A Phase 1/2 Study of SKI-606 in Philadelphia Chromosome Positive Leukemias

• Conditions: 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 version: 14.1Level: LLTClassification code 10034877Term: Philadelphia chromosome positiveSystem Organ Class: 100000004848; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2005-004230-40-SE
• Lead Sponsor: Wyeth Pharmaceuticals Inc., a wholly owned subsidiary of Pfizer Inc., 500 Arcola Road, Collegeville, PA 19426, USA

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2007-06-12
• Last Update Posted: 29 July 2013

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 679

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 since any anti-proliferative 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 reliably
9. Adequate bone marrow function (Chronic Phase subjects only) - Part 1 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 b. Total bilirubin c. Creatinine 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 INRAre the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 551
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 128

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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified