and burden, and prior ipilimumab treatment on pembrolizumab exposure were modest and lacked clinical significance. Furthermore, simulations demonstrated the model has robust power to detect clinically relevant covariate effects on clearance. These results support the use of the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations.

| S-EPMC5270291 | biostudies-literature

A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.

Project description:Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).

| S-EPMC4387250 | biostudies-literature

TCR repertoire and transcriptomic analyses of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-08-06 | GSE120102 | GEO

Transcriptomic analysis of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody [3'SAGE-seq]

Project description:Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed cell death-1 monoclonal antibodies (mAbs) agents or these combinations has improved outcomes of various cancers.However, still not a few patients fail to achieve clinical benefit, this highlights the importance of additional treatment to overcome its resistance. Previously, we showed that administration of the anti-CD4 mAb alone had strong anti-tumor effects that were superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs in B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models. IT1208 (IDAC Theranostics, Tokyo, Japan) is a humanized anti-CD4 immunoglobulin G1 (IgG1) monoclonal antibody with a defucosylated Fc region, which markedly enhances antibody dependent cellular cytotoxicity. In a first-in-human, phase I, open-label, dose-escalation study, we performed transcriptomic analysis of tumors to clarify molecular responses against IT1208 monotherapy in patients with advanced solid tumors.

2019-08-06 | GSE120028 | GEO

A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors.

Project description:BackgroundErtumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells.MethodsPatients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2 cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10-500 μg) applied weekly within 28 days with a 21 day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded.ResultsFourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21 %) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14). Single doses up to 300 μg were well tolerated (total dose up to 800 μg per cycle). We observed one partial remission and two disease stabilizations after first treatment cycle.ConclusionsSingle doses up to 300 μg could be safely administered in an escalating dose scheme. Immunological responses and clinical activity warrant further evaluation in patients with Her2 over expressing tumors.Trial registrationEudraCT number: 2011-003201-14; ClinicalTrials.gov identifier: NCT01569412.

| S-EPMC4937525 | biostudies-literature

Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors.

Project description:Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5%) and decreased appetite, diarrhea, nausea, and vomiting (10.3% each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 ?g/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.

| S-EPMC5502198 | biostudies-literature

Phase I study of pucotenlimab (HX008), an anti-PD-1 antibody, for patients with advanced solid tumors.

Project description:BackgroundPucotenlimab is a humanized immunoglobulin G4 (IgG4) anti programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) with a S228P hinge mutation and an engineered Fc domain. Preclinical data suggests that pucotenlimab exerts antitumor effects. In this phase I study, which was prospectively registered on www.chinadrugtrials.org.cn (CTR20180125), the safety, maximum tolerated dose, preliminary antitumor activity, pharmacokinetics, and immunogenicity of pucotenlimab were evaluated in patients with advanced solid tumors.MethodsPatients with advanced solid tumors refractory to standard therapies were recruited. In a 3+3 dose escalation study, 13 patients received pucotenlimab intravenously every 3 weeks (Q3W) until disease progression or unacceptable toxicity occurred at doses of 1 mg/kg, 3 mg/kg, 10 mg/kg, and 200 mg. 17 additional patients were assigned in the expansion period.ResultsA total of 30 patients were enrolled. No dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common treatment-related adverse events of any grade were proteinuria (40%), fatigue (36.7%), weight loss (26.7%), fever (26.7%), increased aspartate aminotransferase (26.7%), rash (23.3%), and anorexia (20.0%). Partial responses occurred in five patients, with an objective response rate of 16.7%. Pharmacokinetics analysis showed rapid absorption followed by slow terminal elimination, with a mean half-life of 17.1-23.5 days across all dose groups.ConclusionsPucotenlimab had an acceptable toxicity profile at doses up to 10 mg/kg and the maximum tolerated dose was not reached. Based on the pharmacokinetics, efficacy, and safety profile, 3 mg/kg Q3W or 200 mg Q3W are optimal for further drug development.

| S-EPMC8182631 | biostudies-literature

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