Last updated: 11/03/2018 18:42:12
This product has been transferred to Novartis. GSK Clinical Study Register is no longer maintained for this study. The most up to date information is available on clinicaltrials.gov.

An Open-Label, Dose Escalation, Phase I Study to Evaluate the Tolerability, Safety and Pharmacokinetics of Afuresertib Monotherapy and in Combination with Bortezomib and Dexamethasone in Japanese Relapsed Multiple Myeloma Patients

GSK study ID
115960
Clinicaltrials.gov ID
NCT02177682
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
No longer a GSK study
No longer a GSK study
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: An Open-Label, Dose Escalation, Phase I Study to Evaluate the Tolerability, Safety and Pharmacokinetics of Afuresertib Monotherapy and in Combination with Bortezomib and Dexamethasone in Japanese Relapsed Multiple Myeloma Patients
Trial description: 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 and in combination with bortezomib and dexamethasone) in Japanese relapsed multiple myeloma patients. This is an open-label, dose-escalating, two part phase I study. Part 1 is a dose escalation part with afuresertib monotherapy with single and repeated doses of 125 and 150 milligrams (mg). In Part 2, afuresertib 150 mg will be given in combination with bortezomib (BOR) 1.3 mg/square meter (m^2) and dexamethasone (DEX) 40 mg. Afuresertib will be given daily until the subjects meet any study treatment withdrawal criteria including disease progression. BOR and DEX will be given on days 1, 4, 8 and 11 of 21 day-cycles for maximum of 8 cycles or until disease progression or intolerable toxicities or death. A total of 15 or 18 subjects will be enrolled in the study.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Randomized
Primary outcomes:

Part 1: Number of subjects with Dose-limiting toxicities (DLTs) when afuresertib is given as monotherapy

Timeframe: Day 1 to 21 of Cycle 1

Part 2: Number of subjects with DLTs when afuresertib is given in combination with BOR and DEX in Part 2

Timeframe: Day 1 of cycle 1 to Day 1 of cycle 2

Secondary outcomes:

Part 1: Vital signs assessment

Timeframe: From Day -3 until 30 days after the last dose of afuresertib

Part 1: Number of participants with adverse events (AEs)

Timeframe: From Day -3 until 30 days after the last dose of afuresertib

Part 1 and Part 2: Response rate and clinical benefit rate (rate of minor response or better)

Timeframe: Within 4 weeks of Day 1 Cycle 1, at start of each cycle (except Cycle 1), and then every 6 to 9 weeks until 30 days after the last dose of afuresertib

Part 2: 12-lead electrocardiogram (ECG) assessment

Timeframe: From Cycle 1 Day 1 until 30 days after the last dose of afuresertib

Part 2: Composite of PK parameters of afuresertib, BOR and DEX administered as combination, as single and repeated dose

Timeframe: Cycle 1 Day 1 (Pre-dose, 0.5 hr,1 hr, 2 hr, 3 hr, 4hr, 6 hr, 8 hr, 24 hr) and Cycle 1 Day 11 (Pre-dose, 0.5 hr,1 hr, 2 hr, 3 hr, 4hr, 6 hr, 8 hr, 24 hr, 48 hr)

Part 1: Laboratory assessments

Timeframe: From Day -3 until 30 days after the last dose of afuresertib

Part 2: Left ventricular ejection fraction (LVEF) assessment

Timeframe: From Cycle 1 Day 1 until 30 days after the last dose of afuresertib

Part 2: Laboratory assessments

Timeframe: From Cycle 1 Day 1 until 30 days after the last dose of afuresertib

Part 2: Vital signs assessment

Timeframe: From Cycle 1 Day 1 until 30 days after the last dose of afuresertib

Part 2: Number of participants with adverse events

Timeframe: From Cycle 1 Day 1 until 30 days after the last dose of afuresertib

Part 2: ECOG performance status

Timeframe: From Cycle 1 Day 1 until 30 days after the last dose of afuresertib

Part 1: 12-lead electrocardiogram (ECG) assessment

Timeframe: From Day -3 until 30 days after the last dose of afuresertib

Part 1: Eastern Cooperative Oncology Group (ECOG) performance status (PS)

Timeframe: From Day -3 until 30 days after the last dose of afuresertib

Part 1: Composite of pharmacokinetic (PK) parameters of afuresertib monotherapy administered as single and repeated dose

Timeframe: Cycle 0 (Pre-dose, 0.5 hour [hr],1 hr, 2 hr, 3 hr, 4hr, 6 hr, 8 hr, 24 hr, 48 hr, 72 hr) and Cycle 1 Day 8 (Pre-dose, 0.5 hr,1 hr, 2 hr, 3 hr, 4hr, 6 hr, 8 hr, 24 hr)

Part 1: Left ventricular ejection fraction (LVEF) assessment

Timeframe: From Day -3 until 30 days after the last dose of afuresertib

Interventions:
  • Drug: Bortezomib
  • Drug: Dexamethasone
  • Drug: Afuresertib
    • Enrollment:
    18
    Primary completion date:
    2016-05-04
    Observational study model:
    Not applicable
    Time perspective:
    Not applicable
    Clinical publications:
    Not applicable
    Medical condition
    Neoplasms, Haematologic
    Product
    afuresertib
    Collaborators
    Not applicable
    Study date(s)
    August 2014 to August 2016
    Type
    Interventional
    Phase
    1

    Participation criteria

    Sex
    Female & Male
    Age
    20+ years
    Accepts healthy volunteers
    none
    • Written informed consent is provided.
    • Japanese females or males aged 20 years or older (at the time consent is obtained).
    • 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.
    Inclusion and exclusion criteria
    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. For Part 2, patients must have measureable M protein in serum or urine with at least one of the following: serum M-protein >=1 grams (g)/deciliter (dL) (>=10 g/liter [L]); urine M-protein >=200 mg/24hour; serum free light chain (FLC) assay
    • involved FLC level >=10 mg/dL (>=100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65); Biopsy proven plasmacytoma (should be measured within 28 days of Screening)
    • 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. Oral use of DEX is allowed in concurrent with BOR only.
    • 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.

    Trial location(s)

    This study does not involve prospective enrollment of participants.

    Study documents

    No study documents available.

    Results overview

    Study Results yet to be posted

    Recruitment status
    No longer a GSK study
    Actual primary completion date
    Not applicable
    Actual study completion date
    Not applicable

    Plain language summaries

    Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

    Additional information about the trial

    Additional information
    Not applicable
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