Abstract
Purpose: RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell surface proteins. RAAG12 is highly expressed on many adenocarcinomas, particularly those of gastrointestinal origin. A phase 1 dose-escalation safety and pharmacokinetics trial was conducted in patients with metastatic or recurrent adenocarcinomas. Experimental Design: RAV12 was initially given i.v. weekly x4, then by fractionated dosing twice or thrice weekly. Thirty-three patients were treated in the dose escalation segment of the trial in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7); and 0.5 mg/kg biw (3), 0.75 mg/kg biw (3), and 0.5 mg/kg tiw (6). Twenty patients were enrolled in a maximum tolerated dose cohort expansion at 0.75 mg/kg biw. Results: Two clinical syndromes were associated with drug administration: abdominal cramping pain with diarrhea, and asymptomatic, self-limited increases of liver function tests. These effects were partially ameliorated with fractionated dosing. Pharmacokinetics was dose dependent. Maximum concentration was reduced, whereas area under the concentration versus time curve was maintained with fractionated dosing. One patient with colorectal cancer experienced a durable partial remission, with a time to progression (TTP) of >8 months. Three additional patients experienced a TTP of >4 months. Conclusions: RAV12 has activity in recurrent adenocarcinomas. However, the safety profile of the antibody seems to preclude the delivery of highly efficacious doses. Re-engineering the molecule to remove FcRn binding (while maintaining FcγR binding) and to humanize it may improve the toxicity profile and efficacy.
| Original language | English |
|---|---|
| Pages (from-to) | 1673-1681 |
| Number of pages | 9 |
| Journal | Clinical Cancer Research |
| Volume | 16 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 1 2010 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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Phase 1 experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma. / Burris, Howard A.; Rosen, Lee S.; Rocha-Lima, Caio M.; Marshall, John; Jones, Suzanne; Cohen, Roger B.; Kunkel, Lori A.; Loo, Deryk; Baughman, Jan; Stewart, Stanford J.; Lewis, Nancy.
In: Clinical Cancer Research, Vol. 16, No. 5, 01.03.2010, p. 1673-1681.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phase 1 experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma
AU - Burris, Howard A.
AU - Rosen, Lee S.
AU - Rocha-Lima, Caio M.
AU - Marshall, John
AU - Jones, Suzanne
AU - Cohen, Roger B.
AU - Kunkel, Lori A.
AU - Loo, Deryk
AU - Baughman, Jan
AU - Stewart, Stanford J.
AU - Lewis, Nancy
PY - 2010/3/1
Y1 - 2010/3/1
N2 - Purpose: RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell surface proteins. RAAG12 is highly expressed on many adenocarcinomas, particularly those of gastrointestinal origin. A phase 1 dose-escalation safety and pharmacokinetics trial was conducted in patients with metastatic or recurrent adenocarcinomas. Experimental Design: RAV12 was initially given i.v. weekly x4, then by fractionated dosing twice or thrice weekly. Thirty-three patients were treated in the dose escalation segment of the trial in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7); and 0.5 mg/kg biw (3), 0.75 mg/kg biw (3), and 0.5 mg/kg tiw (6). Twenty patients were enrolled in a maximum tolerated dose cohort expansion at 0.75 mg/kg biw. Results: Two clinical syndromes were associated with drug administration: abdominal cramping pain with diarrhea, and asymptomatic, self-limited increases of liver function tests. These effects were partially ameliorated with fractionated dosing. Pharmacokinetics was dose dependent. Maximum concentration was reduced, whereas area under the concentration versus time curve was maintained with fractionated dosing. One patient with colorectal cancer experienced a durable partial remission, with a time to progression (TTP) of >8 months. Three additional patients experienced a TTP of >4 months. Conclusions: RAV12 has activity in recurrent adenocarcinomas. However, the safety profile of the antibody seems to preclude the delivery of highly efficacious doses. Re-engineering the molecule to remove FcRn binding (while maintaining FcγR binding) and to humanize it may improve the toxicity profile and efficacy.
AB - Purpose: RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell surface proteins. RAAG12 is highly expressed on many adenocarcinomas, particularly those of gastrointestinal origin. A phase 1 dose-escalation safety and pharmacokinetics trial was conducted in patients with metastatic or recurrent adenocarcinomas. Experimental Design: RAV12 was initially given i.v. weekly x4, then by fractionated dosing twice or thrice weekly. Thirty-three patients were treated in the dose escalation segment of the trial in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7); and 0.5 mg/kg biw (3), 0.75 mg/kg biw (3), and 0.5 mg/kg tiw (6). Twenty patients were enrolled in a maximum tolerated dose cohort expansion at 0.75 mg/kg biw. Results: Two clinical syndromes were associated with drug administration: abdominal cramping pain with diarrhea, and asymptomatic, self-limited increases of liver function tests. These effects were partially ameliorated with fractionated dosing. Pharmacokinetics was dose dependent. Maximum concentration was reduced, whereas area under the concentration versus time curve was maintained with fractionated dosing. One patient with colorectal cancer experienced a durable partial remission, with a time to progression (TTP) of >8 months. Three additional patients experienced a TTP of >4 months. Conclusions: RAV12 has activity in recurrent adenocarcinomas. However, the safety profile of the antibody seems to preclude the delivery of highly efficacious doses. Re-engineering the molecule to remove FcRn binding (while maintaining FcγR binding) and to humanize it may improve the toxicity profile and efficacy.
UR - http://www.scopus.com/inward/record.url?scp=77649093935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77649093935&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-09-2263
DO - 10.1158/1078-0432.CCR-09-2263
M3 - Article
C2 - 20179219
AN - SCOPUS:77649093935
VL - 16
SP - 1673
EP - 1681
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 5
ER -