An Open Label, Multicentre, Phase Ib/II Study of BGB324 Administered as a Single Agent or in Combination with Cytarabine or Decitabine in Patients with Acute Myeloid Leukemia or as a Single Agent in Patients with Myelodysplastic Syndrome

The goal of this research study is to find the highest tolerable dose of BGB324 that can be given to patients with AML. Another goal of this study is to learn if the highest tolerable dose can help to control AML.

Disease Group: Leukemia

Treatment Agent: ARA-C,BGB324

Treatment Location: Both at MDACC & and Other Sites

Sponsor: BerGenBio, AS

Primary Objectives Part A To identify the maximum tolerated dose (MTD) of BGB324 in AML patients who have received previous treatment with cytotoxic chemotherapy (with or without hematopoietic stem cell transplantation) or a targeted or biologic agent (e.g. hypomethylating agent, tyrosine kinase inhibitor, antibody), and have relapsed after or have been refractory to treatment with such prior therapy. Part B To identify the safety and tolerability of BGB324 as a single agent in patients with AML or MDS (Parts B1 and B4) or in combination with low dose cytarabine (Part B2) or decitabine (Part B3), in patients with AML who are unsuitable for intensive chemotherapy. Secondary Objectives Part A To identify the Dose Limiting Toxicity (DLT) profile of BGB324 To explore the safety and efficacy of BGB324 To characterise the pharmacokinetic (PK) profile of BGB324 Part B To explore the efficacy of BGB324, as a single agent in patients with AML or MDS and in combination with low dose cytarabine (Part B2) or decitabine (Part B3), in patients with AML who are unsuitable for intensive chemotherapy To assess potential PK interaction between BGB324 and cytarabine and BGB324 when given in combination with decitabine Exploratory Objectives Parts A and B To demonstrate the pharmacodynamic activity of BGB324 by: Establishing its effects on relevant biological endpoints in bone marrow (BM) aspirates, peripheral blood mononuclear cells (PBMC) and hair follicles Determining whether the spectrum of mutations or gene expression profiles present within the cancer cell population changes in response to treatment, (in BM aspirates/PBMC and a normal tissue control sample), by genomic and transcriptomic analysis to conduct a retrospective correlation with efficacy Exploring the relationship between ex vivo sensitivity to BGB324 and clinical response

IRB Review and Approval Date: 02/26/2015

Recruitment Status: Open

Projected Accrual: 84

1) Provision of signed written informed consent
2) Histological or cytological confirmation of AML (with the exception of AML M3): a) Part A: Patients with relapsed or refractory AML following treatment with cytotoxic chemotherapy (with or without hematopoietic stem cell transplantation) or a targeted or biologic agent (e.g. hypomethylating agent, tyrosine kinase inhibitor, antibody); b) Part B1: Patients with AML who are unsuitable for intensive chemotherapy as a result of advanced age or co-morbidities. Patients should have relapsed following at least one line of therapy or be refractory to such prior therapy; c) Part B2: Patients with newly diagnosed AML who are not suitable for intensive chemotherapy as a result if advancing age or co-morbidities; d) Part B3: Patients with previously untreated AML who are suitable to receive treatment with decitabine; OR MDS (with the exception of deletion 5q MDS): e) Part B4: Patients with previously treated MDS.
3) Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
4) Age 18 years or older
5) Female patients of childbearing potential must have a negative serum pregnancy test within 3 days prior to taking their first dose of BGB324. Male patients and female patients of reproductive potential must agree to practice highly effective methods of contraception (such as hormonal implants, combined oral contraceptives, injectable contraceptives, intrauterine device with hormone spirals, tubal ligation, total sexual abstinence, vasectomy) throughout the study and for >/= 3 months after the last dose of BGB324. Female patients are considered NOT of childbearing potential if they have a history of surgical sterility or evidence of post-menopausal status defined as any of the following: a) Natural menopause with last menses >1 year ago b) Radiation induced oophorectomy with last menses >1 year ago c) Chemotherapy induced menopause with last menses >1 year ago

