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

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.

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9549 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9549-9549 ◽

Cited By ~ 1

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.

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

Radiotherapy and Oncology ◽

10.1016/s0167-8140(21)01245-7 ◽

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

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

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.2556 ◽

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

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.13515 ◽

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]

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

Vaccine ◽

10.1016/j.vaccine.2012.09.027 ◽

2012 ◽

Vol 30 (50) ◽

pp. 7315-7320 ◽

Cited By ~ 22

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

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189 PHASE 1 STUDY OF AN ANTI-GD3 MONOCLONAL ANTIBODY (KW-2871) IN PATIENTS WITH ADVANCED METASTATIC MELANOMA.

Journal of Investigative Medicine ◽

10.2310/6650.2005.x0008.188 ◽

2006 ◽

Vol 54 (1) ◽

pp. S290.1-S290

Author(s):

J. Shah ◽

A. Forero ◽

R. Carlisle ◽

P. Triozzi ◽

A. LoBuglio ◽

...

Keyword(s):

Monoclonal Antibody ◽

Metastatic Melanoma ◽

Phase 1 ◽

Phase 1 Study

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A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

Investigational New Drugs ◽

10.1007/s10637-020-01055-5 ◽

2021 ◽

Author(s):

Noboru Yamamoto ◽

Toshio Shimizu ◽

Kan Yonemori ◽

Shigehisa Kitano ◽

Shunsuke Kondo ◽

...

Keyword(s):

Liver Function ◽

Solid Tumors ◽

Dose Escalation ◽

Enzyme Inhibitor ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Open Label ◽

Phase 1 Study ◽

Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

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