A Phase I, Dose-finding Study of BEZ235 in Adult Patients With Relapsed or Refractory Acute Leukemia

NCT01756118 | Completed Phase 1

• 2 other identifiers: CBEZ235ZDE01T2011-005050-61
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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 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

Outcome Measures

Primary Outcomes (2)

• 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)

  6 months after inclusion of first patient

• Incidence of dose-limiting toxicity (DLT)

  6 months after inclusion of first patient

Secondary Outcomes (7)

• Adverse events as graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.

  1.5 years

• Investigator-reported best overall response (BOR) as determined from the response categories during treatment period.

  1.5 years

• Time to progression

  1.5 years

• Remission duration

  1.5 years

• Biomarker evaluation

  1.5 years

Study Arms (1)

BEZ235

EXPERIMENTAL

Drug: BEZ235

Interventions

BEZ235 DRUG

A minimum of 3 dose levels

BEZ235

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A) 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).
• 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
• 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.
• 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

You may not qualify if:

• 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.
• 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:
• 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.

Sponsors & Collaborators

• Goethe University: lead

Study Sites (1)

Johann Wolfgang Goethe University Hospitals

Frankfurt am Main, Hesse, 60590, Germany

Location

Related Publications (1)

• 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.

  PMID: 32993794 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute

Interventions

dactolisib

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid

Study Officials

• Joerg Chromik, Dr.

  Johann Wolfgang Goethe University Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.

Study Record Dates

• First Submitted: December 19, 2012
• First Posted: December 24, 2012
• Study Start: June 1, 2012
• Primary Completion: December 1, 2017
• Study Completion: February 7, 2020
• Last Updated: February 16, 2023

Record last verified: 2023-02

Locations

DE (1)