Gemcitabine and ON 01910.Na in Previously Untreated Metastatic Pancreatic Cancer (ONTRAC)

A Phase III, Multi-center, Randomized, Controlled Study to Compare the Efficacy and Safety of Gemcitabine Alone vs. ON 01910.Na Combined With Gemcitabine in Patients With Previously Untreated Metastatic Pancreatic Cancer

The question being asked in this study is: Will patients with advanced pancreatic cancer live significantly longer if they are treated with a combination of Gemcitabine and ON 01910.Na than if they are treated with Gemcitabine alone? There are two parts to this study. In the first part of the study, patients with metastatic pancreatic cancer who have received no prior chemotherapy for this disease will be assigned by chance either to the group that will be treated with both Gemcitabine and ON 01910.Na (about 100 patients will be in this group) or, to the group that will be treated with Gemcitabine only (about 50 patients will be in this group). How long patients survive in the 2 groups will be compared. If it looks like there is no difference between the groups, the study will stop. If it looks like patients in the group that were treated with both Gemcitabine and ON 01910.Na survive longer, the study will continue into a second part where more patients will be treated in order to confirm and better understand the findings of the first part of the study.

Study Overview

• Status: Completed
• Conditions: Metastatic Pancreatic Adenocarcinoma
• Intervention / Treatment: Drug: ON 01910.Na; Drug: Gemcitabine; Drug: Gemcitabine

Detailed Description

This will be a Phase III study with sample size recalculation after 100 events have occurred. The study will be open-label, randomized, controlled, multi-center and will be conducted at approximately 200 to 300 study sites (60 to 80 study sites in the first portion of the trial).

In the first portion of the study, a total of 150 patients with metastatic pancreatic cancer who have received no prior chemotherapy for this disease will be randomized in a 2:1 fashion to 1 of the 2 following treatment regimens:

• Arm A: Gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4 week cycle + ON 01910.Na 1800 mg/m2 via 2 hr continuous intravenous infusion (CIV) infusions administered twice weekly for 3 weeks of a 4 week cycle (approximately 100 patients)
• Arm B: Gemcitabine only, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle (approximately 50 patients).

Patients will be stratified at entry using the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG scores of 0 1 vs. ECOG scores of 2; patients with higher scores will not be enrolled).

Patients will remain on study until disease progression or death from any cause, whichever comes first. Moreover, after treatment discontinuation for any cause, all patients will be followed until death.

After 150 patients have been enrolled, accrual will pause and patients will be followed until 100 deaths have occurred. At that time, the Data Safety Monitoring Committee (DSMC) will oversee a formal interim analysis to compare overall survival (OS) between the 2 groups and may recommend early stopping for futility. If the study continues after interim analysis, then the randomization scheme will continue up to 364 patients or the newly-calculated sample size. The maximum number of enrolled patients will be 650. The number of clinical sites may be expanded up to approximately 200 to 300 centers.

Patients in the gemcitabine-only arm (Arm B) will not be allowed to cross over to the combined treatment arm (Arm A). In addition, no palliative radiotherapy will be allowed during the trial.

The primary analysis will compare OS in the ON 01910.Na + gemcitabine arm (Arm A) vs. gemcitabine-only arm (Arm B) once an appropriate number of events has been reached. There are 2 secondary efficacy outcomes: progression-free survival (PFS) and objective response.

Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Grade 3 and 4 hematologic toxicities and > Grade 2 non-hematologic toxicities will be monitored.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 3

