Abstract
Objectives
Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor.
Methods
This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483–gemcitabine versus gemcitabine alone.
Results
Target international normalized ratio (between 2.0–3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483–gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483–gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months).
Conclusion
Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483–gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.
Keywords: Anti-tumor, Pancreatic cancer, Cancer antigen 19-9, Gemcitabine, Pancreatic carcinoma, Phase II study, Survival
Introduction
Tissue factor (TF) is a transmembrane receptor constitutively expressed by fibroblasts surrounding blood vessels [1]. When the endothelium is breached by injury or tissue damage, TF is exposed to its ligand, protease factor VII (FVII), in circulation. The resulting activated FVII (FVIIa) forms a complex with TF (TF:FVIIa), triggering the blood coagulation cascade [2, 3]. Many tumor types express TF, with increased expression correlating with tumor invasiveness and worsened prognosis [4, 5, 6]. TF:FVIIa may contribute to tumor invasiveness by promoting cell migration through upregulation of chemokines such as interleukin-8 and by inducing angiogenesis through vascular endothelial growth factor signaling [7, 8]. High TF expression correlates with increased venous thromboembolism (VTE) in patients with pancreatic cancer [9]. Patients with cancer have a four-fold greater risk for VTE than the general population, and chemotherapy increases this risk [10]. VTE is associated with advanced cancer stage and poor prognosis [11].
PCI-27483 is a selective, small-molecule FVIIa inhibitor developed to treat TF-overexpressing cancers. PCI-27483 (90 mg/kg b.i.d.) inhibited tumor growth in mice implanted with cancer cells [12, 13]. Previously, studies of prophylactic anticoagulation with low-molecular-weight heparin in advanced pancreatic cancer (APC) have demonstrated a decrease in VTEs but no impact on survival [14, 15]. The first-in-human study of PCI-27483 in healthy adults aimed to determine a pharmacologically effective, single, subcutaneous (SC) dose of PCI-27483 resulting in a cohort mean peak international normalized ratio (INR) ≥2.0 or peak INR ≥3.0 for any subject. With single-dose (≤2.0 mg/kg) PCI-27483, adverse events (AEs) were mild and not treatment related, and no clinically significant laboratory values changed from baseline. Coagulation parameters (including INR) exhibited dose-dependent increases [unpubl. data]. Based on these initial results, we report data from a phase 2 study of PCI-27483 in patients with APC.
Methods
Study Design
This open-label, phase 2 trial (NCT01020006) was conducted across 14 study centers, with enrollment beginning November 2009 and the study ending August 2012. Part A was a nonrandomized, intrapatient, dose escalation lead-in portion starting at 0.8 mg/kg (maximum 1.5 mg/kg) PCI-27483 administered b.i.d. by SC injection in patients concurrently receiving gemcitabine for 12 weeks; in part B, patients were randomized 1: 1 to receive the recommended phase 2 dose (RP2D, 1.2 mg/kg b.i.d.) of PCI-27483 combined with gemcitabine (the standard of care at time of study initiation) or gemcitabine alone. This dose was selected based upon attainment of the targeted pharmacodynamic effect (INR between 2.0 and 3.0) with an acceptable AE profile reported in part A. Gemcitabine was given intravenously at 1 g/m2 once weekly for 3 weeks out of every 4 weeks, and PCI-27483 was self-administered SC b.i.d. continuously. Eligible patients included adults with metastatic ductal adenocarcinoma (mPC) of the pancreas diagnosed ≤4 months prior to enrollment or locally advanced ductal adenocarcinoma (LAPC) of the pancreas diagnosed ≤6 months prior to enrollment (part B). Patients with a history of disease progression during gemcitabine treatment or history of VTE were excluded.
The primary objective for part A was to evaluate safety and tolerability of PCI-27483 and to establish RP2D; the primary objective for part B was to compare safety and tolerability of PCI-27483–gemcitabine with gemcitabine alone in patients with mPC or LAPC. Power computations were not of primary interest, and sample size of the study was not based on safety endpoints but rather on considerations of various activity outcomes. Based on pharmacodynamic and safety profiles obtained from single doses in healthy volunteers and from preclinical studies, planned enrollment for part A was approximately 6 patients. In part B, 40 patients were planned to be randomized to either arm in a 1: 1 ratio based on considerations of various activity outcomes, including approximately 80% power at 1-sided significance level of 0.20 for progression- free survival (PFS) and overall survival (OS) benefit.
