Predictive Biomarkers of Biological Activity and Efficacy of Nilotinib on ZAK Target in Non-metastatic Colon Cancer (ZAK-0)

Phase 0 Study Aiming at Identifying Predictive Biomarkers of Biological Activity and Efficacy of Nilotinib on ZAK Target in Non-metastatic Colon Cancer

This is a monocentric prospective non randomized phase 0 clinical trial targeting patients with colon cancer for whom an upfront surgery has been advised by the pluridisciplinary team.

Study Overview

• Status: Withdrawn
• Conditions: Colon Cancer
• Intervention / Treatment: Drug: Nilotinib

Detailed Description

This is a monocentric prospective non randomized phase 0 clinical trial targeting patients with colon cancer for whom an upfront surgery has been advised by the pluridisciplinary team. The surgical management should not be changed or delayed. The patient is seen in consultation by one of the two surgeons. The patient receives information and consents to participate to the study. A specific colonoscopy is performed in order to take biopsy for biological studies. According to the expression level of ZAK-0, the patient is included in the corresponding arm: ZAK-0 expressor or ZAK-0 non-expressor. Then the patient receives nilotinib orally at the dose of 800 mg/day (400 mg twice a day) for 7 days. The patient is scheduled for surgery the morning after the last take of the nilotinib (12 hours). When the colectomy is performed, the surgeon collects different tumoral samples which are immediately delivered to the laboratory. There are no additional changes in the clinical follow up.

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Institut Bergonié

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:

1. Written informed consent signed prior any study-related procedures.
2. Histological diagnosis of colon cancer.
3. Performance status ECOG 0, 1, or 2.
4. Physical status score ASA 1 or 2.
5. Patient without metastasis.
6. No previous anti-cancer treatment for colon cancer.
7. Age ≥ 18.
8. Preoperative imaging: thorax-abdominal-pelvis CT scan within 2 months.
9. Colonoscopy and biopsies to determine ZAK-0 expression level.
10. Scheduled beginning of the treatment 7 days before surgical procedure.

11. Adequate end organ function as defined by:

    11.1. total bilirubin < 1.5 x ULN,1 11.2. SGOT and SGPT < 2.5 x ULN, 11.3. creatinine < 1.5 x ULN, 11.4. Serum amylase and lipase ≤ 1.5 x ULN, 11.5. Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related.

12. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before initiation of study drug. Women of child-bearing potential must agree to use adequate contraception, according to investigator's instructions.

    Effective contraception must be in place :

    • During the treatment with nilotinib
    • Until 2 weeks after the end of treatment.
13. Patients must have the following laboratory values (≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication): 13.1. Potassium ≥ LLN, 13.2. Magnesium ≥ LLN, 13.3. Phosphorus, ≥ LLN, 13.4. Total calcium (corrected for serum albumin) ≥ LLN.
14. Patients with a French social security in compliance with the French law relating to biomedical research (Article L.1121-11 of French Public Health Code).

Exclusion Criteria:

1. Rectal tumors (up to 15 cm from the anus)
2. Any metastasis.
3. Performance status ECOG ≥ 3.
4. Physical status score ASA ≥ 3.

5. Impaired cardiac function including any one of the following:

   5.1. LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) as determined by locally read echocardiogram. 5.2. Inability to determine the QT interval on ECG. 5.3. Complete left bundle branch block. 5.4. Use of a ventricular-paced pacemaker. 5.5. Congenital long QT syndrome or a known family history of long QT syndrome. 5.6. History of or presence of clinically significant ventricular or atrial tachyarrhythmias. 5.7. Clinically significant resting bradycardia (< 50 beats per minute). 5.8. QTc > 450 msec on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient rescreened for QTc. 5.9. History of clinically documented myocardial infarction. 5.10. History of unstable angina (during the last 12 months). 5.11. Other clinically significant heart disease (e.g. congestive heart failure or uncontrolled hypertension).

6. Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection).
7. History of significant congenital or acquired bleeding disorder unrelated to cancer.
8. Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery.
9. History of non-compliance to medical regimens or inability to grant consent.
10. Use of therapeutic coumarin derivatives (i.e., warfarin, acenocoumarol, phenprocoumon).
11. Patients actively receiving therapy with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
12. Patients actively receiving therapy with strong CYP3A4 inducers (e.g., dexamthasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John's Wort) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
13. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
14. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis.
15. Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease.
16. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
17. Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) female of childbearing potential unwilling to use contraceptive precautions throughout the trial and until two weeks after the end of treatment (post-menopausal women must be amenorrheic for at least 12 months to be considered of nonchildbearing potential). Contra-indication to nilotinib administration.
18. Previous or current malignancies other than colon cancer within the last 5 years, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin.
19. Emergency surgeries, including occlusion.
20. Previous enrolment in the present study.
21. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Nilotinib; A specific colonoscopy is performed in order to take biopsy for biological studies to determine the ZAK-0 expression status. Then the patient receives nilotinib orally at the dose of 800 mg/day (400 mg twice a day) for 7 days. The patient is scheduled for surgery the morning after the last take of the nilotinib (12 hours). When the colectomy is performed, the surgeon collects different tumoral samples which are immediately delivered to the laboratory.

Drug: Nilotinib; Each patient will receive nilotinib 800 mg/day every day for 7 days. Study treatment will be taken twice a day (400 mg - 2 capsules) by oral route with an interval of approximately 12 hours between two doses and should not be taken with food. The entire capsule should be swallowed with water. No food should be consumed for 2 hours before taking the drug and for at least 1 hour after it.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
ZAK expression level by immunohistochemistry on frozen material (surgical specimen) by Western blot and on paraffinembedded tissues section using an immunohistochemistry approach	Day 0
ZAK expression level by immunohistochemistry on frozen material (surgical specimen) by Western blot and on paraffinembedded tissues section using an immunohistochemistry approach	Day 7

Secondary Outcome Measures

Outcome Measure	Time Frame
Efficacy of the 7day nilotinib treatment based on histological response as measured with tumour regression grade	Day 7
Efficacy of the 7day nilotinib treatment based on histological response as measured with the proportion of tumour necrosis	Day 7
Efficacy of the 7day nilotinib treatment based on histological response as measured with the type of tumour necrosis	Day 7
Incidence of Treatment Emergent Adverse Events as assessed by CTCAE v4.0 as assessed by CTCAE v4.0	through study completion, an average of 2 years
Postoperative complications as assessed by Dindo and Clavien classification	through study completion, an average of 2 years
Maximum Plasma Concentration [Cmax] of nilotinib .	Day 7, day 8
Half-life of nilotinib	Day 7

Collaborators and Investigators

• Sponsor: Institut Bergonié
• Collaborators: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Anticipated): November 1, 2017
• Study Completion (Anticipated): November 1, 2017

Study Registration Dates

• First Submitted: April 27, 2016
• First Submitted That Met QC Criteria: May 12, 2016
• First Posted (Estimate): May 17, 2016

Study Record Updates

• Last Update Posted (Actual): October 6, 2017
• Last Update Submitted That Met QC Criteria: October 4, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms
• Other Study ID Numbers: IB 2015-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO