scholarly journals Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma

2020 ◽  
Vol 8 (2) ◽  
pp. e000627 ◽  
Author(s):  
Celine Boutros ◽  
Nathalie Chaput-Gras ◽  
Emilie Lanoy ◽  
Alicia Larive ◽  
Christine Mateus ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Metastatic Melanoma ◽  
T Lymphocyte ◽  
Dose Escalation ◽  
Clinical Benefit ◽  
Cytotoxic T Lymphocyte ◽  
Phase 1 ◽  
Objective Response ◽  
Severe Toxicity ◽  
Phase 1 Study

BackgroundA synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma.Patients and methodsA 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics.Results19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5–2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2–1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS.ConclusionWhen combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation.Trial registration numberNCT01557114.

A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab in patients (pts) with metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9549-9549 ◽  
Author(s):  
Celine Boutros ◽  
Christine Mateus ◽  
Emilie Lanoy ◽  
Emilie Routier ◽  
Salem Chouaib ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Metastatic Melanoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Control ◽  
Severe Toxicity ◽  
Phase 1 Study ◽  
Grade 3

9549 Background: Preclinical findings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of RT combined with ipilimumab in pts with metastatic melanoma. Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT (in 3 fractions) at week 4 combined with 10 mg/kg ipilimumab (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance ipilimumab at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). Results: 19 pts with advanced melanoma received ipilimumab between August 2011 and July 2015. Nine pts received the 4 doses of ipilimumab and 2 pts received maintenance ipilimumab (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, desease-related pain and fever. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). Nine pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy dose. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). The median progression-free survival [95% CI] was 7.2 months [2.4 – 16.8]. The median overall survival [95% CI] was 14.4 months [7.2 – 20.4]. Conclusions: When combined with ipilimumab at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity. Clinical trial information: 2010-020317-93.

PO-1227: A dose escalation phase 1 study of radiotherapy combined with ipilimumab in metastatic melanoma.

2020 ◽  
Vol 152 ◽  
pp. S646-S647
Author(s):  
C. Boutros ◽  
N. Chaput ◽  
E. Lanoy ◽  
A. Larive ◽  
C. Mateus ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Phase 1 Study

Phase 1 study of an anti-GD3 monoclonal antibody, (KW-2871) in patients with advanced metastatic melanoma

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 2556-2556
Author(s):  
J. Shah ◽  
A. Forero ◽  
R. Carlisle ◽  
P. Triozzi ◽  
A. Lobuglio ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Metastatic Melanoma ◽  
Phase 1 ◽  
Phase 1 Study

Clearance of monoclonal antibody (mAb) CP-675,206 by therapeutic plasma exchange (TPE) or plasmapheresis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13515-13515
Author(s):  
A. Sharma ◽  
P. Bumerts ◽  
J. Gomez-Navarro ◽  
D. Pavlov ◽  
A. Ribas
Keyword(s):  
Rheumatoid Arthritis ◽  
Monoclonal Antibody ◽  
Metastatic Melanoma ◽  
T Lymphocyte ◽  
Saline Solution ◽  
Cytotoxic T Lymphocyte ◽  
Oral Methotrexate ◽  
Hepatitis Patient ◽  
In Transit ◽  
Plasma Half Life

13515 Background: CP-675,206 is a fully human, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blocking mAb with immune stimulating properties under development for the treatment of metastatic melanoma. The pharmacokinetics of CP-675,206 is similar to endogenous IgG, with a long plasma half-life (22 days). We explored the use of TPE in two patients (pts) receiving CP-675,206, postulating that TPE could be used to remove mAb in cases where toxicities are thought to result from persistence of mAb in circulation. Methods: For both pts, five TPEs were performed over 7 days using a Cobe Spectra blood cell separator (TPE daily x 3, 2 days rest, and TPE daily x 2). One plasma volume was processed per TPE and replaced with a 60%/40% albumin/saline solution. Plasma CP-675,206 concentration was measured at baseline and after the 3rd and 5th TPE. Results: Patient 1 was a 62 year-old with metastatic melanoma who received 8 monthly doses of CP-675,206 (10 mg/kg). Six days after the last dose, the pt was found to have elevated ALT and bilirubin and detectable anti- smooth muscle and anti-microsomal antibodies. Based on a suspicion of therapy-related autoimmune hepatitis, the pt underwent TPE. Plasma CP-675,206 concentration declined by 96% following the 5th TPE, and ALT and bilirubin normalized over the 4 weeks following TPE with no other evidence of clinical hepatitis. Patient 2 was a 78 year-old with in-transit melanoma who received 3 monthly doses of CP-675,206 (10 mg/kg) and was responding to therapy. Two weeks after the last dose the pt developed diffuse bilateral arthralgias. The pt was diagnosed with rheumatoid factor-negative rheumatoid arthritis, presumably related to therapy with CP-675,206, and underwent TPE. Pre- and post-TPE plasma CP-675,206 concentrations are pending. The arthralgias persisted, and the pt subsequently received oral methotrexate with slow improvement in symptoms over the next 6 months. Conclusions: TPE is highly effective for reducing the plasma concentration of CP-675,206 and may be useful to avert the progression of drug-related adverse events. Clinical benefit from TPE may vary depending on the interval from dosing and may be limited by slow reversibility of T-cell immunostimulation. [Table: see text]

Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9509-9509 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Karen A. Autio ◽  
Talia Golan ◽  
Konstantin Dobrenkov ◽  
Elliot Chartash ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Disposition ◽  
Phase 1 ◽  
Objective Response ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Phase 1 Study

9509 Background: Ligation of GITR on immune cells decreases Treg-mediated suppression and enhances T cell proliferation. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. Data from the first-in-human phase 1 study (NCT02132754) of MK-4166 as monotherapy (mono) or in combination with pembro (combo) are presented. Methods: MK-4166 was tested alone (0.0015 mg IV-900 mg Q3W ×4 doses) or with pembro (fixed dose 200 mg IV Q3W up to 35 doses) in the absence of toxicity or progression. Study included a dose escalation/confirmation cohort (metastatic solid tumors) and an expansion cohort (treatment-naive and pretreated melanoma). A T cell–inflamed gene expression profile (GEP) was assessed using RNA from baseline tumor samples. End points – primary: safety/tolerability, maximum tolerated dose (MTD) of MK-4166; secondary: pharmacokinetics (PK), pharmacodynamics (PD); exploratory: objective response rate (ORR) per irRECIST1.1. Results: Of 113 pts, 48 received mono and 65 combo; 20 were in the melanoma expansion. Common AEs ( > 20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 43 pts had grade ≥3 AEs (38.1%); 6 (5.3%) were treatment-related. One dose-limiting toxicity (bladder perforation in a urothelial pt with a neobladder) possibly related to study drug was observed with mono. MTD was not reached. No treatment-related deaths were observed. MK-4166 PK/PD showed target-mediated drug disposition concomitant with decreased GITR availability on T cells in blood with increasing doses. Four objective responses (4/45; ORR, 9%) were seen with combo in dose escalation. For ICI-naive melanoma pts (n = 13) in expansion, ORR was 69% (95% CI, 38-91), including 4 CRs and 5 PRs. No response was observed in 7 pts previously treated with ICI. High ORRs were observed in noninflamed and inflamed ICI-naive melanoma pts. Conclusions: MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembro was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembro, particularly in pts with melanoma naive to ICIs. Clinical trial information: NCT02132754.

Safety and pharmacokinetics of a human monoclonal antibody to rabies virus: A randomized, dose-escalation phase 1 study in adults

Vaccine ◽  
2012 ◽  
Vol 30 (50) ◽  
pp. 7315-7320 ◽  
Author(s):  
Nithya Gogtay ◽  
Urmila Thatte ◽  
Nilima Kshirsagar ◽  
Brett Leav ◽  
Deborah Molrine ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Rabies Virus ◽  
Dose Escalation ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Phase 1 Study

Dose escalation results from a first-in-human, phase 1 study of the glucocorticoid-induced TNF receptor-related protein (GITR) agonist AMG 228 in patients (Pts) with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2521-2521 ◽  
Author(s):  
Ben Tran ◽  
Richard D. Carvajal ◽  
Aurelien Marabelle ◽  
Sandip P. Patel ◽  
Patricia LoRusso ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Disposition ◽  
Phase 1 ◽  
Objective Response ◽  
Transitional Cell ◽  
Costimulatory Molecule ◽  
Advanced Solid Tumors ◽  
Phase 1 Study

2521 Background: AMG 228 is an agonistic human IgG1 monoclonal antibody that binds to GITR (CD357), a TNFSFR costimulatory molecule expressed by effector/regulatory T cells. Dose escalation of this open label, first in human, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and maximum tolerated dose (MTD) and recommended phase 2 dose of AMG 228 in pts with advanced solid tumors. Methods: Pts with refractory advanced colorectal cancer (n = 13), squamous cell carcinoma of head and neck (n = 10), non–small cell lung cancer (n = 2), urothelial transitional cell carcinoma (n = 4), and melanoma (n = 1) received AMG 228 IV Q3W. Dose escalation was in two stages: single-pt cohorts until AMG 228-related grade > 2 adverse events (AEs), efficacy, or 90 mg dose reached (4 cohorts: 3, 9, 30, and 90 mg), followed by rolling six design (n = 2 to 6) until MTD or highest planned dose of 1200 mg reached (5 cohorts: 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs) and AEs and PK. Additional endpoints were objective response (RECIST 1.1) and evidence of biological activity. Results: In total, 30 pts (median age 63 y) were treated (3, 9, 30, and 90 mg, n = 1; 180 mg, n = 6; 360 mg, n = 4; 600 mg, n = 6; 900 mg, n = 4; 1200 mg, n = 6). Twenty-seven (90%) pts had treatment-emergent AEs; the most common were hypophosphatemia (23%), fatigue (23%), anemia (23%), nausea (20%), and pyrexia (20%). No DLTs occurred; the MTD was not reached. AMG 228 exposure was dose-related, with PK profiles at low doses (3 to 90 mg) consistent with target mediated drug disposition; doses > 360 mg achieved serum levels needed for 95% receptor occupancy on activated PBMCs. No evidence of T cell activation was observed despite complete target coverage in both tumor and peripheral blood. Among 29 evaluable pts, none had an objective response. Conclusions: In this population of pts with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), showing favorable PK. However, no clinical or immunological activity was observed in this limited number of pts. Clinical trial information: NCT02437916.

