Primary objective
To demonstrate a disease free survival benefit by adding bevacizumab to an adjuvant regimen of CAPOX chemotherapy in patients with colorectal liver metastases undergoing radical resection or radical resection in combination with RFA.
The disease free survival is defined as the interval between randomization and recurrence of disease or death, whatever occurs first.
Secondary objective
Secondary objectives are to compare survival, toxicity and quality of life. Survival is defined as the interval between randomization and death of any cause. The grade of toxicity will be assessed using the NCI-CTC criteria version 3.0. Quality of life will be studied by means of the EORTC QLC C30.
Design
The Hepatica study is a two-arm, international, multicenter, randomized, comparative efficacy and safety study comparing adjuvant CAPOX vs CAPOX and bevacizumab in patients with resected or resected in combination with ablated colorectal liver metastases. Randomization is stratified according to clinical prognostication and treatment site.
Stratification
Treatment assignment will be stratified, based on
(i) number (< 4 or ≥ 4) of liver metastases;
(ii) metachronous or synchronous liver metastases;
(iii) prior adjuvant chemotherapy or no prior adjuvant chemotherapy;
(iv) blood transfusion or no blood transfusion post liver surgery;
(v) treatment site;
(vi) neoadjuvant treatment with 3 cycles of CAPOX;
(vii) use of RFA in combination with resection
Criteria for RFA:
Setting
Patients will be enrolled in 28 Dutch hospitals and 3 Swedish centers.
Eligibility criteria
Inclusion Criteria: In order to be eligible for the trial, patients have to fulfil the following criteria:
1. Signed written informed consent obtained prior to any study-specific procedure;
2. Age ≥ 18 years;
3. Liver metastases radically resected (R0 resection) or liver metastases radically resected in combination with RFA
Criteria for RFA:
4. Study medication started ≥ 4 and ≤ 8 weeks post liver surgery;
5. Histologically confirmed liver metastasis of colorectal cancer after surgery;
6. ECOG performance status 0 or 1 (Appendix 1);
7. Adequate hematology: neutrophils ≥ 1.5 × 109/L, platelets ≥100 × 109/L, Hb ≥ 5.5 mmol/L, INR ≤ 1.5, APTT < 1.5 × UNL;
8. Adequate biochemistry: total bilirubin ≤1.5 UNL, ASAT and ALAT ≤ 2.5 × UNL, alkaline phosphatase ≤ 2.5 × UNL, serum creatinin ≤ 1.5 UNL.
9. Urine dipstick < 2+ for protein.
Exclusion Criteria: Patients presenting with any of the following criteria are not eligible for the study:
1 Extra-hepatic metastatic disease;
2 Adjuvant chemotherapy given < 6 months prior to detection of the liver metastases.
3 Chemotherapy for metastatic disease with the exception of max 3× CAPOX given as neoadjuvant therapy max 6 weeks before resection of the colorectal liver metastases;
4 Prior non colorectal malignancies, except adequately treated basalioma of the skin or carcinoma in situ of the cervix;
5 Bleeding diathesis or coagulation disorders or the need for full-dose anticoagulation;
6. Major surgical procedure < 4 weeks prior to start of study treatment;
7. Radiofrequency ablation without resection;
8. Females with a positive pregnancy test (within 14 days before treatment start);
9. Lactating women;
10. Fertile women (< 2 years after last menstruation) and women of childbearing potential not willing to use effective means of contraception;
11. History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake;
12. Clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascular accidents (≤ 6 months prior to randomization), myocardial infarction (≤ 1 year prior to randomization), uncontrolled hypertension while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication;
13. Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication;
14. Known peripheral neuropathy, including oxaliplatin-induced neuropathy > grade 1. Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible;
15. Organ allografts requiring immunosuppressive therapy;
16. Serious, non-healing wound, ulcer, or bone fracture;
17. Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent excluding inhaled steroids);
18. Serious intercurrent infections (uncontrolled or requiring treatment);
19. Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study;
20. Patients with known allergy to Chinese hamster Ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other component of the study drugs.
