Acelarin First Line Randomised Pancreatic Study

NCT03610100 | Suspended Phase 2 DMC

• 1 other identifier: ISRCTN16765355
• Study Type: interventional
• Target: 328
• Locations: 1 country
• Sites: 1

Brief Summary

The primary purpose of this study is to assess whether Acelarin (NUC-1031) is superior to gemcitabine in terms of overall survival for treatment of patients with metastatic pancreatic carcinoma. In addition disease progression, quality of life and comparative safety will be evaluated. Secondary objectives are to compare between the two treatment groups the following:

• Progression Free Survival (PFS)
• Radiological Response and disease control rate
• Toxicity and safety
• Quality of Life Additional, exploratory objectives are to discover and validate possible biomarkers to predict additional benefit of Acelarin (NUC-1031) over gemcitabine alone.

Conditions

Pancreatic Acinar Carcinoma; Pancreatic Neoplasms

Keywords

Pancreatic; Neoplasms; Metastatic; Gemcitabine; Gemzar; Phosphoramidate; Cytidine Aminohydrolase; Deoxycytidine Kinase; Nucleoside Transport Proteins; hENT1 protein, human

Outcome Measures

Primary Outcomes (1)

• Number of participants that have survived throughout treatment and also into follow-up, as measured by the primary cause of death and date of death CRFs.

  4 years

Secondary Outcomes (4)

• Number of participants that survive progression-free and for how long, as assessed by 12-weekly CT scan assessments per RECIST v1.1 and end of study CRF to capture the reasons for coming off study.

  4 years

• Number of participants that show an objective response, as demonstrated by 12-weekly CT scan assessments per RECIST v1.1.

  4 years

• Number of participants deemed to have disease control, as demonstrated by 12-weekly CT scan assessments per RECIST v1.1.

  4 years

• Number of patients with treatment-related adverse events as assessed by CTCAE v4.03. Toxicity is assessed by CTCAE v4.03 alongside Quality of Life Questionnaires, QLQ-C30 and QLQ-PAN26.

  4 years

Other Outcomes (1)

• Discovery of possible biomarkers which may predict any additional benefit of Acelarin over gemcitabine. These will be assessed from plasma, cell pellet and serum samples collected from participants throughout the trial.

  4 years

Study Arms (2)

Acelarin (NUC-1031)

EXPERIMENTAL

825 mg/m2 administered intravenously over 15 to 30 minutes on days 1, 8 and 15 of a 28 day cycle. Patients will be seen on a weekly basis during the time they are on active treatment and will be treated until disease progression.

Drug: Acelarin

Gemcitabine

ACTIVE COMPARATOR

Gemcitabine: 1000mg/m2 administered intravenously as a 30 minute infusion on days 1, 8 and 15 of a 28 day cycle. Patients will be seen on a weekly basis during the time they are on active treatment and will be treated until disease progression.

Drug: Gemcitabine

Interventions

Acelarin DRUG

825 mg/m2 administered intravenously over 15 to 30 minutes on days 1, 8 and 15 of a 28 day cycle. Number of Cycles: until disease progression or unacceptable toxicity develops.

Also known as: NUC-1031

Acelarin (NUC-1031)

Gemcitabine DRUG

1000 mg/m2 administered intravenously as a 30 minute infusion on days 1, 8 and 15 of a 28 day cycle. Number of Cycles: until disease progression or unacceptable toxicity develops.

Also known as: Gemzar

Gemcitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years.
• Histologically or cytologically proven pancreatic ductal adenocarcinoma or undifferentiated carcinoma of the pancreas.
• Metastatic disease precluding curative surgical resection or definitive locally directed therapies such as chemo radiation. Patients who have relapsed following previously resected pancreatic cancer can be included.
• Contrast enhanced computerised tomography (CT) scan of the thorax, abdomen and pelvis within 28 days prior to commencing treatment.
• Unidimensionally measurable disease.
• ECOG performance status 0, 1 or 2 where combination chemotherapy is not deemed appropriate or is declined by the patient.
• Platelets ≥100 x 109/l; WBC ≥ 3 x 109/l; neutrophils ≥ 1.5 x 109/l at entry.
• Documented life expectancy \> 3 months.
• Informed written consent.

You may not qualify if:

• Laboratory results:
• Serum bilirubin ≥ 1.5x the upper limit of reference range (ULRR).
• Haemoglobin \< 10G/dl.
• Creatinine clearance \< 30 mL/minute (calculated by Cockcroft-Gault formula).
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 x ULN or \> 5x ULN if judged by the investigator to be related to liver metastases.
• Medical or psychiatric conditions compromising informed consent.
• Intracerebral metastases or meningeal carcinomatosis.
• Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol.
• Pregnancy or breast feeding.
• Previous chemotherapy for locally advanced and metastatic disease. Adjuvant chemotherapy for resected pancreatic cancer will be permitted provided that chemotherapy was completed \> 12 months previously.
• Radiotherapy within the last 4 weeks prior to start of study treatment.
• Concurrent malignancies or invasive cancers diagnosed within past 5 years except for adequately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix or resected pancreatic cancer.
• Hypersensitivity to gemcitabine or any of the excipients of gemcitabine or Acelarin (NUC-1031).
• All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be from the list below, the other must be a condom\* or abstaining from sexual intercourse, until six months after treatment has ended:
• Combined (oestrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation: either oral, intravaginal or transdermal.

Sponsors & Collaborators

• The Clatterbridge Cancer Centre NHS Foundation Trust: lead
• Cancer Research UK: collaborator
• University of Liverpool: collaborator

Study Sites (1)

Cancer Research UK Liverpool Cancer Trials Unit

Liverpool, Merseyside, L69 3GL, United Kingdom

Location

Related Publications (13)

• Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. doi: 10.1200/JCO.1997.15.6.2403.

  PMID: 9196156 BACKGROUND

• Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. doi: 10.1056/NEJMoa1011923.

  PMID: 21561347 BACKGROUND

• Von Hoff DD, Ervin TJ, Arena FP, et al: "Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT)". 2013 Gastrointestinal Cancers Symposium. J Clin Oncol 31, 2013 (suppl 4; abstract: LBA148)

  BACKGROUND

• Ghazaly, E.A. et al. "ProGem1: Phase I first-in-human study of the novel nucleotide NUC-1031 in adult patients with advanced solid tumors" J Clin Oncol 31, 2013 (suppl; abstr 2576)

  BACKGROUND

• de Sousa Cavalcante L, Monteiro G. Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur J Pharmacol. 2014 Oct 15;741:8-16. doi: 10.1016/j.ejphar.2014.07.041. Epub 2014 Jul 30.

  PMID: 25084222 BACKGROUND

• Achiwa H, Oguri T, Sato S, Maeda H, Niimi T, Ueda R. Determinants of sensitivity and resistance to gemcitabine: the roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non-small cell lung cancer. Cancer Sci. 2004 Sep;95(9):753-7. doi: 10.1111/j.1349-7006.2004.tb03257.x.

  PMID: 15471562 BACKGROUND

• Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R, Mackey JR. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res. 2004 Oct 15;10(20):6956-61. doi: 10.1158/1078-0432.CCR-04-0224.

  PMID: 15501974 BACKGROUND

• Ghazaly, E.A. et al. "ProGem1: A phase I/II study of a first-in-class nucleotide, Acelarin, in patients with advanced solid tumors" J Clin Oncol 32:5s, 2014 (suppl; abstr 2531)

  BACKGROUND

• Sebastiani V, Ricci F, Rubio-Viqueira B, Kulesza P, Yeo CJ, Hidalgo M, Klein A, Laheru D, Iacobuzio-Donahue CA. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res. 2006 Apr 15;12(8):2492-7. doi: 10.1158/1078-0432.CCR-05-2655.

  PMID: 16638857 BACKGROUND

• Kroep JR, van Moorsel CJ, Veerman G, Voorn DA, Schultz RM, Worzalla JF, Tanzer LR, Merriman RL, Pinedo HM, Peters GJ. Role of deoxycytidine kinase (dCK), thymidine kinase 2 (TK2), and deoxycytidine deaminase (dCDA) in the antitumor activity of gemcitabine (dFdC). Adv Exp Med Biol. 1998;431:657-60. doi: 10.1007/978-1-4615-5381-6_127. No abstract available.

  PMID: 9598147 BACKGROUND

• Philip PA, Chansky K, LeBlanc M, Rubinstein L, Seymour L, Ivy SP, Alberts SR, Catalano PJ, Crowley J. Historical controls for metastatic pancreatic cancer: benchmarks for planning and analyzing single-arm phase II trials. Clin Cancer Res. 2014 Aug 15;20(16):4176-85. doi: 10.1158/1078-0432.CCR-13-2024. Epub 2014 Jun 9.

  PMID: 24914040 BACKGROUND

• Slusarczyk M, Lopez MH, Balzarini J, Mason M, Jiang WG, Blagden S, Thompson E, Ghazaly E, McGuigan C. Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development. J Med Chem. 2014 Feb 27;57(4):1531-42. doi: 10.1021/jm401853a. Epub 2014 Feb 14.

  PMID: 24471998 BACKGROUND

• Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. doi: 10.1200/JCO.2006.07.9525. Epub 2007 Apr 23.

  PMID: 17452677 BACKGROUND

MeSH Terms

Conditions

Pancreatic Neoplasms; Neoplasms; Neoplasm Metastasis

Interventions

NUC-1031; Gemcitabine

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Daniel H Palmer, BSC, PhD

  University of Liverpool

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2016
• First Posted: August 1, 2018
• Study Start: December 1, 2015
• Primary Completion: September 1, 2020
• Study Completion: December 1, 2022
• Last Updated: October 29, 2019

Record last verified: 2019-05

Locations

GB (1)