scholarly journals Autoimmunity Correlates With Tumor Regression in Patients With Metastatic Melanoma Treated With Anti–Cytotoxic T-Lymphocyte Antigen-4

2005 ◽  
Vol 23 (25) ◽  
pp. 6043-6053 ◽  
Author(s):  
Peter Attia ◽  
Giao Q. Phan ◽  
Ajay V. Maker ◽  
Michael R. Robinson ◽  
Martha M. Quezado ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
T Lymphocyte ◽  
Response Rate ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Regression ◽  
Objective Response ◽  
Prior History ◽  
Human Antibody ◽  
Peptide Vaccination ◽  
Lymphocyte Antigen

Purpose Previously, we reported our experience treating 14 patients with metastatic melanoma using a fully human antibody to cytotoxic T-lymphocyte antigen-4 (anti–CTLA-4) in conjunction with peptide vaccination. We have now treated 56 patients to evaluate two different dose schedules of anti–CTLA-4 and to explore the relationship between autoimmunity and tumor regression. Patients and Methods A total of 56 patients with progressive stage IV melanoma were enrolled onto the study. All had Karnofsky performance status ≥ 60% with no prior history of autoimmunity. Twenty-nine patients received 3 mg/kg anti–CTLA-4 every 3 weeks, whereas 27 received 3 mg/kg as their initial dose with subsequent doses reduced to 1 mg/kg every 3 weeks. In both cohorts patients received concomitant vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). Results Two patients achieved a complete response (ongoing at 30 and 31 months, respectively) and five patients achieved a partial response (durations of 4, 6, 25+, 26+, and 34+ months, respectively), for an overall objective response rate of 13%. Tumor regression was seen in lung, liver, brain, lymph nodes, and subcutaneous sites. Of 14 patients with grade 3/4 autoimmune toxicity, five (36%) experienced a clinical response compared with only two responses in the 42 patients (5%) with no autoimmune toxicity (P = .008). There were no significant differences in response rate or toxicity between the two dose schedules. Conclusion Administration of anti–CTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses, which correlate with the induction of autoimmunity, in patients with metastatic melanoma.

A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2609-2609 ◽  
Author(s):  
Monica Arnedos ◽  
Crystal Shereen Denlinger ◽  
Wael A. Harb ◽  
Olivier Rixe ◽  
John Charles Morris ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Clinical Benefit ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Clinical Benefit Rate

2609 Background: MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been implicated in driving cancer growth and in the development of resistance to conventional chemotherapies across multiple malignancies. Here we present results of an open-label, Phase 1, multicenter, non-randomized, dose-escalation trial which recently completed enrollment evaluating MM-121 in combination with one of the following chemotherapies: Gemcitabine (Arm A, n=11), carboplatin (Arm B, n=11), pemetrexed (Arm C, n=10), or cabazitaxel (Arm D, n=11). Methods: Patients were treated in a dose escalation “3+3” design to assess the safety, tolerability and pharmacokinetics (PK) of MM-121 administered weekly in combination with anticancer therapies in subjects with advanced cancer. Doses were escalated until the maximum tolerated dose (MTD) was identified or the combination was shown to be tolerable at the highest planned doses. Secondary objectives included: Determining the objective response rate, clinical benefit rate, PK and immunogenicity of MM-121. Data summarized are as of 1/17/2013 from a live database. Results: Overall, 43 patients, [22 (51%) female and 21 (49%) male] have been treated with a median treatment duration of 57 days (range 1-302). The median age was 59 years (range 42-84) and patients had received a median of four prior lines of therapy (range 0-13). Common (>20%) adverse events of any grade and causality across all arms included diarrhea (74%), nausea (54%), fatigue (51%), anemia (44%), vomiting (33%), hypokalemia (30%), decreased appetite (26%), thrombocytopenia (26%), peripheral edema (23%), neutropenia (21%), and constipation (21%). Four DLTs were observed: Two in combination with carboplatin (G4 thrombocytopenia and G3 rash), one with gemcitabine (G4 thrombocytopenia), and one with pemetrexed (G4 hyperuricemia). Overall 38 (88%) patients were evaluable for response and the overall clinical benefit rate (PR or SD >18 weeks), is 32% (12/38). Conclusions: MM-121 can be combined at its recommended single agent dose with standard doses of gemcitabine, pemetrexed, and cabazitaxel and adapted doses of carboplatin. Clinical trial information: NCT01447225.

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