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Clinical Trial VICCHEM1323

Title

A Phase II Randomized, Multicenter Study of Treatment-Free Remission in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients Who Achieve and Sustain MR4.5 After Switching to Nilotinib

Principal Investigator(s)

Sanjay Mohan

Details

  • Protocol No. VICCHEM1323
  • Open Date: 10/03/2013
  • Staging: Phase II
  • Age Group: Adults
  • Scope: National
  • Objective: To evaluate molecular relapse free rates 6 months after discontinuation from nilotinib therapy in patients with MR4.5
  • Disease Sites: Leukemia
  • Therapies: Molecular Targeted Agents / Immunotherapy / Biologics
  • Drugs: AMN107; Nilotinib
  • Participating Institutions: Vanderbilt University
  • National Clinical Trial ID: NCT01698905
  • Secondary Protocol No: CAMN107AUS37

Description

Nilotinib (Tasigna) is a medicine which has been approved by the United States Food and Drug Administration (FDA) for the treatment of CML. The medicine is currently available for purchase in the U.S. Outside of this study, all CML patients are continuing to take nilotinib (Tasigna) indefinitely. Current clinical practice for CML treatment is to treat patients indefinitely with drugs that are tyrosine kinase inhibitors (TKIs), such as Nilotinib. TKIs work by inhibiting the activity of the Bcr-Abl gene. Bcr-Abl is an abnormal gene found in most people with CML. Treatment with TKIs has been found to be very effective for a number of patients. Studies, such as this one, are looking into stopping treatment once a patients Bcr-Abl level is undetectable for a sustained period of time. The purpose of this study is to evaluate patients Bcr-Abl levels 6 months after stopping the study drug, Nilotinib. Patients will take Nilotinib, and if their Bcr-Abl levels reach MR.4.5 (or 0.0032%) and stay at that level for 1 or 2 years, they will stop taking the study drug. (MR.4.5 or 0.0032% means that you have a very low level of Leukemia cells in your blood.) After stopping treatment, patients Bcr-Abl levels will be monitored every month for the first 6 months, then every 2 months for the next 18 months, and then every 3 months until the end of the study. If patients Bcr-Abl levels increase over MR.4.5, they will begin treatment with Nilotinib again. Since Tasigna- was first approved in Switzerland in July 2007, approximately 9,789 patients have been treated with Tasigna- in Novartis-sponsored trials.

Eligibility

Ages Eligible for Study:N/A and older
Genders Eligible for Study:Both
Accepts Healthy Volunteers:No

Criteria

Inclusion Criteria:
1. Male or female patients >= 18 years of age
2. ECOG Performance Status of 0, 1, or 2
3. Patient with diagnosis of BCR-ABL positive CML CP
4. Patient has received a minimum of 3 years of tyrosine kinase inhibitor treatment (first with imatinib (> 4 weeks) and then switched to nilotinib) since initial diagnosis
5. Patient has at least 2 years of nilotinib treatment prior to study entry.
6. Patient has achieved MR4.5 (local laboratory assessment) during nilotinib treatment, and determined by a Novartis designated central PCR lab assessment at screening
7. Adequate end organ function as defined by:
• Direct bilirubin ≤ 1.5 x ULN except for i) patient with documented Gilbert's syndrome for whom any bilirubin value is allowed and ii) for patients with asymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatase within normal range)
• SGOT(AST) and SGPT(ALT) < 3 x ULN (upper limit of normal)
• Serum lipase ≤ 2 x ULN
• Alkaline phosphatase ≤ 2.5 x ULN
• Serum creatinine < 1.5 x ULN
8. Patients must have the following electrolyte values ≥ LLN (lower limit of normal) limits or corrected to within normal limits with supplements prior to the first dose of study medication:
• Potassium
• Magnesium
• Total calcium (corrected for serum albumin)
9. Patients must have normal marrow function as defined below:
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 9.0 g/dL
10. Written informed consent obtained prior to any screening procedures
Exclusion Criteria:
1. Prior AP, BC or allo-transplant
2. Patient has documented MR4.5 at the time when switched from imatinib to nilotinib
3. Patients with known atypical transcript
4. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past)
5. Dose reductions due to neutropenia or thrombocytopenia in the past 6 months
6. Patient ever attempted to permanently discontinue imatinib or nilotinib treatment
7. Known impaired cardiac function including any one of the following:
• Inability to determine the QT interval on ECG
• Complete left bundle branch block
• Long QT syndrome or a known family history of long QT syndrome
• History of or presence of clinically significant ventricular or atrial tachyarrhythmias
• Clinically significant resting bradycardia
• QTcF > 480 msec
• History or clinical signs of myocardial infarction within 1 year prior to study entry
• History of unstable angina within 1 year prior to study entry
• Other clinically significant heart disease (e.g. uncontrolled congestive heart failure or uncontrolled hypertension)
8. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes (defined as HbA1c > 9%), uncontrolled infection)
9. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis
10. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer
11. History of other active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ treated curatively
12. Patients who have not recovered from prior surgery
13. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1
14. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. See Appendix 14.1 for a list of these medications. This list may not be comprehensive.
15. Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.
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 safely discontinued or switched to a different medication prior to study entry. (Please see www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval.)
17. 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)
18. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must have a negative serum pregnancy test before initiation of study treatment and must also use highly effective methods of contraception while enrolled in the study. The use of highly effective contraception should continue for at least 14 days after the last dose of study treatment or until the last day of TFR/TFR-2, or for the duration of a monthly cycle of oral contraception, whichever is longer. Acceptable forms of highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception and male/female sterilization defined as:
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed and documented by follow up hormone level assessment
• Male sterilization (at least 6 months prior to screening). For female patients on the study, study participation assumes the vasectomized male partner is the sole partner for that patient or b. A combination of any two of the following (i+ii or i+iii or ii+iii): i) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository ii) Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception iii) Placement of an intrauterine device (IUD) or intrauterine system (IUS)