A Phase Ib Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the Oral AKT Inhibitor GSK2110183 Administered in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed/Refractory Multiple Myeloma

Inclusion Criteria:

- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.

- Male or female, 18 years or older.

- Performance status score of 0 - 2 according to the Eastern Cooperative Oncology Group
(ECOG) scale.

- Able to swallow and retain oral medication.

- Histologically confirmed diagnosis of Multiple Myeloma (MM). Subjects enrolled in the
Safety/Clinical Activity Cohort (Part 2) must have relapsed MM (bortezomib-naive or
bortezomib sensitive) with at least one of the following: Serum M-protein ≥1.0g/dl
(≥10gm/l); Urine M-protein ≥200 mg/24h; Serum Free Light Chain (FLC) assay: Involved
FLC level ≥5mg/dl (≥50mg/l) and an abnormal serum free light chain ratio (<0.26 or
>1.65); Biopsy proven plasmacytoma (should be measured within 28 days of Screening
Visit)

- Failed 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.

- Subjects with a history of autologous stem cell transplant are eligible for study
participation provided the following eligibility criteria are met:

- transplant was > 100 days prior to study enrolment

- no active infection

- subject meets the remainder of the eligibility criteria outlined in this protocol

- Fasting serum glucose <126 mg/dL (<7 mmol/L). Subjects diagnosed previously with
Type 2 diabetes must also meet the additional following criteria:

- Diagnosis of diabetes ≥6 months prior to enrolment

- HbA1c≤8% at Screening visit

- Adequate organ system function as defined in protocol.

- A female subject is eligible to participate if she is of non-childbearing potential
(i.e. physiologically incapable of becoming pregnant) defined as pre-menopausal
females with a documented tubal ligation or hysterectomy; or postmenopausal defined
as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with
simultaneous follicle stimulating hormone (FSH) > 40 MIU/ml and estradiol <40 MIU/ml
and estradiol <40 pg/ml (<147pmol/L) is confirmatory. Females on hormone replacement
therapy (HRT) and whose menopausal status is in doubt will be required to use one of
the contraception methods in the protocol if they wish to continue their HRT during
the study. Otherwise, they must discontinue HRT to allow confirmation of
post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4
weeks will elapse between the cessation of therapy and the blood draw; this interval
depends on the type and dosage of HRT. Following confirmation of their
post-menopausal status, they can resume use of HRT during the study without use of a
contraceptive method.

- Child-bearing potential, has a negative serum pregnancy test during the screening
period, and agrees to use one of the contraception methods in protocol from screening
until four weeks after the last dose of study drug.

- Male subjects with female partners of childbearing potential must have had a prior
vasectomy or agree to use one of the contraception methods in protocol. This must be
followed from the time of the first dose of study drug until 3 months after the last
dose of study drug.

Exclusion Criteria:

- Chemotherapy, radiotherapy, immunotherapy, or other anti-myeloma therapy within 14
days prior to the first dose of any one of the drugs in the combination regimen. In
addition, any drug-related toxicity should have recovered to Grade 1 or less.

- Use of an investigational drug within 14 days or five half-lives, whichever is
shorter, preceding the first dose of any one of the drugs in the combination regimen.

- History of an allogeneic stem cell transplant. Subjects with a history of an
autologous stem cell transplant are NOT excluded if they meet Inclusion Criteria #7.

- Current use of prohibited medication listed in the protocol during treatment with
GSK2110183.

- Current use of oral corticosteroids, with the exception of inhaled or topical
steroids. Dexamethasone will be given only in combination with bortezomib on this
study.

- Anticoagulants are permitted only if the subject meets Partial Thromboplastin Time
(PTT) and International Normalized Ratio (INR) entry criteria. Their use must be
monitored in accordance with local institutional practice.

- Presence of active gastrointestinal disease or other condition that could affect
gastrointestinal absorption (e.g. malabsorption syndrome) or predispose subject to
gastrointestinal ulceration.

- Evidence of mucosal or internal bleeding.

- Presence of > Grade 1 peripheral neuropathy at screening.

- Unresolved toxicity (except alopecia) ≥ Grade 2 National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [NCI-CTCAE, 2009]
from previous anti-cancer therapy.

- Any major surgery within the last four weeks.

- Type 1 diabetes mellitus.

- Any serious or unstable pre-existing medical, psychiatric, or other condition
(including lab abnormalities) that could interfere with subject's safety or providing
informed consent.

- Known 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, unstable hypertension).

- Primary or metastatic malignancy of the central nervous system.

- Previous or concurrent malignancies are allowed if it is clear that the other tumor
is not contributing to the subject's illness. The subject must not be receiving
active therapy for this disease and the disease must be considered medically stable..

- QTc interval ≥ 470 msec

- Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd
degree atrioventricular (AV) block.

- History of myocardial infarction, acute coronary syndromes (including unstable
angina), coronary angioplasty, or stenting or bypass grafting within six months of
Screening.

- Class III or IV heart failure as defined by the New York Heart Association (NYHA)
(1994) functional classification system.

- Known hypersensitivity to any of the components of the study treatment.

- Pregnant or lactating female.

- History of known HIV infection.

- Subjects with a positive test for Hepatitis C (HCV) antibody are excluded, regardless
of viral load. If hepatitis C antibody is positive, confirmatory tests may be
performed.

- History of "active" Hepatitis B (HBV) infection. Hepatitis B carriers are eligible
only if antiviral therapy is administered as outlined in the guidelines in the
protocol. Hepatitis B carrier is defined as HBsAg and HBcAb positive by liver enzymes
(AST and ALT) are normal.