Gemcitabine And ON 01910.Na In Previously Untreated Metastatic Pancreatic Cancer

Study Overview

Gemcitabine and ON 01910.Na in 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.

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.

Metastatic Pancreatic Adenocarcinoma

DRUG: ON 01910.Na
DRUG: Gemcitabine
DRUG: Gemcitabine

04-22
11PAN01 (OTHER Identifier) (OTHER: Academic Oncology GI Cancer Consortium)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2011-05-24	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2016-08-02
First Submitted that Met QC Criteria 2011-05-25	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2016-08-04
First Posted (ESTIMATED) 2011-05-26	Results First Posted N/A	Last Verified 2016-08

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

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. DRUG: Gemcitabine Gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.
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.

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.

DRUG: Gemcitabine

Gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.

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.

Primary Outcome Measures	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	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

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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.

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.).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Academic GI Cancer Consortium (AGICC)

Investigators

STUDY_CHAIR: Wells Messersmith, MD, Anschutz Cancer Pavilion

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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.
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.
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. doi: 10.1093/annonc/mdv477.. Leichman, L [added]. Ann Oncol. 2016 Jun;27(6):1180. doi: 10.1093/annonc/mdw095.

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