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary, 1078
    • Semmelweis University Department of Diagnostic Radiology and Oncotherapy
  • Budapest, Hungary, 1125
    • Semmelweis University, 3rd Department of Internal Medicine
  • Szolnok, Hungary, 5004
    • Hetenyi Geza Hospital 5004, Szolnok, Hungary
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500034
      • Basavatarakam Indo-American Cancer Hospital
  • Kerala
    • Thiruvananthapuram, Kerala, India, 695001
      • Regional Cancer Center
  • Maharashtra
    • Mumbai, Maharashtra, India, 400026
      • Jaslok Hospital & Research Centre
    • Nashik, Maharashtra, India, 422005
      • Shatabdi Superspeciality Hospital
    • Pune, Maharashtra, India, 411001
      • Ruby Hall Clinic
  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600096
      • Lifeline Multispeciality Hospitals
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • State Budget Medical Institution of the Arkhangelsk Region
  • Chelyabinsk, Russian Federation, 454087
    • Chelyabinsk Regional Clinical Oncology Center
  • Krasnodar, Russian Federation, 350040
    • State Budget Medical Institution Clinical Oncology Center 1
  • Omsk, Russian Federation, 644013
    • Budget Medical Institution of the Omsk Region: Clinical Oncology Center
  • Saint Petersburg, Russian Federation, 194291
    • State Budget Medical Institution: Leningrad Regional Clinical Hospital
  • Tula, Russian Federation, 300053
    • State Medical Institution: Tula Regional Oncology Center
• Ukraine
  • Uzhhorod, Ukraine, 88014
    • Zakarpattia Regional Clinical Oncology Center Department of Chemotherapy
• United States
  • California
    • La Jolla, California, United States, 92037
      • UCSD Moores Cancer Center
    • Palm Springs, California, United States, 92262
      • Desert Comprehensive Cancer Center
    • Salinas, California, United States, 93901
      • Pacific Cancer Care
    • Santa Monica, California, United States, 90404
      • Premiere Oncology
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
    • Denver, Colorado, United States, 80205
      • Kaiser Permanente Colorado
    • Fort Collins, Colorado, United States, 80528
      • Poudre Valley Cancer Center of the Rockies
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale Cancer Center
  • Florida
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Comprehensive Cancer Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • UMass Medical School
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Montana
    • Billings, Montana, United States, 59101
      • Billings Clinic Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Lineberger Comprehensive Cancer Center
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
    • Greensboro, North Carolina, United States, 27403
      • Cone Health Cancer Center
    • Hendersonville, North Carolina, United States, 28971
      • Hendersonville Hematology and Oncology at Pardee
    • Raleigh, North Carolina, United States, 27607
      • Rex Cancer Center UNC Healthcare
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • St. Alexis Medical Center-Mid Dakota Clinic PC
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente NW
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina - Hollings Cancer Center
    • Florence, South Carolina, United States, 29506
      • McLeod Regional Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients at least 18 years old presenting with histopathologically or cytologically confirmed metastatic adenocarcinoma of the pancreas; metastatic disease is defined as disease which has spread beyond the peri-pancreatic lymph nodes.
• Patients must have received no prior chemotherapy for pancreatic cancer, including adjuvant chemotherapy.
• Measurable disease, defined as lesions that can be accurately measured in at least 1 dimension with longest diameter (LD) ≥20 mm using conventional techniques or ≥10 mm with spiral computed tomography (CT) scan; measurable lymph nodes must be ≥15 mm in the short axis.
• ECOG Performance Status of 0, 1, or 2.
• Patients must have adequate renal function and serum creatinine ≤2.0 mg/dL.
• Patients must have adequate liver function as defined by total bilirubin ≤2.0 mg/dL and transaminase levels no higher than 3.0 times the institution's upper limit of normal (ULN). Patients with hepatic metastases may have transaminase levels of up to 5.0 times the ULN.
• All patients must have a serum albumin ≥3.0 g/dL.
• Patients must have adequate bone marrow (BM) function as defined by a granulocyte count ≥1,500/mm3, a platelet count ≥100,000/mm3, and hemoglobin >9 g/dL.
• Disease-free period of more than 5 years from prior malignancies other than pancreas (except curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix and ductal carcinoma in situ [DCIS] breast disease).
• Adequate contraceptive regimen (including prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine device [IUD], double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) before entry and throughout the study for female patients of reproductive potential or female partners of male patients.
• Female patient with reproductive potential must have a negative urine beta human chorionic gonadotropin (bHCG) pregnancy test at Screening.
• Willing to adhere to the prohibitions and restrictions specified in this protocol.
• Patient must have signed an informed consent document.