Assessments
Safety data were collected from time of first dose until week 16 or 28 ± 2 days after last dose, whichever occurred last. Vital signs and Eastern Cooperative Oncology Group performance status (ECOG PS) were measured at screening and during selected study visits. Efficacy evaluations included PFS, OS, serum cancer antigen 19-9 measurements, objective tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and spiral computed tomography, at baseline and every 8 weeks. Arm comparisons were performed in part B. PFS and OS were analyzed by log-rank test; hazard ratios (HRs) were estimated by Cox regression, and overall response rates were compared using the Cochran-Mantel-Haenszel χ2 test. All tests were stratified by local advanced or metastatic disease.
Results
In part A, 8 patients enrolled and received PCI-27483–gemcitabine. In part B, 34 patients were randomized to receive either PCI-27483–gemcitabine (n = 18) or gemcitabine alone (n = 16); the study closed to accrual due to slow enrollment. Patient demographics and baseline characteristics were balanced for patients enrolled in part B (Table 1), though differences in biomarkers were not clinically meaningful given the small numbers in each arm.
Table 1.
Baseline characteristics
| Part A |
Part B |
||
|---|---|---|---|
| PCI-27483–gemcitabine (n = 8) |
PCI-27483–gemcitabine (n = 18) |
Gemcitabine (n = 16) |
|
| Age, years | 61 (54–80) | 62 (48–82) | 66 (55–86) |
| Male sex | 4 (50) | 11 (61) | 10 (63) |
| Disease type | |||
| Locally advanced | 2 (25) | 2 (11) | 2 (13) |
| Metastatic | 6 (75) | 16 (89) | 14 (88) |
| Liver metastasis | 1 (13) | 11 (61) | 13 (81) |
| ECOG PS | |||
| 0 | 4 (50.0) | 10 (56) | 6 (38) |
| 1 | 4 (50.0) | 8 (44) | 9 (56) |
| 2 | 0 | 0 | 1 (6) |
| Serum CA 19–9 | |||
| Median (range), U/mL | 147 (2–2,669) | 1,055 (13–216,604)a | 274 (2–126,422) |
| ≤39 U/mL | 1 (13) | 2 (11) | 4 (25) |
| >39 U/mL | 7 (88) | 15 (83) | 12 (75) |
| Baseline IL-8 | |||
| <6 pg/mL | 1 (13) | 10 (56) | 4 (25) |
| 6–10 pg/mL | 4 (50) | 4 (22) | 6 (38) |
| >10 pg/mL | 0 | 3 (17) | 4 (25) |
| INR | 1.0 (1.0–1.5) | 1.1 (1.0–2.3) | 1.1 (0.9–1.4) |
Data are presented as median (range) or n (%). ECOG PS, Eastern Cooperative Oncology Group performance status; IL-8, interleukin-8; INR, international normalized ratio; serum CA 19–9, serum cancer antigen 19–9.
n = 17 for PCI-27483–gemcitabine.
The overall safety profile of grade ≥3 AEs was similar in patients who received PCI-27483–gemcitabine versus gemcitabine. Nonetheless, serious AEs were higher in the PCI-27483–gemcitabine arm compared to gemcitabine (Table 2). AEs leading to PCI-27483 dose modification occurred in 14/26 PCI-27483-treated patients; increased INR (31%) and prolonged prothrombin time (12%) were the only AEs occurring in more than 1 patient. Overall, the most common AEs leading to PCI-27483 discontinuation were gastrointestinal disorders, including gastrointestinal hemorrhage, and increased INR. AEs that occurred with a ≥20% difference in incidence between patients who received PCI-27483–gemcitabine versus gemcitabine primarily affected coagulation and hemoglobin parameters, including increased INR (46% vs. 0), injection site hematoma (38% vs. 0), and also included dizziness (23% vs. 0). The incidence of any-grade bleeding events was higher for PCI-27483– gemcitabine than gemcitabine (65% vs. 19%), with similar incidence of grade ≥3 bleeding events (15% vs. 13%). Overall, 9 patients treated with PCI-27483–gemcitabine received transfusions. One of 26 patients (4%) treated with PCI-27483–gemcitabine experienced VTE (grade 2), while 2/16 patients (13%) treated with gemcitabine experienced VTE (grade 2 and grade 4).
