Abstract
Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody–drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary–derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. Results: The AGS-16M8F study (n ¼ 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7–83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n ¼ 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100–143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5–141 weeks). Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4399-4406 |
| Number of pages | 8 |
| Journal | Clinical Cancer Research |
| Volume | 24 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 15 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Phase I trials of anti-ENPP3 antibody–drug conjugates in advanced refractory renal cell carcinomas. / Thompson, John A.; Motzer, Robert J.; Molina, Ana M.; Choueiri, Toni K.; Heath, Elisabeth I.; Redman, Bruce G.; Sangha, Randeep S.; Ernst, D. Scott; Pili, Roberto; Kim, Stella K.; Reyno, Leonard; Wiseman, Aya; Trave, Fabio; Anand, Banmeet; Morrison, Karen; Doñate, Fernando; Kollmannsberger, Christian K.
In: Clinical Cancer Research, Vol. 24, No. 18, 15.09.2018, p. 4399-4406.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phase I trials of anti-ENPP3 antibody–drug conjugates in advanced refractory renal cell carcinomas
AU - Thompson, John A.
AU - Motzer, Robert J.
AU - Molina, Ana M.
AU - Choueiri, Toni K.
AU - Heath, Elisabeth I.
AU - Redman, Bruce G.
AU - Sangha, Randeep S.
AU - Ernst, D. Scott
AU - Pili, Roberto
AU - Kim, Stella K.
AU - Reyno, Leonard
AU - Wiseman, Aya
AU - Trave, Fabio
AU - Anand, Banmeet
AU - Morrison, Karen
AU - Doñate, Fernando
AU - Kollmannsberger, Christian K.
PY - 2018/9/15
Y1 - 2018/9/15
N2 - Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody–drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary–derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. Results: The AGS-16M8F study (n ¼ 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7–83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n ¼ 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100–143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5–141 weeks). Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks.
AB - Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody–drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary–derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. Results: The AGS-16M8F study (n ¼ 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7–83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n ¼ 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100–143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5–141 weeks). Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks.
UR - http://www.scopus.com/inward/record.url?scp=85053192021&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053192021&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-0481
DO - 10.1158/1078-0432.CCR-18-0481
M3 - Article
AN - SCOPUS:85053192021
VL - 24
SP - 4399
EP - 4406
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 18
ER -