Exclusion Criteria:

• Patients with unresectable locally advanced disease without evidence of disease elsewhere.
• Life expectancy of less than 12 weeks.
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or seizure disorder.
• Active infection not adequately responding to appropriate therapy.
• Symptomatic or clinically evident ascites.
• Serum sodium less than 130 mEq/L or conditions that may predispose patients to hyponatremia.
• Female patients who are pregnant or lactating.
• Male patients with female sexual partners who are unwilling to follow the strict contraception requirements described in this protocol.
• Major surgery without full recovery or major surgery within 3 weeks of ON 01910.Na treatment start.
• Evidence of brain metastases.
• Any concurrent administration and/or prior administration within 4 weeks of the first dose of study drug, of radiotherapy, or immunotherapy.
• Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements, or inability to comply with study and/or follow-up procedures (e.g., drug addition, chronic non-compliance, etc.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Combination; Arm A: Gemcitabine, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle, + ON 01910.Na, 1800 mg/m2 via 2 hr CIV infusions administered twice weekly for 3 weeks of a 4 week cycle.	Drug: ON 01910.Na; ON 01910.Na, 1800 mg/m2 via 2 hr CIV infusions administered twice weekly for 3 weeks of a 4 week cycle.; Other Names: rigosertib sodium; Drug: Gemcitabine; Gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.; Other Names: Gemzar; Gemcitabine HCl; Drug: Gemcitabine; Gemcitabine, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.; Other Names: Gemzar; Gemcitabine HCl
Active Comparator: Arm B: Gemcitabine only; Arm B: Gemcitabine only, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.	Drug: Gemcitabine; Gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.; Other Names: Gemzar; Gemcitabine HCl; Drug: Gemcitabine; Gemcitabine, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.; Other Names: Gemzar; Gemcitabine HCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	This study's primary outcome is overall survival, defined as the time from randomization to death from any cause. All patients will be followed until death. Patients lost to follow-up will be censored at the time last known alive.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Progression-free survival is defined as the time from the randomization to documented disease progression or death. Patients who are alive and do not have disease progression by the clinical cutoff will be censored at the dates of their last tumor evaluation. Kaplan-Meier curves for PFS will be compared using a stratified log-rank test (stratified by ECOG status: 0-1 vs. 2). Hazard ratios and 95% confidence intervals will be estimated using stratified Cox proportional hazards models.	18 months
Tumor size	Objective tumor response rates using Response Evaluation Criteria In Solid Tumors (RECIST).	18 months
Safety/tolerability	Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03	18 months
QOL questionnaire	Quality of life (QOL) questionnaire, using the European Organisation for Research and Treatment of Cancer(EORTC) QLQ-C30 version 3.	18 months
Biomarkers	In this study, archival tissue will be collected and analyzed in order to identify molecular characteristics of pancreas tumors, which may confer susceptibility or resistance to gemcitabine alone or in combination with ON 01910.Na.	18 months
Population Pharmacokinetics	Measurement of ON 01910.Na in plasma of all patients in Arm A 1 hour after starting ON 01910.Na infusion at Day 1 and Day 15 in Cycle 1 only.	18 months
Full Pharmacokinetics	At a limited number of sites, blood samples for measurement of ON 01910.Na and gemcitabine will be obtained at Cycle 1 Day 1 only, in a subset of 10 patients in Arm A, at the following 12 time-points: predose; 15 min after starting gemcitabine infusion; 30 min, immediately before ending gemcitabine infusion; 15 min after starting ON 01910.Na infusion; 30 min after ON 01910.Na infusion start; immediately before ending ON 01910.Na infusion; and, 15 min, 30 min, 1 hr, 2 hr, 4 hr and 8 hr after ending ON 01910.Na infusion.	18 Months

Collaborators and Investigators

• Sponsor: Onconova Therapeutics, Inc.
• Collaborators: Academic GI Cancer Consortium (AGICC)
• Investigators: Study Chair: Wells Messersmith, MD, Anschutz Cancer Pavilion; Study Chair: Lawrence P. Leichman, MD, Academic Oncology Gastrointestinal Cancer Consortium; Study Chair: Antonio Jimeno, MD, PhD, Anschutz Cancer Pavilion

