| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Philadelphia Chromosome positive leukemias occur as a result of a reciprocal translocation between chromosomes 9 and 22. Its most common phenotype is Chronic Myelogenous Leukemia (CML), which has three disease phases (chronic, accelerated and blast) of increasing leukemic blast count and clinical severity. Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ ALL) resembles blast phase CML in clinical severity. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034877 |
| E.1.2 | Term | Philadelphia chromosome positive |
| E.1.2 | System Organ Class | 100000004848 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1 (Dose-escalation part): Part 1 of study is Completed
- Define the maximum tolerated dose, less than or equal to 1000 mg/day, in subjects with CML in chronic phase resistant or refractory to imatinib
- Evaluate the overall PK parameters in this population.
Part 2 (Efficacy components):
- Determine the rate of attaining major cytogenetic response in subjects entering with imatinib-resistant chronic phase CML, who have no prior Src, Abl, or Src-Abl kinase inhibitor exposure other than imatinib
- Determine the population PK parameters of this population |
|
| E.2.2 | Secondary objectives of the trial |
Part 2- Estimate:
- Time to and duration of major cytogenetic response in subjects entering with imatinib-resistant chronic phase CML who have no prior Src, Abl, or Src/Abl kinase inhibitor exposure other than imatinib
- MCyR rate in CP CML subjects intolerant of imatinib, who have no prior Src, Abl, or Src/Abl kinase inhibitor exposure other than imatinib
- Time to and duration of major cytogenetic response in CP CML subjects intolerant of imatinib who have no prior Src, Abl, or Src/Abl kinase inhibitor exposure other than imatinib
- Time to and duration of CHR in the imatinib-resistant and imatinib-intolerant groups
- MCyR rate in CP CML subjects who have failed imatinib and are resistant to other tyrosine kinase inhibitors (dasatinib or nilotinib)
- Assess safety of SKI-606 during prolonged oral exposure in a leukemic population
- Estimate overall survival and progression free survival rates at 1 and 2 yrs |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated institutional review board (IRB) or independent ethics committee (IEC)-approved informed consent form before any protocol-specific screening procedures.
2. Cytogenetic or PCR based diagnosis of any phase of Ph+ CML or Ph+ ALL whose disease is resistant to full-dose imatinib (>/=600mg), or are intolerant of any dose of imatinib.
3. Adequate duration of prior imatinib therapy (See section 10.1.2)
4. ECOG Performance Status of 0 or 1 for chronic phase subjects, and 0, 1 or 2 for Advanced Stage subjects.
5. At least 7 days prior to first dose of SKI 606 since any anti-proliferative or anti-leukemia treatment, (except hydroxyurea & anagrelide see Concomitant Treatment – Permitted Medications for details)
6. Recovered to Grade 0-1, or to baseline, from any toxicities of prior anticancer treatment, other than alopecia
7. At least 3 months post allogeneic stem cell transplantation
8. Able to take daily oral capsules or tablets reliably
9. Adequate bone marrow function (Chronic Phase resistant subjects only)
a. Absolute neutrophil count > 1000/mm^3 (>1x10^9/L)
b. Platelets >/= 100,000/mm^3 (>100 x 10^9/L), absent any platelet transfusions during the preceding 14 days
10. Adequate hepatic, and renal function
a. AST/ALT </= 2.5 x upper limit of normal (ULN) or </= 5 x ULN if attributable to liver involvement of leukemia
b. Total bilirubin </= 1.5 x ULN
c. Creatinine </= 1.5 x ULN
11. Age >/= 18 years
12. Willingness of male and female subjects, who are not surgically sterile or postmenopausal, to use reliable methods of birth control (oral contraceptives, intrauterine devices, or barrier methods used with a spermicide) for the duration of the study and for 30 days after the last dose of SKI-606
13. Documented normal INR if not on oral anticoagulant therapy (OAT), or if no OAT consistent target INR</= 3. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with Philadelphia chromosome and bcr-abl negative CML.
2. Subjects previously intolerant of imatinib - Part 1 (dose escalation only)
3. Overt leptomeningeal leukemia. Subjects must be free of CNS involvement for a minimum of 2 months. Subjects with CNS symptoms must have a diagnostic lumbar puncture prior to study enrolment.
4. Subjects with extramedullary disease only
5. In part 1, no prior exposure to Src, Abl, or Src/Abl kinase inhibitors is allowed.
6. Ongoing requirement for warfarin or other OAT (Part 1 only)
7. Ongoing requirement for hydroxyurea or anagrelide (Part 1 only)
8. Graft Versus Host Disease (GVHD)
a. part 1 - no previous GVHD allowed
b. Part 2 - no treated or untreated GVHD within 60 days of study start
9. Major surgery within 14 days or radiotherapy within 7 before the first dose of SKI-606 (recovery from any previous surgery should be complete before day 1)
10. Ongoing clinical requirement for administration of a strong inhibitor of CYP-3A4 (See attachment 3) - Part 1 only
11. A history of a clinically-significant or uncontrolled cardiac disease including:
· history of or active congestive heart failure
· uncontrolled angina or hypertension within 3 months
· myocardial infarction (within 12 months)
· clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
· diagnosed or suspected congenital or acquired prolonged QT syndrome
· unexplained syncope
· history of prolonged QTc
12. Prolonged QTc (>0.45 sec, average of triplicate readings at screening)
13. Concomitant use of or need for medications known to prolong the QT interval (See Attachment 4)
14. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval
15. Recent (within 30 days of study entry) or ongoing clinically significant gastrointestinal disorder (e.g., malabsorption, short bowel syndrome, bleeding or Grade >1 diarrhea, nausea or emesis lasting more than 2 days, despite adequate medical therapy)
16. Pregnant or breastfeeding women
17. Evidence of serious active infection, or significant medical or psychiatric illness
18. Known seropositivity to HIV, or current acute or chronic Hepatitis B or Hepatitis C (antigen positive), cirrhosis, or clinically significant abnormal laboratory finding that would, in the investigator's judgment, make the subject imappropriae for this study.
19. Documented history of T315I Bcr-Abl mutation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety -
Primary endpoints:
-Incidence and severity of dose-limiting toxicities (DLTs) at each dose level
-Incidence, severity and duration of adverse events at each dose level and for all subjects combined
Secondary endpoints:
- Changes in laboratory test results, inlcuding electrocardiogram (ECG), and chest x-ray.
-Concomitant medications used for management of AEs
- Changes in ECIG performance score or physical examination
Efficacy-
Primary endpoint:- MCyR rate in chronic phase patients, who have no prior Src, Abl, or Src-Abl inhibitor exposure other than imatinib, who have completed at least 24 weeks of treatment, or obtained MCyR prior to 24 weeks
Secondary endpoint:
- Disease-phase-appropriate hematologic and cytogenetic endpoint assessments (MCyR for chronic phase and CHr for advance leukemia patients)
- Molecular response at 1 year |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last patient undergoing the trial (Please refer to protocol) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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