Early termination of NCT04617067, a phase II, open label, clinical trial of oral paricalcitol in combination with gemcitabine and NAB-paclitaxel therapy in advanced pancreatic cancer

Abstract

Background: Pancreatic cancer (PDAC) often responds poorly to chemotherapy, represents an unmet clinical need and new therapeutic approaches are urgently required. Desmoplasia is a hallmark of PDAC. Multiple preclinical studies suggest cancer associated fibroblasts (CAF) support cancer growth, and attention has recently turned towards inclusion of anti-stromal agents into chemotherapy trials. Our objective was to evaluate safety and tolerability of oral paricalcitol in combination with systemic chemotherapy in patients with advanced PDAC.

Methods: This was a phase II, single-arm study in patients with advanced PDAC who had received no prior systemic chemotherapy. Gemcitabine and NAB-paclitaxel were administered weekly for 3 of every 4 weeks (days 1, 8 and 15) and paricalcitol administered orally every day of a 28-day cycle. Patients were treated until disease progression with an interim analysis. The primary efficacy endpoint was progression free survival (PFS). Secondary efficacy endpoints were evaluation of overall survival (OS), time to treatment failure (TTF) and tumour response rate (TRR).

Results: Fifteen patients were enrolled. Median PFS was 14.6 weeks with 95% CI of (7.9–24.0). Estimated PFS rate at 24 weeks was 18.0% with 95% CI of (2.9–43.4). Five patients achieved stable disease; one achieved a partial response. Confirmed tumour response rate was 8.3% with 90% CI of (0.4–33.9). Mild hypercalcaemia, previously associated with vitamin D receptor agonists, occurred in nine (60%) patients, moderate (Grade 3) hypercalcaemia in 2 patients and there was no grade 4/5 hypercalcaemia. The study did not meet its primary objective and discontinued following interim analysis.

Conclusions: Oral paricalcitol was safely combined with chemotherapy. The prespecified efficacy threshold for 6-month progression free survival probability (≥ 70%) was not met. The study was stopped early after the planned interim analysis as the criterion pre-specified in order to move to the next stage of the study was not met. Efficacy of paricalcitol in advanced PDAC was lower than expected, with a non-significant trend towards decreased PFS. Our study has implications for interpretation and design of clinical trials incorporating paricalcitol for patients with advanced pancreatic cancer.

Trial registration: ClinicalTrials.gov identifier: NCT04617067, registration date 10/27/2020.

Keywords: Hypercalcaemia; Stromal targeting; Vitamin D receptor agonist.

Fig. 1

Schematic of study design: a phase II, single arm, multi-centre trial, incorporating an interim analysis. A Simon two-stage design was used to evaluate anti-tumour efficacy of paricalcitol in combination with gemcitabine and NAB-paclitaxel

Fig. 2

Swimmer plot for all patients enrolled in the study, indicating duration of treatment, response at week 12 and reason for discontinuation of study treatment. Patient 6 achieved stable disease at 12 weeks with a partial response after 24 weeks of treatment. Patient 11 had stable disease at 10 weeks and thereafter was unable to attend for further restaging scans due to malaise

Fig. 3

Kaplan Meier plot. Progression Free Survival (PFS) for intention-to-treat patients (N = 13). Two patients were withdrawn before post baseline RECIST assessments (with no evidence of clinical progression) and were excluded from PFS analysis

Fig. 4

Kaplan Meier plot. Time to Treatment Failure (TTF) for intention-to-treat patients (N = 14). One patient had no post-baseline RECIST assessment, continued on treatment for 4 weeks post study closure and was excluded from TTF analysis. One patient had no post-baseline RECIST assessment, with no clinical progression and discontinued study treatment due to an adverse event

Fig. 5

Kaplan Meier plot. Overall Survival for intention-to-treat patients (N = 15). Patients with event (N = 12), Patients censored (N = 3)

Fig. 6

Waterfall plot for evaluable patients with elevated CA19-9 at baseline, showing change of CA19-9 (between baseline and end of treatment). Patient 5 had no baseline assessment and was excluded