Acute Lymphoblastic LeukemiaPhase 1NCT01756118
A Phase I, Dose-finding Study of BEZ235 in Adult Patients With Relapsed or Refractory Acute Leukemia
A Phase 1 study testing BEZ235 in people with Acute Lymphoblastic Leukemia and Leukemia, Myelocytic, Acute, run by Goethe University at 1 site in Germany.
Trial summary
Primary objectives: To establish the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D) of BEZ235 when administered twice daily (BID) as a single agent in patients with relapsed or refractory acute leukemia To determine the dose-limiting toxicity (DLT) Secondary objectives: Assess the safety and… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Lymphoblastic Leukemia, Leukemia, Myelocytic, Acute, Chronic Myelogenous Leukemia With Crisis of Blast Cells
- What is being tested?
- BEZ235
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteGermany
- Study dates
- Jun 2012to 7 Feb 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Target population for the dose escalation phase:
- 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:
- 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:
- 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).
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- or:
- 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:
- 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
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Male or female patients, age ≥ 18 years
- Life expectancy of ≥ 6 weeks
- Ability to understand and willingness to sign a written informed consent
- 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
- Adequate hepatic function
- International Normalized Ratio (INR) ≤ 1,5
- Adequate renal function
- Fasting plasma glucose (FPG) ≤ 160mg/dL
- HbA1c ≤ 8 %
- 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.
Who cannot join
- Patient has received previous treatment with PI3K and/or mTOR inhibitors
- Eligibility for allogeneic (hematopoietic stem cell transplantation (HSCT) at the time of enrollment (as defined by disease status, performance status and availability of donor)
- Patients with Ph+ ALL eligible for treatment with dasatinib or imatinib or with CML-BP eligible for treatment with imatinib, nilotinib or dasatinib
- 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.
- 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.
- Patient has had major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery.
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- Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or anti-fungal therapy
- Known impaired cardiac function
- Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235
- Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
- Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or known active infection with hepatitis B or C
- Patient has confirmed diagnosis of acute promyelocytic leukemia.
- Concurrent severe diseases which exclude the administration of therapy
- 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:
- 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.
- 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.
- At least 1 month must have elapsed between prior therapy with Rituximab
- 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.
- 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
- Treatment with any other investigational product after signature of informed consent
- 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)
- Required anticoagulation therapy with an agent such as warfarin or heparin
- 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.).
- Patient has insulin dependent diabetes mellitus or a history of gestational diabetes mellitus
- Patient is not able to understand or to comply with study instructions and requirements or has a history of non-compliance to medical regimen.
- Patient is a pregnant or nursing (lactating) woman.
- Women of child-bearing potential or adults of reproductive potential not employing an effective method of birth control
- 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)
- Patients with known hypersensitivity to the trial drug
Trial locations and contacts
1 site in 1 country.
Germany1 site
Johann Wolfgang Goethe University Hospitals
Frankfurt am Main, Hesse, 60590
About this study
Official title: A Phase I, Dose-finding Study of the Oral, Dual Phosphatidylinositol 3(PI3)-Kinase / Mammilian Target of Rapamycin (mTOR) Inhibitor BEZ235 in Adult Patients With Relapsed or Refractory Acute Leukemia
Primary objectives:
- To establish the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D) of BEZ235 when administered twice daily (BID) as a single agent in patients with relapsed or refractory acute leukemia
- To determine the dose-limiting toxicity (DLT)
Read more
Secondary objectives:
- Assess the safety and tolerability of daily oral administration of BEZ235 with a BID schedule
- To describe preliminary anti-leukemic activity of BEZ235 in patients with acute leukemia
- To correlate changes in pharmacodynamic biomarkers with basic pharmacokinetic data
Exploratory objectives:
- To assess pre-treatment phosphatidylinositol 3-kinase (PI3K) pathway-related genes in blast cells and all other malignant cells derived from blood or bone marrow.
- To assess the pharmacodynamic changes in components of the PI3K-protein kinase B (AKT)-mTOR pathway in bone marrow following treatment as potential predictive biomarkers of pharmacodynamic (PD) activity of BEZ235 in association with clinical responses.
- To identify potential resistance mechanisms and biomarkers that may correlate with efficacy and response from blood and bone marrow samples pre-and post-treatment in case of resistance
- Conditions
- Acute Lymphoblastic Leukemia, Leukemia, Myelocytic, Acute, Chronic Myelogenous Leukemia With Crisis of Blast Cells
- Being tested
- BEZ235
- Medical subject headings
- Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BEZ235Drug
A minimum of 3 dose levels
| Study group | Role | What they receive |
|---|---|---|
| BEZ235 | Experimental | Not described Receives: Drug: BEZ235 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recommended Phase 2 dose (RP2D) of BEZ235 in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and chronic myeloid leukemia in blastic phase (CML-BP)
Measured: 6 months after inclusion of first patient
Incidence of dose-limiting toxicity (DLT)
Measured: 6 months after inclusion of first patient
Secondary outcomes (7)
Adverse events as graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.
Measured: 1.5 years
Investigator-reported best overall response (BOR) as determined from the response categories during treatment period.
Measured: 1.5 years
Time to progression
Measured: 1.5 years
Remission duration
Measured: 1.5 years
Biomarker evaluation
Measured: 1.5 years
BEZ235 and metabolite levels in plasma
Measured: 1.5 years
Clinical laboratory tests as graded by NCI CTCAE v4.
