Phase I trials of anti-ENPP3 antibody–drug conjugates in advanced refractory renal cell carcinomas

John A. Thompson, Robert J. Motzer, Ana M. Molina, Toni K. Choueiri, Elisabeth I. Heath, Bruce G. Redman, Randeep S. Sangha, D. Scott Ernst, Roberto Pili, Stella K. Kim, Leonard Reyno, Aya Wiseman, Fabio Trave, Banmeet Anand, Karen Morrison, Fernando Doñate, Christian K. Kollmannsberger

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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 languageEnglish (US)
Pages (from-to)4399-4406
Number of pages8
JournalClinical Cancer Research
Volume24
Issue number18
DOIs
StatePublished - Sep 15 2018

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Pyrophosphatases
Phosphoric Diester Hydrolases
Renal Cell Carcinoma
Hybridomas
Cricetulus
Pharmacokinetics
Safety
Therapeutics
monomethyl auristatin F

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Thompson, J. A., Motzer, R. J., Molina, A. M., Choueiri, T. K., Heath, E. I., Redman, B. G., ... Kollmannsberger, C. K. (2018). Phase I trials of anti-ENPP3 antibody–drug conjugates in advanced refractory renal cell carcinomas. Clinical Cancer Research, 24(18), 4399-4406. https://doi.org/10.1158/1078-0432.CCR-18-0481

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 journalArticle

Thompson, JA, Motzer, RJ, Molina, AM, Choueiri, TK, Heath, EI, Redman, BG, Sangha, RS, Ernst, DS, Pili, R, Kim, SK, Reyno, L, Wiseman, A, Trave, F, Anand, B, Morrison, K, Doñate, F & Kollmannsberger, CK 2018, 'Phase I trials of anti-ENPP3 antibody–drug conjugates in advanced refractory renal cell carcinomas', Clinical Cancer Research, vol. 24, no. 18, pp. 4399-4406. https://doi.org/10.1158/1078-0432.CCR-18-0481
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. / Phase I trials of anti-ENPP3 antibody–drug conjugates in advanced refractory renal cell carcinomas. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 18. pp. 4399-4406.
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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.",
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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.

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