Randomization
After having properly checked all eligibility criteria, stratification parameters and having obtained patient's written informed consent, patients will be randomized by fax at the Trial Office IKO Nijmegen (fax 024-3619080). Randomized treatment will be confirmed by fax or email within one (1) working day. Randomization takes place wit TENALEA, this program uses a minimization procedure.
Ethics
This study is to be conducted according to globally accepted standards of Good Clinical Practice, and in agreement with the latest revision of the Declaration of Helsinki (2000, including the notes of clarification 2002 and 2004) and local regulations.
This protocol has been submitted and approved by the Ethical Committee (EC) of the University Medical Centre Utrecht http://www.umcutrecht.nl/MeTC and the Central Committee on Research Involving Human Subjects http://www.ccmo.nl in accordance with Dutch legal requirements. The independent medical ethics committees of all participating hospitals have approved the study protocol
Administrative changes to the protocol are minor corrections and/or clarifications that have no impact on the study conduct. The EC may be notified of administrative changes at the discretion of the investigator. Oral and written informed consent in form is obtained from all patients prior to randomization.
Safety
All serious adverse events during the study period, whether or not considered by the Investigator to be related to study treatment, must be reported by fax to the central data management office (Trial Office IKO, 024-361 90 80) within 24 hours using the completed SAE report. The principal investigators are responsible for the management of the safety reporting requirements according to the local regulations and guidelines. Copies of all report submissions by the principal investigators to regulatory authorities and to the ethical committee that has approved the study will be provided to the pharmacovigilance department of the license holders of the study drugs. If necessary, additional information and clarifications on cases will be forwarded to the license holders by the principal investigator.
An independent monitoring committee will discuss all reported (serious) adverse events.
Monitoring
A data and safety monitoring board will monitor the recruitment, the reported serious adverse events and the data quality at least every 2 months. Relevant information will be included in regular study reports, and will be made available to an Independent Data Monitoring Committee (IDMC), which will be independent of the trial organizers.
The IDMC will review the data and safety data on a regular basis and report their findings to the principal investigator. The principal investigator will submit these reports to the ethics committee.
Data quality assurance
Data forms will be entered in the database of the NKI-AVL Data centre by a double data entry procedure. Computerized and visual consistency checks will be performed on newly entered forms; queries will be issued in case of inconsistencies.
On-site quality control
The sponsor will perform on-site monitoring. The monitoring visits will be scheduled at a frequency of about 1 visits per site every 6 months which may be adapted according to the site accrual.
The aim of on-site visits will be:
- To evaluate the local facilities available to the responsible investigator for performing clinical trials and to comply to all requirements of the present protocol;
- To assess the consistency of the data reported on the CRF with the source data (source data verification);
- To check that all SAE's have been properly reported;
- To resolve all previous unanswered queries.
Interim Analysis
An interim analysis will be conducted 12 months after all participating hospitals have started the inclusion of patients or 18 months after inclusion of the first patient. An independent data monitoring committee (IDMC) will assess:
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1.
Safety, especially any unexpectedly high frequency of serious adverse events;
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2.
Data compared with previous experience which are the basis of the current the trial;
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3.
Any safety or efficacy data that do not justify the continuation of the trial as planned, including statistically significant differences between treatments.
The IDMC will decide on the impact of any findings for the continuation of the trial.
Statistical Analysis
All statistical analyses will be done according to the intention-to-treat principle, i.e. all eligible patients will be included in the analysis in the arm to which they were randomized independently of whether they received the assigned treatment or not. The final analysis will be performed when 191 events (recurrences or deaths) will be observed. It is estimated that this will be possible approximately 1 year after the last patient is randomized in the study. In the final analysis tables presenting the distribution of the stratification and other important factors of all cases entered by treatment arm will be included.
Disease free survival and survival curves will be constructed by means of the Kaplan Meier technique. Curves by treatment arm will be compared using the log rank test. To adjust for possible confounding factors, the treatment effect will also be estimated by adjusting Cox's proportional hazard regression model.
Clinical and laboratory toxicity graded according NCI-CTC (version 3.0) will be collected for all patients. Comparisons by treatment of the continuous variables will be done by means of Student's t-test. Comparisons of categorical date (e.g. grades of toxicity) will be done by the chi-square test.
