Clinical trial NCT01360853: Gemcitabine and ON 01910.Na in Previously Untreated Metastatic Pancreatic Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Pancreatic Adenocarcinoma
Keywords: pancreatic cancer
gemcitabine
ON 01910.Na
rigosertib sodium
Lead sponsor: Traws Pharma, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Academic GI Cancer Consortium (AGICC)
First posted: 2011-05-26
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.).

Primary outcomes:
measure: Survival
timeFrame: 18 months
Secondary outcomes:
measure: Progression-free survival
timeFrame: 18 months
measure: Tumor size
timeFrame: 18 months
measure: Safety/tolerability
timeFrame: 18 months
measure: QOL questionnaire
timeFrame: 18 months
measure: Biomarkers
timeFrame: 18 months
measure: Population Pharmacokinetics
timeFrame: 18 months
measure: Full Pharmacokinetics
timeFrame: 18 Months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD Moores Cancer Center
state: California
city: Palm Springs
country: United States
facility: Desert Comprehensive Cancer Center
state: California
city: Salinas
country: United States
facility: Pacific Cancer Care
state: California
city: Santa Monica
country: United States
facility: Premiere Oncology
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Denver
country: United States
facility: Kaiser Permanente Colorado
state: Colorado
city: Fort Collins
country: United States
facility: Poudre Valley Cancer Center of the Rockies
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Honolulu
country: United States
facility: University of Hawaii Cancer Center
state: Hawaii
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Worcester
country: United States
facility: UMASS Medical School
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Billings
country: United States
facility: Billings Clinic Cancer Center
state: Montana
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Lineberger Comprehensive Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Greensboro
country: United States
facility: Cone Health Cancer Center
state: North Carolina
city: Hendersonville
country: United States
facility: Hendersonville Hematology and Oncology at Pardee
state: North Carolina
city: Raleigh
country: United States
facility: Rex Cancer Center UNC Healthcare
state: North Carolina
city: Bismarck
country: United States
facility: St. Alexis Medical Center-Mid Dakota Clinic PC
state: North Dakota
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center
state: Ohio
city: Portland
country: United States
facility: Kaiser Permanente NW
state: Oregon
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina - Hollings Cancer Center
state: South Carolina
city: Florence
country: United States
facility: McLeod Regional Medical Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Budapest
country: Hungary
facility: Semmelweis University Department of Diagnostic Radiology and Oncotherapy
city: Budapest
country: Hungary
facility: Semmelweis University, 3rd Department of Internal Medicine
city: Szolnok
country: Hungary
facility: Hetenyi Geza Hospital 5004, Szolnok, Hungary
city: Hyderabad
country: India
facility: Basavatarakam Indo-American Cancer Hospital
state: Andhra Pradesh
city: Thiruvananthapuram
country: India
facility: Regional Cancer Center
state: Kerala
city: Mumbai
country: India
facility: Jaslok Hospital & Research Centre
state: Maharashtra
city: Nashik
country: India
facility: Shatabdi Superspeciality Hospital
state: Maharashtra
city: Pune
country: India
facility: Ruby Hall Clinic
state: Maharashtra
city: Chennai
country: India
facility: Lifeline Multispeciality Hospitals
state: Tamil Nadu
city: Arkhangelsk
country: Russian Federation
facility: State Budget Medical Institution of the Arkhangelsk Region
city: Chelyabinsk
country: Russian Federation
facility: Chelyabinsk Regional Clinical Oncology Center
city: Krasnodar
country: Russian Federation
facility: State Budget Medical Institution Clinical Oncology Center 1
city: Omsk
country: Russian Federation
facility: Budget Medical Institution of the Omsk Region: Clinical Oncology Center
city: Saint Petersburg
country: Russian Federation
facility: State Budget Medical Institution: Leningrad Regional Clinical Hospital
city: Tula
country: Russian Federation
facility: State Medical Institution: Tula Regional Oncology Center
city: Uzhhorod
country: Ukraine
facility: Zakarpattia Regional Clinical Oncology Center Department of Chemotherapy
Study officials:
affiliation: Anschutz Cancer Pavilion
name: Wells Messersmith, MD
role: STUDY_CHAIR
affiliation: Academic Oncology Gastrointestinal Cancer Consortium
name: Lawrence P. Leichman, MD
role: STUDY_CHAIR
affiliation: Anschutz Cancer Pavilion
name: Antonio Jimeno, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.