1) Patients who have a matched donor and are candidates for allogeneic bone marrow transplantation.
2) Pregnant or lactating
3) History of the following cardiac conditions: Congestive cardiac failure of >Class II severity according to the NYHA (defined as symptomatic at less than ordinary levels of activity); Ischemic cardiac event including myocardial infarction within 3 months prior to first dose; Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension (i.e. sustained systolic BP >160 mmHg or diastolic BP >90 mmHg), or need to change medication within 6 weeks of provision of consent due to lack of disease control; History or presence of sustained bradycardia (</=55 BPM), left bundle branch block, cardiac pacemaker or ventricular arrhythmia. Note: Patients with a supraventricular arrhythmia requiring medical treatment, but with a normal ventricular rate are eligible; Family history of long QTc syndrome; personal history of long QTc syndrome or previous drug-induced QTc prolongation of at least Grade 3 (QTc >500 ms)
4) Abnormal left ventricular ejection fraction on echocardiography or Multi Gated Acquisition Scan (MUGA) (less than the lower limit of normal for a patient of that age at the treating institution or <45%, whichever is lower)
5) Serum troponin above the upper limit of normal
6) Current treatment with any agent known to cause Torsades de Pointes which cannot be discontinued at least five half-lives or two weeks prior to the first dose of study treatment.
7) Screening 12-lead ECG with a measurable QTc interval according to Fridericia’s correction >450 ms
8) Ongoing infection requiring systemic treatment. Patients who are on prophylactic antimicrobials or who have been afebrile for 48 hours following the initiation of antimicrobials are eligible
9) Inadequate liver function as demonstrated by serum bilirubin >/=1.5 times the upper limits of normal range (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >/=2.5 times the ULN (or >/=5 times the ULN for AST or ALT in the presence of liver involvement by leukemia)
10) Inability to tolerate oral medication
11) Existing gastrointestinal disease affecting drug absorption such as celiac disease or Crohn’s disease
12) Known lactose intolerance
13) Requires vitamin K antagonists. Note: Patients receiving low doses prescribed to maintain the patency of venous access devices may be included
14) Treatment with any of the following; histamine receptor 2 inhibitors, proton pump inhibitors or antacids within 3 days or 5 half-lives of administration of BGB234, whichever is longer
15) Treatment with any medication which is predominantly metabolized by CYP3A4 and has a narrow therapeutic index
16) Previous bowel resection that would interfere with drug absorption
17) Evidence of ongoing gastrointestinal graft versus host disease
18) Hematopoietic stem cell transplantation within 6 months
19) Impaired renal function as demonstrated by a creatinine clearance of </=30 mL/min determined by Cockcroft-Gault formula
20) Radiotherapy or chemotherapy within the 14 days prior to the first dose of BGB324 being administered (other than hydroxyurea)
21) Receiving an investigational anti-cancer treatment concurrently or within 14 days or five half-lives (whichever is shorter) of either the parent drug or any known active metabolite prior to the start of BGB324
22) Unresolved CTCAE >/=Grade 2 toxicity (other than stable toxicity) from previous anti-cancer therapy excluding alopecia
23) Any evidence of severe or uncontrolled systemic conditions (e.g., severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol
24) Known active, uncontrolled central nervous system (CNS) disease including CNS leukemia
25) Active infection with human immunodeficiency virus (HIV), hepatitis B or C viruses - screening for viral infections is not required for entry to this study
26) Major surgery within 28 days prior to the start of BGB324 - excluding skin biopsies and procedures for insertion of central venous access devices
27) Hypersensitivity to cytarabine, deciatbine or any of their excipients
28) Prior exposure to Astellas ASP2215

713-794-5783

Phone Number: 1-877-MDA-6789

clinicaltrials.gov NCT No: NCT02488408