A Phase 1/2 Study of SKI-606 in Philadelphia Chromosme Positive Leukemias - CML study

Phase 1

• 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: 14.1 Level: LLT Classification code 10034877 Term: Philadelphia chromosome positive System Organ Class: 100000004848

• Registration Number: EUCTR2005-004230-40-GB
• Lead Sponsor: Wyeth Research Division of Wyeth Pharmaceuticals Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2007-10-15
• Study Completion: 2015-08-06
• Last Update Posted: 30 June 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 570

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 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 INR Are 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
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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.

Study & Design

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