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.

Figure 1:

Study schema outlining the cohorts of this study.

Figure 2:

A: Waterfall plot depicting the maximum change in sum of target lesions in diameter among all patients treated with IPA, G and Nab-P. Nine patients (35%) had partial responses and 12 patients had stable disease as their best response with an unconfirmed overall response rate of 35%, and clinical benefit rate of 81%. PD = Progressive Disease; SD = stable disease; PR = partial response; CR = complete response. B: Kaplan Meyer curves demonstrating progression free survival (PFS) and overall survival (OS) among the intent to treat (ITT) population with median PFS of 5.9 months (95% CI: 3.4-18.4) and median OS of 9.7 months (95% CI: 7.0-14.0). 2 patients remained on treatment following termination of the study under compassionate use. One patient was treated for 665 days before progression. The second patient remains on treatment for 59 months with ongoing response.

Figure 3:

(A). Representation of down regulation of Wnt-pathway genes expression in hair follicles among patients (in red) and controls (in gray). (B) Fold change in expression of Wnt-pathway gene AXIN2 expression fold change induced by IPA treatment in hair follicles of 20 patients represented by the different cohorts.

Figure 4:

Evaluation of 6-gene signature on RNA isolated from FFPE PDAC tumor samples of 14 patients using a cutoff at the 50th percentile. (A) Association of 6-gene signature with PFS; (B) Association of 6-gene signature with OS; (C) Assocation of 6-gene signature with OS on pancreatic ductal carcinoma RNA Seq dataset from The Cancer Genome Atlas (TCGA). High signature levels ≥ 50^th percentile (green line) compared to low signature levels < 50^th percentile (red line).OS-Overall Survival.