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. |
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E.1.1.1 | Medical condition in easily understood language |
Blood cancer with chromosome translocation (9;22) which results in too many white blood cells in bone marrow and blood, some of which are immature (blasts). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
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 |
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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 |
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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 dasatinib (1); who have failed imatinib and are intolerant to dasatinib (2)
- CHR rate in advanced leukemia subjects
- Assess safety of SKI-606 during prolonged oral exposure in a leukemic population
- Explore overall survival and progression free survival rates at 1 and 2 yrs |
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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 treament, (except hydroxyurea and anagrelide - see Concomitant treatment - Permitted Medications for details)
6. Recovered to Grade 0-1, or to baseline, from any toxicities of prior 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 (>1000x10^9/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. |
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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 ventricular arrhythmia, congenital or acquired prolonged QT interval, a baseline QTcF > 0.47 sec (average of triplicate readings) or unexplained syncope, uncontrolled or symptomatic congestive heart failure (CHF) within 3 months, or myocardial infarction (MI) within 6 months.
12. Concomitant use of or need for medications known to prolong the QT interval (see attachment 4)
13. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval
14. 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)
15. Pregnant or breastfeeding women
16. Evidence of serious active infection, or significant medical or psychiatric illness
17. Known seropositivity to HIV, or current acute or chronic Hepatitis B or Hepatitis C (antigen positive), cirrhosis, hypokalemia (anygrade), or clinically significant abnormal laboratory finding that would, in the investigator's judgment, make the subject imappropriae for this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
SAFETY
-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
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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
When MTD occurs in Phase 1 and then ongoing during the study based on cumulative data. For details see protocol. |
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E.5.2 | Secondary end point(s) |
SAFETY
- Changes in laboratory test results, inlcuding electrocardiogram (ECG), and chest x-ray.
- Concomitant medications used for management of AEs
- Changes in ECOG performance score or physical examination EFFICACY
- Disease-phase-appropriate hematologic and cytogenetic endpoint assessments (MCyR for chronic phase and CHr or OHR for advance leukemia patients)
- Overall survival (OS) and progression free survival (PFS) rates at 1 and 2 years |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ongoing during the study based on cumulative data and MCyR rates at 24 weeks and OHR rate in imatinib-resistant accelerated phase and blast phase CML subjects at 48 weeks. For details see protocol. |
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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 | Yes |
E.7.1.3.1 | Other trial type description |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
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 | No |
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 |
Argentina |
Australia |
Austria |
Brazil |
Canada |
Chile |
China |
Colombia |
Finland |
Germany |
Hong Kong |
Hungary |
India |
Italy |
Korea, Republic of |
Netherlands |
Norway |
Spain |
Sweden |
Mexico |
Peru |
Russian Federation |
Singapore |
South Africa |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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Lats visit of the last patient undergoing the trial (Please refer to protocol) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial months | 4 |