| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Myeloid Leukemia (CML) |
|
| E.1.1.1 | Medical condition in easily understood language |
| CML is a type of Philadelphia Chromosome positive leukaemia resulting due to changes in chromosomes. It is characterized by the uncontrolled growth of white blood cells. |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009012 |
| E.1.2 | Term | Chronic myelogenous leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To allow long term bosutinib treatment in patients with chronic or advanced phases of Ph+ CML who received bosutinib in a previous Pfizer sponsored CML study (ie, studies B1871006 and B1871008) and who have the potential, as judged by the investigator, to derive clinical benefit from continued treatment with bosutinib;
• To collect long term safety and efficacy data for bosutinib;
• To assess the duration of clinical benefit for Ph+ CML patients treated with bosutinib;
• To fulfill the European Medicines Agency (EMA) post approval requirement for the collection and analysis of safety data about diarrhea incidence after switch from clinical study to commercial bosutinib formulation. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.
2. Previous enrollment in the bosutinib arm of one of the two Pfizer parent studies: B1871006 or B1871008. This includes:
a. Patients still receiving bosutinib in either study B1871006 or B1871008;
b. Patients who have discontinued bosutinib but are still in the long term follow up phase of the study B1871006 or B1871008;
c. Patients from study B1871006 who have discontinued bosutinib and have already completed the long term follow up period.
3. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Male and female patients of childbearing potential must agree to use 2 highly effective methods of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
In order to be considered a female of non-childbearing potential the patient must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause or;
a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c. Have medically confirmed and documented ovarian failure.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential. |
|
| E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the study:
1. Participation in other studies involving investigational drug(s) (Phases 1-4) while patient in the active treatment phase of the current study.
2. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.
3. Other severe acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
4. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The objective of the study is to provide long term access to bosutinib treatment and assess long term safety, tolerability and duration of clinical benefit, without any formal hypothesis testing; therefore, there is no formal primary endpoint.
In addition, data to be collected, specifically efficacy data, are planned to be different in the first line CP patients relative to the later line and advanced patients.
For all patients regardless of the line of treatment:
• Long term safety of bosutinib, including type, incidence, severity, timing, seriousness and relatedness of AEs and laboratory abnormalities as well as reason of treatment discontinuation. A special focus will be made on diarrhea in order to satisfy the EMA post commitment request;
• BCR ABL mutations present at the time patients discontinue Bosutinib. (Samples collected for all patients except those enrolled at sites in China)
• Overall survival (OS);
• Fulfill the EMA post-approval requirement to compare the pharmacokinetic analysis of Ctrough of bosutinib in this study to Ctrough of previous studies. (Samples collected for all patients except those enrolled at sites in China)
For 2nd or later line patients coming from study B1871006 who are still on treatment with bosutinib, the following efficacy endpoints will be assessed:
• Duration of hematologic and cytogenetic responses;
• Progression free survival;
• Time to transformation to accelerated or blast phase. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For CML 1st line patients coming from B1871008:
• AEs collected at ≤ 28 days from last dose on parent study, at site month 3 & every 12 months, phone calls every 3 months, and ≤ 28 days after last dose of bosutinib.
For CML 2nd and later line patients coming from B1871006:
• AEs collected at ≤ 28 days from last dose on parent study, at site month 3 &every 6 months, phone calls every 3 months, and ≤ 28 days after last dose of bosutinib.
For all patients:
• Diarrhea information collected at ≤ 28 days from last dose on parent study and at month 3 site visit.
• BCR ABL mutation analysis at ≤ 28 days after last dose of bosutinib.
• Survival follow-up at every 3 months from last dose of bosutinib until the last patient reaches 10 years from first dose (including parent study). |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| extension study - phase is N/A |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Finland |
| France |
| Germany |
| Hong Kong |
| Hungary |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| LVLS (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 | 6 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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