Table 2.
Adverse events
| PCI-27483-gemcitabine | Gemcitabine | |||
|---|---|---|---|---|
| Part A (n = 8) |
Part B (n = 18) |
Total (n = 26) |
Part B (n = 16) |
|
| PCI-27483 exposure, weeks | 19 (1–75) | 8 (<1–97) | NA | NA |
| Gemcitabine exposure, cycles | 5 (1–19) | 3 (1–24) | NA | 2 (1–10) |
| Grade ≥3 AEs | 6 (75) | 17 (94) | 23 (89) | 14 (88) |
| Serious AEs | 5 (63) | 12 (67) | 17 (65) | 7 (44) |
| AEs leading to PCI-27483 dose modification | 6 (75) | 8 (44) | 14 (54) | NA |
| AEs leading togemcitabine dose modification | 6 (75) | 5 (28) | 11 (42) | 8 (50) |
| AEs leading to PCI-27483 dose discontinuation | 4 (50) | 7 (39) | 11 (42) | NA |
| AEs leading to gemcitabine dose discontinuation | 3 (38) | 5 (28) | 8 (31) | 6 (38) |
| Deaths on studya | 1 (13) | 4 (22) | 5 (19) | 3 (19) |
| Bleeding events | ||||
| Any grade | 7 (88) | 10 (56) | 17 (65) | 3 (19) |
| Grade ≥3 | 1 (13) | 3 (17) | 4 (15) | 2 (13) |
| Venous thromboembolism | ||||
| Any grade | 0 (0) | 1 (6) | 1 (4) | 2 (13) |
| Grade ≥3 | 0 (0) | 0 (0) | 0 (0) | 1 (6) |
Data are presented as median (range) or n (%). AE, adverse event; NA, not applicable.
Death within 30 days of last dose of study treatment.
Pharmacokinetics
Steady-state PCI-27483 exposure was approximately dose proportional: the respective mean steady-state PCI-27483 maximum plasma concentration (Cmax) at 0.8 mg/kg and 1.2 mg/kg b.i.d. was 5.14 and 6.26 μg/mL, respectively. Based on prior pharmacokinetic data in healthy volunteers, peak INR was projected to be 2.06 at 0.8 mg/kg b.i.d. PCI-27483, 2.61 at 1.2 mg/kg b.i.d., and 3.02 at 1.5 mg/kg b.i.d. Actual steady-state INR values were consistent with these estimates. In part A, median INR (min, max) increased from 1.0 (1.0, 1.5) at baseline to 1.6 (1.2, 1.7) within 2 hours after the first 0.8 mg/kg PCI-27483 dose. Median INR peaked at 2.9 (2.8, 7.5) on day 8 of cycle 3 (C3D8; 1.5 mg/kg dose). The dose of 1.2 mg/kg b.i.d. was selected to target an INR between 2.0 and 3.0 to further evaluate in part B. In part A, median INR was 2.1 (1.9, 3.1) at 2 hours pre-PCI-27483–gemcitabine dose and 2.8 (1.7, 5.1) 2 hours post-dose on C3D1; among patients randomized to PCI-27483–gemcitabine in part B, on C3D1 median INR was 1.9 (1.3, 2.6) pre-dose and 2.7 (2.0, 3.3) 2 hours post-dose. Median INR for patients receiving gemcitabine alone was 1.0 (1.0, 1.4) on C3D1. INR was measured in the gemcitabine group at baseline, C1D15, C2D1, and C3D1; median INRs ranged from 1.0 to 1.1.
Efficacy
The overall response rate was zero for part A, and for part B it was 11% for patients who received PCI-27483–gemcitabine and 6% for gemcitabine (odds ratio, 1.87; p = 0.612). In part B, median PFS was 3.7 months for patients who received PCI-27483–gemcitabine and 1.9 months for gemcitabine (Fig. 1a), with a nonsignificant trend in favor of PCI-27483–gemcitabine (HR, 0.62; p = 0.307). The median OS was 5.7 months for patients who received PCI-27483–gemcitabine and 5.6 months for patients who received gemcitabine in part B (HR, 0.95; p = 0.898; Fig. 1b). There was no significant difference in OS between PCI-27483–gemcitabine versus gemcitabine.
