Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer.

Abstract

PURPOSE:

The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).

PATIENTS AND METHODS:

Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.

RESULTS:

A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2-4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4-18.4], median overall survival was 9.7 m (95% CI, 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.

CONCLUSIONS:

Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.

• Authors: Efrat Dotan, Dana B Cardin, Heinz-Josef Lenz, Wells Messersmith, Bert O'Neil, Steven J Cohen, Crystal S Denlinger, Safi Shahda, Igor Astsaturov, Ann M Kapoun, Rainer K Brachmann, Shailaja Uttamsingh, Robert J Stagg, Colin Weekes
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 20 Pg. 5348-5357 (10 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32694153 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• 130-nm albumin-bound paclitaxel
• Albumins
• Immunoglobulin Fc Fragments
• Receptors, G-Protein-Coupled
• Recombinant Fusion Proteins
• Wnt Proteins
• Deoxycytidine
• OMP-54F28
• Paclitaxel
• Fluorouracil
• Gemcitabine

Topics

• Adenocarcinoma (drug therapy, genetics, pathology)
• Adult
• Aged
• Albumins (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives)
• Fluorouracil (administration & dosage)
• Humans
• Immunoglobulin Fc Fragments (administration & dosage, adverse effects)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Staging
• Paclitaxel (administration & dosage, adverse effects)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Receptors, G-Protein-Coupled (administration & dosage)
• Recombinant Fusion Proteins (administration & dosage, adverse effects)
• Wnt Proteins (antagonists & inhibitors)
• Gemcitabine