| Eligibility |
Inclusion Criteria:
A) Target population for the dose escalation phase:
1. Patients with Philadelphia chromosome (Ph) / breakpoint cluster region abelson
tyrosine protein kinase 1(bcr-abl) negative B- or T-precursor ALL relapsed after at
least induction and consolidation chemotherapy or having refractory disease and for
whom no standard treatment is available or considered feasible.
or:
2. Patients with Philadelphia chromosome and/or bcr-abl positive B-precursor ALL or
CML-BP who have relapsed after or are refractory to first- and second-line therapy
that included at least two abelson tyrosine protein kinase 1 (ABL kinase) inhibitors.
If a point mutation threonine 315 to isoleucine (T315I) bcr-abl mutation has been
identified, prior treatment with a second TKI is not required.
or:
3. Patients with Philadelphia chromosome and/or bcr-abl positive B-precursor ALL or prior
CML-BP with presence of minimal residual disease (MRD) and the presence of T315I
mutation or a high-resistance mutation shown to be unresponsive to approved thyrosine
kinase inhibitors (TKI).
or:
4. Patients with a cytopathologically confirmed diagnosis of AML, who are either relapsed
after or refractory to standard therapy, and are considered inappropriate candidates
for conventional salvage therapy.
or:
5. Patients with a cytopathologically confirmed diagnosis of AML who are previously
untreated but due to age, poor prognosis, or concurrent medical conditions are
considered inappropriate candidates for standard induction therapy, or those who
refuse standard induction therapy
B) Target population: expansion cohort The target population for the dose expansion
includes all categories of AML, ALL and CML-BP patients as for the dose escalation phase.
Inclusion criteria
1. Eastern Cooperative Oncology Group (ECOG) performance status = 2
2. Male or female patients, age = 18 years
3. Life expectancy of = 6 weeks
4. Ability to understand and willingness to sign a written informed consent
5. Normal serum levels > lower limit of normal (LLN) of potassium and magnesium, or
corrected to within normal limits with supplements, prior to the first dose of study
medication
6. Adequate hepatic function
7. International Normalized Ratio (INR) = 1,5
8. Adequate renal function
9. Fasting plasma glucose (FPG) = 160mg/dL
10. HbA1c = 8 %
11. White blood cell count (WBC) = 30 x 109/L. Prior cytoreductive therapy with
hydroxyurea, vincristine, cyclophosphamide, or corticosteroids is permitted. For
patients with CML-BP or Ph+ ALL a prior therapy with TKIs is also permitted.
Intrathecal therapy consisting of depocyte or triple therapy with methotrexate (up to
15 mg), Ara C (up to 40 mg) and corticosteroids (up to 4 mg dexamethasone) may be
administered up to 2 weeks and 1 weeks prior to first dose of BEZ235, respectively.
Exclusion Criteria:
1. Patient has received previous treatment with PI3K and/or mTOR inhibitors
2. Eligibility for allogeneic (hematopoietic stem cell transplantation (HSCT) at the time
of enrollment (as defined by disease status, performance status and availability of
donor)
3. Patients with Ph+ ALL eligible for treatment with dasatinib or imatinib or with CML-BP
eligible for treatment with imatinib, nilotinib or dasatinib
4. Patient has active uncontrolled or symptomatic central nervous system (CNS) leukemia
Note: A patient with controlled and asymptomatic CNS leukemia may participate in this
trial. As such, the patient must have completed any prior treatment for CNS (including
radiotherapy and/or surgery) leukemia more than 28 days prior to start of treatment in
this study and should not be receiving chronic corticosteroid therapy for CNS
leukemia.
5. Patient has received wide field radiotherapy (including therapeutic radioisotopes such
as strontium 89) = 28 days or limited field radiation for palliation = 14 days prior
to starting study drug or has not recovered from side effects of such therapy.
6. Patient has had major surgery within 28 days prior to starting study drug or has not
recovered from major side effects of the surgery.
7. Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial,
anti-viral or anti-fungal therapy
8. Known impaired cardiac function
9. Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of BEZ235
10. Patients with a history of another primary malignancy that is currently clinically
significant or currently requires active intervention
11. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
mandatory) or known active infection with hepatitis B or C
12. Patient has confirmed diagnosis of acute promyelocytic leukemia.
13. Concurrent severe diseases which exclude the administration of therapy
14. At least 2 weeks or 5 half-lives (whichever is longer) must have elapsed from the last
dose of prior cytotoxic chemotherapy, biologic agent or experimental therapy and
initiation of study therapy with the exception of the following:
i. Medications typically used as part of a maintenance or prephase therapy for ALL,
such as vincristine, mercaptopurine, low-dose (<15 mg/m²) methotrexate and low-dose
(cumulative dose < 1g/m²) cyclophosphamide may be given up to one week prior to the
first dose of BEZ235 ii. Glucocorticoids and hydroxyurea may be administered up to 1
day prior to the first dose of BEZ235 iii. At least 6 weeks must have elapsed between
prior therapy with nitrosoureas, mitomycin C and liposomal doxorubicin.
iv. At least 5 half-lives must have elapsed since the last dose of an approved TKI v.
Intrathecal therapy consisting of depocyte or triple therapy with methotrexate (up to
15 mg), Ara C (up to 40 mg) and corticosteroids (up to 4 mg dexamethasone) may be
administered up to 2 weeks and 1 weeks prior to first dose of BEZ235, respectively.
vi. At least 1 month must have elapsed between prior therapy with Rituximab
15. Patient is receiving chronic treatment with systemic steroids or another
immuno-suppressive agent at start of study treatment.
Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways
diseases), eye drops or local injections (e.g., intra-articular) are allowed.
16. Patient is being treated at start of study treatment with any of the following drugs:
- Drugs known to be moderate and strong inhibitors or inducers of cytochrome P450
isoenzyme 3A4 (CYP3A4) including herbal medications
- Drugs with a known risk to induce Torsades de Pointes
- cytochrome P450 isoenzyme 2C9 (CYP2C9) substrate with narrow therapeutic margin
such as Warfarin and coumadin analogues
- Luteinising hormone releasing hormone (LHRH) agonists
17. Treatment with any other investigational product after signature of informed consent
18. Active graft versus host disease (GVHD) if symptomatic > grade II, or requiring
current medical treatment that has the potential to interact with BEZ235 in terms of
QT prolongation or p450 microsomal enzymes)
19. Required anticoagulation therapy with an agent such as warfarin or heparin
20. Patient has other concurrent severe and/or uncontrolled medical condition that would,
in the investigator's judgment contraindicate her participation in the clinical study
(e.g. chronic pancreatitis, active chronic hepatitis etc.).
21. Patient has insulin dependent diabetes mellitus or a history of gestational diabetes
mellitus
22. Patient is not able to understand or to comply with study instructions and
requirements or has a history of non-compliance to medical regimen.
23. Patient is a pregnant or nursing (lactating) woman.
24. Women of child-bearing potential or adults of reproductive potential not employing an
effective method of birth control
25. Unwillingness of fertile males, defined as all males physiologically capable of
conceiving offspring, to use a condom for contraception during treatment, for 5 T1/2
(8 days) after stopping treatment and for additional 12 weeks (3 months in total after
study drug discontinuation)
26. Patients with known hypersensitivity to the trial drug
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