Fig. 1.
Progression-free survival (a) and overall survival (b) of patients treated with PCI-27483–gemcitabine versus gemcitabine alone in part B (safety population).
Discussion
This phase 2 study was designed to evaluate the safety of PCI-27483 in patients with mPC or LAPC receiving concurrent gemcitabine. Upregulated TF has been linked with tumor invasiveness and increased VTE [16, 17]. Since PCI-27483 inhibits FVIIa, which initiates the coagulation cascade after binding with TF [2], it was hypothesized that PCI-27483 may reduce VTE complications and potentially increase survival in patients with APC.
Combination PCI-27483–gemcitabine was well tolerated and did not appear to affect the safety or tolerability of gemcitabine. Incidence of grade ≥3 severe bleeding in patients treated with PCI-27483–gemcitabine was comparable to that of gemcitabine, although low-grade bleeding was more common with PCI-27483–gemcitabine. There was a trend toward lower incidence of VTE with PCI-27483–gemcitabine versus gemcitabine.
In part B, INR values in patients treated with PCI-27483 were mostly within the targeted range: median INR increased from 1.1 at baseline to 2.0 within 2 hours post-first dose of PCI-27483–gemcitabine and to 2.7 at 2 hours post-dose C3D1. An increase in INR was observed solely in patients treated with PCI-27483–gemcitabine, consistent with the mechanism of action of PCI-27483.
There was a nonsignificant trend toward longer PFS in patients receiving PCI-27483–gemcitabine. There was no significant difference in OS between treatment groups. Even though significant clinical efficacy between PCI-27483–gemcitabine and gemcitabine was not reached, targeted inhibition of the coagulation cascade was achieved. While PCI-27483 will not be evaluated further in APC, this study demonstrates the potential for and hypothesis of targeted inhibition of the coagulation cascade for treatment of APC.
Statement of Ethics
This study was approved by institutional review boards at participating institutions, and all patients provided written informed consent. The study met the standards of the Declaration of Helsinki and its amendments.
Disclosure Statement
Pharmacyclics LLC, an AbbVie company, sponsored and designed the study. Study investigators and their research teams collected the data. The sponsor confirmed data accuracy and performed analysis of the data. Medical writing support was provided by Valerie Hilliard, PhD, and funded by Pharmacyclics LLC, an AbbVie Company.
R.K.R.: honoraria from Data Safety Monitoring Board. G.W.T.: employment with South Carolina Cancer Specialists; consultancy/advisory role for Gilead Sciences, Cardinal Health, IntegraConnect, TRM Oncology, Bayer Oncology, Alexion, Pfizer, Insight, AstraZeneca, Clovis Oncology, Biotheranostics; research funding from Amgen, Puma Biotechnology, Incyte, United BioSource. A.A.K.: honoraria from and consultancy/advisory role for Sanofi, Pfizer, Janssen, Halozyme, Bayer, Angiodynamics; research funding from Amgen, Merck, and BMS; travel expenses from Bayer, Janssen, Pfizer. S.S.: nothing to disclose. C.Z.: employment with Pharmacyclics, an AbbVie company; equity ownership in AbbVie. S.W.: equity ownership in AbbVie. G.C.: employment with Pharmacyclics, an AbbVie company; equity ownership in AbbVie. D.J.: employment with Pharmacyclics, an AbbVie company; equity ownership and patent applications with AbbVie; husband is employed by and has equity ownership in AbbVie. N.Y.G.: honoraria from Johnson & Johnson, Heron, AbbVie, and Taiho; research funding from Heron, Johnson & Johnson, Taiho, and Tesaro; participated in speakers' bureau with Bayer, Acerta, Johnson & Johnson, Taiho, Senofi, Incyte, AbbVie, Amgen, BMS, Celgene, Halozyme, and Gilead.
Funding Sources
This study was funded by Pharmacyclics, LLC, an AbbVie Company, Sunnyvale, CA, USA.
Author Contributions
Conception and design: R.K.R., G.W.T., A.A.K., S.S., N.Y.G. Provision of study materials or patients: R.K.R., G.W.T., A.A.K., S.S., N.Y.G. Collection and assembly of data: R.K.R., G.W.T., A.A.K., S.S., N.Y.G., C.Z. Data analysis and interpretation: all authors. Manuscript writing: all authors. Final approval of manuscript: all authors.
