The purpose of this multicenter, single-arm, phase II trial is to evaluate the efficacy of Nilotinib in patients with unresectable or metastatic gastrointestinal stromal tumors (GIST).

The study planned a 6-month recruitment phase to enroll 40 subjects, followed by a 6-month treatment phase with monthly visits. Patients benefiting from the treatment could continue during a follow-up phase.

On May 5, 2011, Novartis decided to discontinue the ongoing clinical trials with Nilotinib in GIST. This decision was influenced by the discontinuation of the ENESTg1 study (CAMN107G2301), which showed that Nilotinib was unlikely to demonstrate superiority to Imatinib in progression-free survival, the primary endpoint. The independent Data Management Committee (DMC) also reported no safety issues in either trial arm. Following the decision to close-out the Novartis- Sponsored studies CAMN107G2301 (NCT00785785) and CAMN107DDE05 (NCT01289028), the enrollment of the study CAMN107DDE06 was re-opened in order to ensure continued access to nilotinib to the patients currently in the CAMN107G2301 trial and CAMN107DDE05 trial in Germany and benefiting from the nilotinib treatment.

Inclusion criteria

• Age ≥18 years

• Histologically confirmed diagnosis of GIST that is unresectable and/or metastatic and therefore not amenable to surgery or combined modality with curative intent prior to or at Visit 1

• At least one measurable site of disease on CT/MRI scan at Visit 1, as defined by RECIST criteria. The scans should be at maximum 2 weeks old. New scans are only required as baseline scans if they are older than approx. 2 weeks.

• WHO Performance Status of 0, 1 or 2

• 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.):

  1. Potassium ≥ LLN,
  2. Magnesium ≥ LLN,
  3. Phosphorus ≥ LLN,
  4. Total calcium (corrected for serum albumin) ≥ LLN

• Patients must have normal organ, electrolyte, and marrow function as defined below:

  1. Absolute Neutrophil Count (ANC) ≥ 1.5x 109/L;
  2. Platelets ≥ 100 x 109/L;
  3. ALT and AST ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if considered due to tumor;
  4. Alkaline phosphatase ≤ 2.5 x ULN unless considered due to tumor;
  5. Serum bilirubin ≤ 1.5 x ULN;
  6. Serum lipase and amylase ≤ 1.5 x ULN;
  7. Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min. (calculated creatinine clearance using Cockroft formula is acceptable)

• Ability to understand and willingness to sign a written informed consent

Exclusion criteria

• Prior treatment with nilotinib

• Treatment with any cytotoxic and/or investigational cytotoxic drug ≤ 4 weeks (6 weeks for nitrosurea or mitomycin C) prior to Visit 1 with the exception of imatinib targeted therapy as an adjuvant therapy or imatinib in first line treatment for maximum of 4 weeks.

• Prior or concomitant malignancies requiring active treatment other than GIST with the exception of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ

• Impaired cardiac function at including any one of the following:

  1. LVEF < 45% or below the institutional LLN range (whichever is higher) as determined by echocardiogram at Visit 1
  2. Complete left bundle branch block
  3. Use of a ventricular paced cardiac pacemaker
  4. Congenital long QT syndrome or family history of long QT syndrome
  5. History of or presence of significant ventricular or atrial tachyarrhythmias
  6. Clinically significant resting bradycardia (< 50 beats per minute)
  7. QTc > 450 msec on screening ECG (using the QTcF formula). If QTc > 450 msec and electrolytes are not within normal ranges (electrolytes should be corrected and then the patient rescreened for QTc.
  8. Right bundle branch block plus left anterior hemiblock, bifascicular block
  9. Myocardial infarction within 12 months prior to Visit 1
  10. Other clinically significant heart disease (e.g., unstable angina, congestive heart failure or uncontrolled hypertension,)

• Patients with 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. impairment of gastrointestinal (GI) function, or GI disease that may significantly alter the absorption of the study drugs, uncontrolled diabetes

• Use of therapeutic coumarin derivatives (i.e. warfarin, acenoucumarol, phenprocoumon)

• Use of any medications that prolong the QT interval and CYP3A4 inhibitors if the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug administration. Please see www.qtdrugs.org for a comprehensive list of agents that prolong the QT interval as well as [Post-Text Supplement 2].

• Patients who have undergone major surgery ≤ 2 weeks prior to Visit 1 or who have not recovered from side effects of such surgery

• Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation < 2 weeks prior to Visit 1 or who have not recovered from side effects of such therapy

• A history of noncompliance to medical regimens or inability or unwillingness to return for scheduled visits

• Patients who are pregnant, breast feeding or women of childbearing potential (WOCBP). Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential Women of reproductive potential, to include female partners of heterosexual or bisexual patients, must agree to use an effective method of contraception during the study and for up to three months following termination of the study.

• Patients unwilling or unable to comply with the protocol

Eligibility criteria for patients from studies CAMN107G2301 or CAMN107DDE05 Patients currently participating in the Novartis-sponsored studies CAMN107G2301 or CAMN107DDE05 and benefiting from the nilotinib treatment according to the investigator will be offered the possibility to continue treatment with nilotinib in study CAMN107DDE06.

They will be included in study CAMN107DDE06 if the following criteria are fulfilled:

• Patient has an histologically confirmed diagnosis of GIST that is unresectable and/or metastatic

• Patient is currently enrolled in the studies CAMN107G2301 or CAMN107DDE05 in Germany and is on treatment with nilotinib

• Patient is currently benefiting from the treatment with nilotinib, as determined by the investigator

• Patient has demonstrated compliance, as assessed by the investigator, within the CAMN107G2301 or CAMN107DDE05 protocols requirements

• Patient has willingness and ability to comply with scheduled visits, treatment plans and any other study procedures

• Written informed consent obtained prior to enrollment in the study

• 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.

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 30 days of study medication. Highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

  • 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 by follow up hormone level assessment

  • Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.

  • Combination of any two of the following (a+b or a+c, or b+c):

    1. 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.
    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

• Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
• Sexually active males unless they use a condom during intercourse while taking drug and for 30 days after stopping study medication and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Adverse events were collected from first dose through the end of the study (core and follow-up phases), including all visits up to the follow-up database lock (approximately 16 years).

Any signs or symptoms were collected from first dose through the end of the study (core and follow-up phases), including all visits up to the follow-up database lock (approximately 16 years).