Quality of life will be measured using the QLC-C30 questionnaire will be completed by the patients between surgery and the start of adjuvant treatment and every 6 months thereafter, until 2 years after surgery. Quality of life assessment is discontinued when adjuvant treatment is discontinued (i.e. in case of progression in arm A or B or when off-study for any reason).
Changes over time in quality of life items will be evaluated with a repeated measurement ANOVA using a mixed effect modeling procedure (SAS Proc Mixed). This model allows retaining in the analysis patients who drop out during follow-up. F-tests are used for testing main effects of group and time and an interaction effect of group and time
Sample Size
The primary endpoint of the study is the DFS measured from randomization. Patients will be randomized just after R0 resection (+/- RFA). Patients receiving 3 courses of CAPOX before resection will also be included in the study. It is expected that about 1/4 of the patients will have been treated by resection and RFA. The median DFS is estimated to be 9 months for RFA treated patients and 20 months in resection treated patients. The median of the whole mixed group is estimated to be 17 months.
Based on the results in previous recent series, it is hypothesized that the addition of bevacizumab to CAPOX would result in a decrease of at least 1/3 of the hazard of progression (HR = 0.67) [34–36]. The total number of events that is necessary to provide 80% power to detect such a decrease, if truly present, with a 2 tailed logrank test at 5% significance is 191. Assuming an accrual rate of 100 patients per year, a total of 300 patients would be randomized (150 receiving Bevacizumab and 150 not) in 3 years. If all patients are followed for about 1 year further after accrual is completed, 191 events would be observed and the study will have the required power.
The total duration of the study would then be 4 years and patients would have been followed for 1 to 4 years, depending on whether they were included at beginning or by the end of the accrual in the study.
Follow-up
Assessments during Study Treatment Phase
- Adverse events will be collected continuously during the Study Treatment Phase and followed until the event is either resolved or adequately explained, even after the patient has completed his/her study treatment.
- Concomitant diseases/treatment and compliance to study drugs will be monitored continuously during the Study Treatment Phase.
- History, vital signs, weight, ECOG Performance Status, urinalysis (dipstick) will be performed at each visit. Toxicity assessment, hematology, serum chemistry will be performed at each visit until cycle 8. If dipstick analysis shows ≥2+ protein, 24-hours urine needs to be collected for accurate measurement of renal protein excretion.
- ECG and chest X-ray will be performed as clinically indicated.
- Assessment for recurrence (abdominal CT, CEA measurements AND chest CT) will be done after surgery but before randomization (before cycle 1). Thereafter every 3 months in the first two years. If the patient shows signs of a recurrence/new colorectal cancer (e.g. clinical status OR rising CEA), possible re-operation or/and further cancer therapy will be recorded.
- Nature and duration of any hospitalization, treatment of any adverse event and nature and duration of any outpatient care will be recorded during the Study Treatment Phase.
Assessment during Follow up Phase
- CEA determinations will be done every 3 months after surgery for the first two years and thereafter every 6 months until a confirmed recurrence/new CRC and at end of follow-up after 5 years.
- Assessment for recurrence (abdominal CT AND chest CT) will be done every 3 months for the first two years after cycle 8 of chemotherapy and every 6 months thereafter until a confirmed recurrence/new CRC and at the end of follow-up after 5 years, or if the patient shows signs of a recurrence/new colorectal cancer (e.g. clinical status OR rising CEA). Possible re-operation or/and further cancer therapy will be recorded.
- Extended follow-up of hypertension, proteinuria and wound healing complication until resolution.
- Additional cancer therapy to be recorded as it occurs.
Study medication
Capecitabine
Capecitabine is an oral fluoropyrimidine carbamate rationally designed to generate 5-FU preferentially in tumor tissue through exploitation of high intratumoral concentrations of thymidine phosphorylase (TP), an enzyme present at significantly increased concentrations in a wide range of tumor types, including colorectal, breast and gastric cancers, compared with normal tissue [37].
Human pharmacokinetic studies have shown that after oral administration, capecitabine is readily and almost completely absorbed through the gastro-intestinal wall, thus avoiding direct intestinal exposure to 5-FU. Capecitabine is metabolized to 5-FU via a three-step enzymatic cascade, with the final stage of this conversion mediated by TP [38].
Oxaliplatin
Oxaliplatin is a platinum derivative in which the platinum atom is complexed with a 1,2 diaminocyclohexane (DACH) and with an oxolate ligand. It was synthesized with the goal of trying to overcome resistance to first- and second generation platinum compounds (Sanofi-Synthelabo, 2001). The mechanism of action of oxaliplatin is similar to that of cisplatin as well as other platinum (Pt) compounds. Studies conducted to date indicated that the types and percentages of Pt-DNA adducts formed by oxaliplatin were qualitatively similar to those formed by cisplatin, but preclinical data suggested several unique attributes of the cytotoxic/antitumor activity of oxaliplatin. Oxaliplatin demonstrated a broad spectrum of in vitro cytotoxicity and in vivo antitumor activity that differed from that of either cisplatin or carboplatin. Oxaliplatin was active against several cisplatin-resistant cell lines, colon carcinoma and other solid tumors that were not responsive to cisplatin. In addition, oxaliplatin in combination with 5-FU led to synergistic antiproliferative activity in several in vivo models [39].
Bevacizumab
Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF or VEGF-A) which is a ligand with a central role in signaling pathways controlling tumor blood vessel development and survival [40–43]. VEGF binding to cell surface receptors stimulates the process of angiogenesis, the formation of blood vessels. These receptors, VEGF receptors 1 and 2, are found on vascular endothelial cells. VEGF binding stimulates endothelial cell proliferation, migration and survival [41, 44, 45].
The mode of action of bevacizumab can be summarized as follows:
- Prevents the formation of new blood vessels, thereby inhibiting the growth of existing tumors and preventing metastases from developing blood supply.
- Normalizes existing tumor blood vessels. The subsequent effects include reduction of the tortuousness of tumor blood vessels and normalization of vessel permeability. The latter effect is important because tumors usually exhibit high interstitial pressure which can prevent chemotherapeutic agents penetrating tumors and accessing tumor cells, where they exert their effects. Normalization of permeability, and therefore intratumoral pressure gradients, thus, promotes chemotherapy access [46].
- Produces blood vessel breakdown, probably through inhibition of the anti-apoptotic effects of VEGF on immature endothelial cells. VEGF also has activities beyond angiogenesis, affecting immune function via inhibition of dendritic cell maturation, formation of lymph vessels and lymphatic metastasis. All of these actions indicate that VEGF may be an important target for anticancer drug development. Bevacizumab has proven to be clinically effective in fase III studies with solid tumors.
Treatment program
Arm A (CAPOX+Bevacizumab) consists of 8 cycles of CAPOX (either all cycles postoperatively or 3 cycles preoperatively followed by 5 cycles postoperatively).
Postoperatively patients will be treated with: bevacizumab at 7.5 mg/kg, administered as an intravenous infusion over 20-30 minutes for a maximum of 48 weeks. CAPOX will be given as follows: oxaliplatin administered as a 130 mg/m2 intravenous infusion over 2 hours (day 1, every 3 weeks) in combination with capecitabine, which will be administered orally at a dose of 1000 mg/m2 twice-daily (equivalent to a total daily dose of 2000 mg/m2), with first dose the evening of day 1 and the last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week. without treatment). After completion of the 8 CAPOX cycles, bevacizumab will be continued as single agent (7.5 mg/kg q3w) treatment. Bevacizumab will be stopped after 48 weeks
Arm B (CAPOX) consists of 8 cycles of CAPOX (either all cycles postoperatively or 3 cycles preoperatively followed by 5 cycles postoperatively). CAPOX will be given as follows: Oxaliplatin administered as a 130 mg/m2 intravenous infusion over 2 hours (day 1, every 3 weeks) in combination with capecitabine, which will be administered orally at a dose of 1000 mg/m2 twice daily (equivalent to a total daily dose of 2000 mg/m2), with first dose the evening of day 1 and the last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment).