Acknowledgments
We thank all the patients who participated in this trial and their families.
References
- 1.Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol. 1989 May;134((5)):1087–97. [PMC free article] [PubMed] [Google Scholar]
- 2.Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg. 2009 May;108((5)):1447–52. doi: 10.1213/ane.0b013e31819bceb1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol. 2004 Jun;24((6)):1015–22. doi: 10.1161/01.ATV.0000130465.23430.74. [DOI] [PubMed] [Google Scholar]
- 4.Ueno T, Toi M, Koike M, Nakamura S, Tominaga T. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration. Br J Cancer. 2000 Jul;83((2)):164–70. doi: 10.1054/bjoc.2000.1272. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Koomägi R, Volm M. Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis. Int J Cancer. 1998 Feb;79((1)):19–22. doi: 10.1002/(sici)1097-0215(19980220)79:1<19::aid-ijc4>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
- 6.Tieken C, Verboom MC, Ruf W, Gelderblom H, Bovée JV, Reitsma PH, et al. Tissue factor associates with survival and regulates tumour progression in osteosarcoma. Thromb Haemost. 2016 May;115((5)):1025–33. doi: 10.1160/TH15-07-0541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hjortoe GM, Petersen LC, Albrektsen T, Sorensen BB, Norby PL, Mandal SK, et al. Tissue factor-factor VIIa-specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration. Blood. 2004 Apr;103((8)):3029–37. doi: 10.1182/blood-2003-10-3417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Zhang J, Ding J, Zhang X, Shao X, Hao Z. Regulation of vascular endothelial growth factor (VEGF) production and angiogenesis by tissue Factor (TF) in SGC-7901 gastric cancer cells. Cancer Biol Ther. 2005 Jul;4((7)):769–72. doi: 10.4161/cbt.4.7.1871. [DOI] [PubMed] [Google Scholar]
- 9.Khorana AA, Ahrendt SA, Ryan CK, Francis CW, Hruban RH, Hu YC, et al. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Res. 2007 May;13((10)):2870–5. doi: 10.1158/1078-0432.CCR-06-2351. [DOI] [PubMed] [Google Scholar]
- 10.Heit JA, Mohr DN, Silverstein MD, Petterson TM, O'Fallon WM, Melton LJ., 3rd Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000 Mar;160((6)):761–8. doi: 10.1001/archinte.160.6.761. [DOI] [PubMed] [Google Scholar]
- 11.Sørensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000 Dec;343((25)):1846–50. doi: 10.1056/NEJM200012213432504. [DOI] [PubMed] [Google Scholar]
- 12.Loury D, Thiemann P, Prescott J, Buggy J. PCI-27483, a small molecule inhibitor of factor VIIa, inhibits tumor growth in vivo. Mol Cancer Ther. 2007;6(suppl):B286. [Google Scholar]
- 13.Prescott J, Thiemann P, Loury D. PCI-27483, a small molecule inhibitor of factor VIIa, inhibits growth of BxPC3 pancreatic adenocarcinomaxenograft tumors. Cancer Res. 2008;68(suppl):5669. [Google Scholar]
- 14.Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer. 2012 Jun;48((9)):1283–92. doi: 10.1016/j.ejca.2011.10.017. [DOI] [PubMed] [Google Scholar]
- 15.Pelzer U, Opitz B, Deutschinoff G, Stauch M, Reitzig PC, Hahnfeld S, et al. Efficacy of prophylactic low-molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO-004 trial. J Clin Oncol. 2015 Jun;33((18)):2028–34. doi: 10.1200/JCO.2014.55.1481. [DOI] [PubMed] [Google Scholar]
- 16.Heit JA. Cancer and venous thromboembolism: scope of the problem. Cancer Contr. 2005 Sep;12((3_suppl Suppl 1)):5–10. doi: 10.1177/1073274805012003S02. [DOI] [PubMed] [Google Scholar]
- 17.Anand M, Brat DJ. Oncogenic regulation of tissue factor and thrombosis in cancer. Thromb Res. 2012 Apr;129(Suppl 1):S46–9. doi: 10.1016/S0049-3848(12)70015-4. [DOI] [PubMed] [Google Scholar]