Kathleen N Moore1, Camille C Gunderson2, Paul Sabbatini3, D Scott McMeekin2, Gina Mantia-Smaldone4, Robert A Burger5, Mark A Morgan6, Ann M Kapoun7, Rainer Karl Brachmann8, Robert Stagg9, Azeez Farooki10, Roisin E O'Cearbhaill11. 1. Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK 800 NE 10th Street, OKC, OK 73104, United States of America. Electronic address: kathleen-moore@ouhsc.edu. 2. Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK 800 NE 10th Street, OKC, OK 73104, United States of America. 3. Memorial Sloan Kettering Cancer Center New York, NY and Weill Cornell Medical College, New York, NY, United States of America. Electronic address: sabbatip@mskcc.org. 4. Fox Chase Cancer Center, Philadelphia, PA, United States of America. Electronic address: Gina.Mantia-Smaldone@fccc.edu. 5. University of Pennsylvania, Philadelphia, PA, United States of America. Electronic address: Robert.burger@uphs.upenn.edu. 6. University of Pennsylvania, Philadelphia, PA, United States of America. Electronic address: mark.morgan@uphs.upenn.edu. 7. OncoMed Pharmaceuticals Inc., Redwood City, CA, United States of America. Electronic address: ann.kapoun@oncomed.com. 8. OncoMed Pharmaceuticals Inc., Redwood City, CA, United States of America. Electronic address: rainer.brachmann@oncomed.com. 9. OncoMed Pharmaceuticals Inc., Redwood City, CA, United States of America. Electronic address: Robert.stagg@oncomed.com. 10. OncoMed Pharmaceuticals Inc., Redwood City, CA, United States of America. Electronic address: azeez.farooki@oncomed.com. 11. Memorial Sloan Kettering Cancer Center New York, NY and Weill Cornell Medical College, New York, NY, United States of America. Electronic address: ocearbhr@mskcc.org.
Abstract
OBJECTIVES: The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS: Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P). RESULTS: 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR). CONCLUSIONS: IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.
OBJECTIVES: The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS: Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patientcohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P). RESULTS: 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR). CONCLUSIONS: IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.
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