Trial Title:
A Study to See if hENT1 Testing on Tumour Tissue Can Predict Response to Treatment With Gemcitabine Chemotherapy and if a Different Chemotherapy Called FOLFOX is Better Than Gemcitabine in Metastatic Pancreas Cancer
NCT ID:
NCT01586611
Condition:
Metastatic Pancreas Cancer
Conditions: Official terms:
Pancreatic Neoplasms
Leucovorin
Gemcitabine
Oxaliplatin
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Unknown status
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
5FU, leucovorin, oxaliplatin
Description:
Oxaliplatin 100 mg/m2 IV day 1 Leucovorin 400 mg/m2 IV day 1 5-FUl 400 mg/m2 IV day 1
5-FU 2400 mg/m2 IV continuous infusion over 46 hours starting day 1
Arm group label:
FOLFOX
Intervention type:
Drug
Intervention name:
Gemcitabine
Description:
1000 mg/m2 IV weekly for 3 weeks then one week off
Arm group label:
Gemcitabine
Summary:
Chemotherapy is often used to help shrink the cancer temporarily and may improve survival
for patients with incurable pancreas cancer that has spread to other organs. In Canada,
the gemcitabine chemotherapy is used to treat pancreas cancer that has spread. The
combination of oxaliplatin with other chemotherapies, including 5-fluorouracil,
leucovorin, and irinotecan has also been studied and has benefit for patients with
advanced pancreas cancer. To date, there is no test that can be done on a patient's
tumour to tell if chemotherapy will work in pancreatic cancer. Human equilibrative
nucleoside transporter 1 (hENT1) has been shown to be a possible predictor that
gemcitabine may or may not work but this needs to be proven in a randomized study where
patients get treated with gemcitabine or a different kind of chemotherapy while their
tumours get tested for hENT1.
This study is being done because we want to prove that hENT1 can predict if gemcitabine
will work in advanced pancreas cancer and if it can, we also would like to show that a
different chemotherapy combination called FOLFOX (a combination of 5-fluorouracil,
leucovorin, and oxaliplatin) will be helpful for patients whose tumours don't have hENT1.
Detailed description:
Pre-clinical and retrospective clinical data indicates hENT1 may be a predictive and
prognostic biomarker for gemcitabine (Gem) efficacy. To ultimately prove its use as a
biomarker, a prospective randomized study with hENT1 stratification is required. This
study would provide the highest level of confidence, and would, if positive, vault Gem
into the select few anticancer agents for which a truly sensitive population can be
rationally treated. By this "molecular triage", the risk/benefit ratio of Gem therapy for
pancreas cancer (PC) could be meaningfully improved while also providing rationale for
the use of a different treatment regimen should tumours have low hENT1. The comparator
arm of FOLFOX was chosen because of the recent data showing impressive patient outcomes
with the use of oxaliplatin-based treatments.
This is a randomized, open-label, multicentre, phase III trial in which eligible patients
with metastatic pancreatic adenocarcinoma will be randomized between Gem and FOLFOX with
predefined upfront testing for hENT1. To be eligible, patients will have to have adequate
tissue available for hENT1 testing which the Cross Cancer Institute (CCI) will ensure
prior to treatment randomization. Patients will have their tumour sample tested for the
expression of hENT1. A blinded pathologist with expertise knowledge and experience with
hENT1 staining at the lead centre (CCI) will be responsible for pathologic hENT1
classification via IHC. hENT1 IHC will be determined and scored as previously
outlined.(1) Once hENT1 status has been confirmed, patients will then be randomized 1:1
between Gem and FOLFOX. Patients will be treated on study until disease progression,
overwhelming toxicity, or patient withdrawal of consent. Dose adjustments for one or more
of the study drugs will be based on toxicities encountered by individual patients.
Specific dose-adjustment and treatment guidelines for hematologic and non-hematologic
toxicities including neutropenia, diarrhea, renal toxicity, and neurotoxicity will be
outlined in the protocol. Prior to enrolment, screening procedures will document
compliance with inclusion and exclusion criteria. The primary endpoint will be
determination of the difference in PFS in the two study arms, defined from the study
start date until either an increase in the sum of the products of the diameters of
measurable lesions by ≥ 20% bases on revised RECIST guidelines version 1.1 (2), the
appearance of any new lesion, or a deterioration in clinical status that is consistent
with disease progression. Secondary endpoints will be determination of the differences in
overall response rate (ORR), disease control rate (DCR), and overall survival (OS).
Administered dose intensity of Gem and FOLFOX will be reported. Health-related quality of
life (HRQL) will be assessed for the duration of active treatment on study.