Measured: 1.5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2012 (estimated)
- Study startJun 2012
- Primary completionDec 2017
- Study completion7 Feb 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Lymphoblastic LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Goethe University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. med. Joerg Chromik, Goethe University
- Investigators
- Joerg Chromik, Dr., Study director, Johann Wolfgang Goethe University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01756118
- Sponsor's protocol ID
- CBEZ235ZDE01T
- Other IDs
- 2011-005050-61
- Status last verified
- Feb 2023
- First submitted
- 19 Dec 2012
- Last updated
- 16 Feb 2023
- Results posted
- No
- Data monitoring committee
- No
Publications
Lang F, Wunderle L, Badura S, Schleyer E, Bruggemann M, Serve H, Schnittger S, Gokbuget N, Pfeifer H, Wagner S, Ashelford K, Bug G, Ottmann OG. A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia. BMC Pharmacol Toxicol. 2020 Sep 29;21(1):70. doi: 10.1186/s40360-020-00446-x.
PubMed 32993794
Study at a glance
From the registry record, last updated by the sponsor on 16 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Dose-finding Study of the Oral, Dual Phosphatidylinositol 3(PI3)-Kinase / Mammilian Target of Rapamycin (mTOR) Inhibitor BEZ235 in Adult Patients With Relapsed or Refractory Acute Leukemia
- ClinicalTrials.gov ID
- NCT01756118
- Acronym / sponsor ID
- CBEZ235ZDE01T
- Conditions
- Acute Lymphoblastic Leukemia, Leukemia, Myelocytic, Acute, Chronic Myelogenous Leukemia With Crisis of Blast Cells
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Goethe UniversityUniversity, hospital or other
- Study start
- Jun 2012
- Primary completion
- Dec 2017 (actual)
- Study completion
- 7 Feb 2020 (actual)
- First posted
- 24 Dec 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Primary objectives:
- To establish the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D) of BEZ235 when administered twice daily (BID) as a single agent in patients with relapsed or refractory acute leukemia
- To determine the dose-limiting toxicity (DLT)
Secondary objectives:
- Assess the safety and tolerability of daily oral administration of BEZ235 with a BID schedule
- To describe preliminary anti-leukemic activity of BEZ235 in patients with acute leukemia
- To correlate changes in pharmacodynamic biomarkers with basic pharmacokinetic data
Exploratory objectives:
- To assess pre-treatment phosphatidylinositol 3-kinase (PI3K) pathway-related genes in blast cells and all other malignant cells derived from blood or bone marrow.
- To assess the pharmacodynamic changes in components of the PI3K-protein kinase B (AKT)-mTOR pathway in bone marrow following treatment as potential predictive biomarkers of pharmacodynamic (PD) activity of BEZ235 in association with clinical responses.
- To identify potential resistance mechanisms and biomarkers that may correlate with efficacy and response from blood and bone marrow samples pre-and post-treatment in case of resistance
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| BEZ235 | Experimental | Drug: BEZ235 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Target population for the dose escalation phase:
- 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.
- 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.
- 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).
- 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.
Key exclusion criteria (34 listed)
- Patient has received previous treatment with PI3K and/or mTOR inhibitors
- Eligibility for allogeneic (hematopoietic stem cell transplantation (HSCT) at the time of enrollment (as defined by disease status, performance status and availability of donor)
- Patients with Ph+ ALL eligible for treatment with dasatinib or imatinib or with CML-BP eligible for treatment with imatinib, nilotinib or dasatinib
- 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BEZ235A minimum of 3 dose levels | Drug | BEZ235 |
Primary outcome
Recommended Phase 2 dose (RP2D) of BEZ235 in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and chronic myeloid leukemia in blastic phase (CML-BP)
Time frame: 6 months after inclusion of first patient
Incidence of dose-limiting toxicity (DLT)
Time frame: 6 months after inclusion of first patient
7 secondary outcomes
Adverse events as graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.
Time frame: 1.5 years
Investigator-reported best overall response (BOR) as determined from the response categories during treatment period.
Time frame: 1.5 years
Time to progression
Time frame: 1.5 years
Remission duration
Time frame: 1.5 years
Biomarker evaluation
Time frame: 1.5 years
BEZ235 and metabolite levels in plasma
Time frame: 1.5 years
Clinical laboratory tests as graded by NCI CTCAE v4.
Time frame: 1.5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Feb 2023.
- Derived from this study: PubMed 32993794Lang F, Wunderle L, Badura S, Schleyer E, Bruggemann M, Serve H, Schnittger S, Gokbuget N, Pfeifer H, Wagner S, Ashelford K, Bug G, Ottmann OG. A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia. BMC Pharmacol Toxicol. 2020 Sep 29;21(1):70. doi: 10.1186/s40360-020-00446-x.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joerg Chromik, Dr. study director
Johann Wolfgang Goethe University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing BEZ235 in people with Acute Lymphoblastic Leukemia and Leukemia, Myelocytic, Acute, run by Goethe University at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recommended Phase 2 dose (RP2D) of BEZ235 in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and chronic myeloid leukemia in blastic phase (CML-BP) (time frame: 6 months after inclusion of first patient). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01756118, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Feb 2023.