Study of Afuresertib Monotherapy in Japanese Relapsed Multiple Myeloma Patients

An Open-label, Dose Escalation, Phase I Study to Evaluate the Tolerability, Safety and Pharmacokinetics of Afuresertib Monotherapy in Japanese Relapsed Multiple Myeloma Patients.

Afuresertib, an AKT inhibitor, has shown in vitro and in vivo activity in multiple myeloma models. AKT inhibitor has also demonstrated encouraging clinical activity in multiple myeloma. This study is designed to determine the tolerability, safety, pharmacokinetics and efficacy of afuresertib as monotherapy in Japanese relapsed multiple myeloma patients. This is an open label, dose-escalating, phase I study. Afuresertib will be given daily until the subjects meet any study treatment withdrawal criteria including disease progression. A total of up to 24 subjects will be enrolled in the study.

Inclusion Criteria:

• Written informed consent is provided.
• Japanese females or males aged 20 years or older (at the time consent is obtained).
• Histologically confirmed diagnosis of relapsed multiple myeloma.
• Performance score of 0 and 1 according to the ECOG scale.
• Relapsed after at least 1 line of systemic therapy. The preparative regimen (with or without total body irradiation) and subsequent autologous stem cell rescue used for an autologous stem cell transplant are considered as one line of therapy.
• Able to swallow and retain oral medication.
• Male subjects with a female partner of childbearing potential must have had a prior vasectomy or agree to use adequate contraception from the time of the first dose of study drug until three months after the last dose of study drug.
• A female subject is eligible to participate if she is of: (A) Non-childbearing potential (i.e. physiologically incapable of becoming pregnant): Pre-menopausal females with a documented tubal ligation or hysterectomy; Postmenopausal defined as 12 months of spontaneous amenorrhea [if unclear, simultaneous follicle stimulating hormone >40 milli-international units (MIU)/milliliter (mL) and oestradiol <40 picograms (pg)/mL (<140 picomoles [pmol]/L) is required as confirmation]. (B) Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt must discontinue HRT to confirm post-menopausal status prior to study enrolment. Following confirmation, they can resume HRT during the study without use of a contraceptive method. (C) Child-bearing potential, has a negative serum pregnancy test within 7 days prior to enrolment, and agrees to use adequate contraception from screening until four weeks after the last dose of study drug. Note: The recommended contraceptive methods are abstinence of sexual intercourse, use of intrauterine device/system, vasectomy, and use of condom with spermicidal agent. An oral contraceptive drug does not offer a reliable contraceptive method as a drug-drug interaction may occur.
• Adequate organ system functions as defined in the protocol
• Subjects with a history of autologous stem cell transplant are eligible provided the following criteria are met: transplant completed >180 days prior to enrolment; no active infection (e.g. cytomegalovirus, varicella-zoster virus); meets the remainder of the eligibility criteria outlined in this protocol.

Exclusion Criteria:

• Chemotherapy, radiotherapy, immunotherapy or other anti-myeloma therapy within 28 days prior to enrolment. In addition, any toxicity (except alopecia) should be recovered to <=Grade 1 by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0.
• Use of an investigational drug within 30 days or five half-lives, whichever is longer.
• History of an allogenic stem cell transplant. For patients with history of autologous stem cell transplant, inclusion criteria 10 must be met.
• History of PI3K/AKT inhibitors.
• Current use of prohibited medication or subject who requires any of these medications during treatment of afuresertib, as well as subject who cannot meet the protocol specified meals and dietary restrictions
• Current use of oral corticosteroids, except inhaled or topical use.
• Uncontrolled diabetes mellitus by diet, exercise or medicinal therapies including insulin, and with fasting serum glucose >=130 mg/dL (>=7.28 millimoles [mmol]/L).
• Use of anticoagulants other than low dose (prophylactic) anticoagulants for subject whose Prothrombin time (PT)/international normalization ratio (INR) and activated partial thromboplastin time (APTT) is <=1.5 x upper limit of normal (ULN).
• Presence of active Gastro-intestinal (GI) disease or other condition that could affect GI absorption (e.g. malabsorption syndrome) or predispose subject to GI ulceration.
• Any major surgery that required hospitalization within last four weeks.
• Any serious or unstable pre-existing medical, psychiatric, or other conditions (including lab abnormalities) that could interfere with subject safety or obtaining informed consent.
• Active infection requiring parenteral or oral anti-infective treatment.
• Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease).
• Central nervous system malignancies, primary or metastatic.
• Diagnosis of or treatment history for another malignancy within 2 years, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
• History of known infection with human immunodeficiency virus (HIV).
• Positive hepatitis B surface (HBs) antigen or hepatitis B virus (HBV) Deoxyribonucleic acid (DNA). If negative for HBs antigen and positive for both or either of hepatitis B core (HBc) and HBs antibodies, HBV DNA needs to be negative.
• Positive hepatitis C virus (HCV) antibody
• Corrected QT interval (QTc) >450 milliseconds (msec) or QTc > 480 msec for patients with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF). Note: The QTc should be based on single or averaged QTc values of triplicate ECGs obtained over a brief recording period.
• Other clinically significant ECG abnormalities, including 2nd or 3rd degree atrioventricular block.
• History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty or stenting or bypass grafting within the past six months.
• Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
• Pregnant or lactating female.
• Known hypersensitivity to any components of the study treatment.
• Others who are considered as inappropriate to participate in this study by investigators.