Patient Population: The target population is patients with measurable metastatic
adenocarcinoma of the pancreas who have not been previously treated with systemic therapy
for their metastatic disease and who have tumour samples amenable to hENT1 testing. Fine
needle aspiration biopsies will not be permitted. Patients who have received prior
chemotherapy delivered as part of initial curative therapy (i.e. neoadjuvant, adjuvant,
and/or concurrently delivered with radiation and/or surgery) are permitted as long as
that treatment was completed at least 6 months prior to study start date. Patients may
have received prior radiotherapy or surgery ≥ 4 weeks before study entry and must have
recovered from the toxic effects from any prior therapy. Patients with locally advanced
adenocarcinoma of the pancreas will be excluded. Full inclusion and exclusion criteria
are detailed in the protocol.
Study Objectives:
Primary Objective: To determine the difference PFS between Gem and FOLFOX treated
patients in hENT1 high and hENT1 low pancreatic adenocarcinoma.
Secondary Objectives: 1) To determine the difference in ORR between the two treatment
arms; 2) To determine the rate of disease control, defined as the sum of complete
response rate, partial response rate, and stable disease between the two treatment arms;
3) To determine the difference in OS between the two treatment arms; 4) To determine the
differences in HRQL of patients on the two treatment arms.
Exploratory Objectives: 1) To investigate the role of hCNT3 and its interaction with
hENT1-related patient outcomes. 2) To evaluate excision repair cross complementing 1
(ERCC1) and microsatellite instability (MSI) in tumour samples, both of which are
increasingly being linked to efficacy in oxaliplatin-based therapy but for which
information in PC is lacking.
Duration of Treatment: Treatment will continue until objective or symptomatic disease
progression, overwhelming toxicity, or patient withdrawal of consent. A patient may
continue to receive all or any combination of study drugs for as long as the investigator
feels is appropriate, but will be discontinued from study in case of:
1) Clinical and/or radiological documented disease progression (as determined by
revised RECIST 1.1 criteria).(2) All drugs will be discontinued and the patient
removed from study; 2) Occurrence of unacceptable toxicity (this may be due to one
or more drugs resulting in one or more study drug discontinuation); if all three
drugs are discontinued the patient will be removed from study; 3) Failure to recover
from hematologic and/or non-hematologic toxicity to re-treatment level despite
dosing interruption of up to 28 days (this may be due to one or more study drugs
resulting in one or more study drug discontinuation); if all drugs in regimen are
discontinued the patient will be removed from study; 4) Patient's request
(withdrawal of consent) or Investigator's recommendation (this may be one or more
study drugs); if all three study drugs are discontinued patient will be removed from
study; 5) Patient death (complete Serious Adverse Event Report for deaths occurring
within 30 days after last study drug dose OR for deaths occurring after 30 days,
only if considered related to study drug).
Efficacy Endpoints: Response assessments will be performed every 8 weeks, regardless of
treatment cycle. History, physical exam, laboratory work, imaging, ECOG performance
status (PS), will be required at each response assessment. PS will be measured using the
ECOG performance status scale. Tumor marker (CA19-9) may be followed at the discretion of
the investigator but should not be used in determination of disease response and are not
a requirement of the study. Tumor response will be evaluated according to the revised
RECIST criteria 1.1.(2) Symptomatic progression will be defined as new or worsening
disease symptoms deemed by the treating oncologist to incompatible with continuation of
study medication or the requirement for palliative radiation therapy or a fall in ECOG
performance status to ≥ 3 deemed to be due to disease and not study treatment. Should
symptomatic progression occur, imaging to confirm progression is advised but if not
possible due to performance status, the study stop date will be recorded as the date of
progression.
Safety: The NCI CTCAE (version 4.0) will be used to evaluate the clinical safety of the
treatment in this study. Subjects will be assessed for adverse events at each clinical
visit and as necessary throughout the study. Safety will be assessed via vital signs,
physical exams, laboratory tests (including hematologic, serum chemistry, and liver
function testing), and adverse event determination. Pregnant and nursing females will be
excluded from participation in the trial.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Histologically documented metastatic pancreatic adenocarcinoma not previously
treated with palliative systemic therapy
- Metastatic disease based on the presence of clinically and/or radiologically
documents Measurable disease base on RECIST.
- Adequate tissue (core biopsy) available for IHC testing of hENT1. This may be from
primary tumour or metastatic site. Fine needle aspiration biopsies will not be
allowed. Histological/cytological confirmation of tissue to ensure sufficient
material is available for hENT1 analysis by the Cross Cancer Institute is required
prior to starting a patient on study. Biopsies from metastatic sites must be
obtained ≥ 3 months after any adjuvant chemotherapy (if applicable). If a patient
has had previous surgical resection of their primary tumours, that tissue can be
utilized. Tissue sufficient for preparing ≥ 10 unstained slides for central storage
and testing is required.
- ECOG performance status of 0 - 1.