Publications and helpful links

General Publications

• Jimeno A, Li J, Messersmith WA, Laheru D, Rudek MA, Maniar M, Hidalgo M, Baker SD, Donehower RC. Phase I study of ON 01910.Na, a novel modulator of the Polo-like kinase 1 pathway, in adult patients with solid tumors. J Clin Oncol. 2008 Dec 1;26(34):5504-10. doi: 10.1200/JCO.2008.17.9788. Epub 2008 Oct 27.
• Jimeno A, Chan A, Cusatis G, Zhang X, Wheelhouse J, Solomon A, Chan F, Zhao M, Cosenza SC, Ramana Reddy MV, Rudek MA, Kulesza P, Donehower RC, Reddy EP, Hidalgo M. Evaluation of the novel mitotic modulator ON 01910.Na in pancreatic cancer and preclinical development of an ex vivo predictive assay. Oncogene. 2009 Jan 29;28(4):610-8. doi: 10.1038/onc.2008.424. Epub 2008 Nov 24.
• O'Neil BH, Scott AJ, Ma WW, Cohen SJ, Aisner DL, Menter AR, Tejani MA, Cho JK, Granfortuna J, Coveler AL, Olowokure OO, Baranda JC, Cusnir M, Phillip P, Boles J, Nazemzadeh R, Rarick M, Cohen DJ, Radford J, Fehrenbacher L, Bajaj R, Bathini V, Fanta P, Berlin J, McRee AJ, Maguire R, Wilhelm F, Maniar M, Jimeno A, Gomes CL, Messersmith WA. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2016 Jun;27(6):1180. doi: 10.1093/annonc/mdw095. Epub 2016 Mar 3. No abstract available.
• O'Neil BH, Scott AJ, Ma WW, Cohen SJ, Leichman L, Aisner DL, Menter AR, Tejani MA, Cho JK, Granfortuna J, Coveler L, Olowokure OO, Baranda JC, Cusnir M, Phillip P, Boles J, Nazemzadeh R, Rarick M, Cohen DJ, Radford J, Fehrenbacher L, Bajaj R, Bathini V, Fanta P, Berlin J, McRee AJ, Maguire R, Wilhelm F, Maniar M, Jimeno A, Gomes CL, Messersmith WA. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2015 Dec;26(12):2505. doi: 10.1093/annonc/mdv477. Epub 2015 Oct 21. No abstract available.
• O'Neil BH, Scott AJ, Ma WW, Cohen SJ, Aisner DL, Menter AR, Tejani MA, Cho JK, Granfortuna J, Coveler L, Olowokure OO, Baranda JC, Cusnir M, Phillip P, Boles J, Nazemzadeh R, Rarick M, Cohen DJ, Radford J, Fehrenbacher L, Bajaj R, Bathini V, Fanta P, Berlin J, McRee AJ, Maguire R, Wilhelm F, Maniar M, Jimeno A, Gomes CL, Messersmith WA. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2015 Sep;26(9):1923-1929. doi: 10.1093/annonc/mdv264. Epub 2015 Jun 19. Erratum In: Ann Oncol. 2015 Dec;26(12):2505. Leichman, L [added]. Ann Oncol. 2016 Jun;27(6):1180.

Helpful Links

• Related information about Academic Oncology Gastrointestinal Cancer Consortium (AGICC).
• Related information about Onconova Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: May 24, 2011
• First Submitted That Met QC Criteria: May 25, 2011
• First Posted (Estimate): May 26, 2011

Study Record Updates

• Last Update Posted (Estimate): August 4, 2016
• Last Update Submitted That Met QC Criteria: August 2, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: pancreatic cancer; gemcitabine; ON 01910.Na; rigosertib sodium
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; ON 01910
• Other Study ID Numbers: 04-22; 11PAN01 (Other Identifier: Academic Oncology GI Cancer Consortium)