- Age ≥ 18 years.
- Life expectancy of at least 3 months based on discretion of treating oncologist.
- Adequate hematologic function defined by the following laboratory parameters:
- Hemoglobin ≥ 100
- Platelet count ≥ 100
- Absolute granulocyte count ≥ 1.5
- Adequate hepatic and renal function defined by the following laboratory parameters:
- AST and ALT ≤ 2.5 X upper limit of institutional normal (≤ 5 if liver metastases)
- bilirubin ≤ upper limit of institutional normal
- calculated creatinine clearance of ≥ 50 mL/min using the Cockcroft-Gault formula, if
just below 50 mL/min based on this formula then GFR ≥ 50 mL/min as determined by 24
hr urine collection
- Patients who have received prior chemotherapy or radiation delivered as part of
initial curative therapy (i.e. neoadjuvant or adjuvant chemotherapy administered
alone and/or concurrently delivered with radiation and/or surgery) are permitted as
long as that treatment was completed at least 6 months prior to study start date.
- Patients may have received prior palliative radiotherapy (unless radiation was
curative therapy to pelvis or to ≥ 25% of bone marrow stores) if this radiation was
≥ 4 weeks before study entry and patients must have recovered from the toxic effects
of this treatment
- Patients may have received prior surgery if this surgery was ≥ 4 weeks before study
entry and patients must have recovered from the toxic effects of this treatment.
- Patients must have the ability to read, understand, and sign an informed consent and
must be willing to comply with study treatment and follow-up.
Exclusion Criteria:
- Patients who have received prior palliative chemotherapy for their metastatic
pancreatic adenocarcinoma.
- Radical pancreatic resections (e.g. Whipple procedure) are not allowed < 6 months
prior to randomization. Exploratory laparotomy, palliative (e.g. bypass) surgery, or
other procedures (e.g. stents) are not allowed < 14 days prior to randomization. In
any of the above cases, patients must be adequately recovered and stable prior to
randomization.
- Prior treatment with > 6 cycles of traditional alkylating agent-based chemotherapy,
> 2 cycles of carboplatin-based chemotherapy, prior treatment with irinotecan or
oxaliplatin chemotherapy, or concurrent treatment with other experimental drugs or
anti-cancer therapy.
- Curative radiation treatment to the pelvis or radiation therapy to ≥ 25% of bone
marrow stores.
- Lack of physical integrity of the upper gastrointestinal tract, malabsorption
syndrome, short gut syndrome, or history of bowel obstruction due to peritoneal
metastases.
- Previous or concurrent malignancies, excluding curatively treated in situ carcinoma
of the cervix or non-melanoma skin cancer, unless at least 5 years have elapsed
since last treatment and the patient is considered cured.
- Any serious medical condition within 6 months prior to study entry such as
myocardial infarction, uncontrolled congestive heart failure, unstable angina,
active cardiomyopathy, unstable ventricular arrhythmia, cerebrovascular diseases,
uncontrolled hypertension, uncontrolled diabetes, uncontrolled psychiatric disorder,
serious infection, active peptic ulcer disease, or other medical condition that may
be aggravated by treatment.
- Known dihydropyrimidine dehydrogenase (DPD) deficiency.
- Pre-existing neuropathy ≥ grade 2 from any cause.
- Patients with unstable metastasis to the central nervous system are excluded.
Patients who have treated brain metastasis and are off steroids, anticonvulsants,
and have documented stability of lesions for at least 3 months may be eligible. A CT
scan or MRI is NOT required to rule out brain metastases unless there is clinical
suspicion of CNS involvement.
- Pregnant or lactating women; women of child bearing potential must have a negative
serum pregnancy test within 7 days of trial registration. Women or men of child
bearing potential must use effective contraception (defined by the treating
physician) which must be documented in study CRFs.
- Any other reason the investigator considers the patient should not participate in
the study.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Cross Cancer Institute
Address:
City:
Edmonton
Zip:
T6G 1Z2
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Jennifer L Spratlin, MD FRCPC
Phone:
780-432-8514
Email:
Jennifer.Spratlin@albertahealthservices.ca
Contact backup:
Last name:
Karen Mulder, MC FRCPC
Phone:
780-432-8514
Email:
Karen.Mulder@albertahealthservices.ca
Investigator:
Last name:
Jennifer L Spratlin, MD FRCPC
Email:
Sub-Investigator
Investigator:
Last name:
Karen Mulder, MD FRCPC
Email:
Sub-Investigator
Investigator:
Last name:
Karen King, MC FRCPC
Email:
Principal Investigator
Start date:
June 2012
Completion date:
June 2015
Lead sponsor:
Agency:
AHS Cancer Control Alberta
Agency class:
Other
Source:
AHS Cancer Control Alberta
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT01586611
