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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

Phase 1
18 Years
Open (Enrolling)
Multiple Myeloma

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Trial Information

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

This is a Phase Ib, open-label study to evaluate the safety, tolerability, pharmacokinetics
(PK), pharmacodynamics (PD) and clinical activity of GSK2110183 dosed in combination with
bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM) subjects who have
failed at least one line of systemic treatment. Part 1 will identify the maximum tolerated
dose(s) (MTD) of the combination regimen.

Part 1, Schedule A will assess the safety and pharmacodynamics of GSK2110183 administered
once daily with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) given biweekly. It is
estimated that up to 35-45 evaluable subjects will be enrolled in Part 1. Part 2 will
explore further the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical
activity of the MTD(s) identified in Part 1. A minimum of 15 and maximum of 40 subjects
will enroll in Part 2 Safety/Clinical Activity Cohort for each Schedule explored. The Part
2 PK/PD cohort will enroll up to 18 subjects. This pharmacokinetic cohort will explore
whether exposure to GSK2110183 at the MTD is similar when GSK2110183 is administered alone
or in combination with bortezomib and dexamethasone. The same relationship will be explored
for bortezomib and dexamethasone when the two drugs are given by themselves or in
combination with GSK2110183. The identified MTD(s) and pharmacodynamic results in this study
will inform the doses for future development of the regimen of GSK2110183 dosed in
combination with bortezomib and dexamethasone in subjects with relapsed/refractory MM.

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

- 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

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

- 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

- 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

- 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The recommended Phase II dose (RP2D) and schedule of GSK2110183, bortezomib and dexamethasone dosed in combination.

Outcome Description:

Dose and schedule determined using adverse events and changes in safety assessments (laboratory parameters, vital signs and ECG parameters). Recommended Phase 2 Dose (RP2D) will be defined in Part 1. The specific number of subjects to be enrolled is dependent on the number of dose limiting toxicities (DLTs) reported; enrollment of up to 45 subjects in Part 1 is estimated. Subjects will continue on study from the date of randomization until the date of the first documented disease progression or when the subject meets one of the Treatment Discontinuation criteria, whichever comes first

Outcome Time Frame:

Estimation is that each subject may be assessed for up to 48 months.

Safety Issue:


Principal Investigator

GSK Clinical Trials

Investigator Role:

Study Director

Investigator Affiliation:



Ireland: Irish Medicines Board

Study ID:




Start Date:

March 2012

Completion Date:

September 2013

Related Keywords:

  • Multiple Myeloma
  • AKT Inhibitor
  • hematologic malignancies
  • GSK2110183
  • bortezomib
  • multiple myeloma
  • dexamethasone
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



GSK Investigational Site Phoenix, Arizona  85013 - 4496
GSK Investigational Site Bakersfield, California  93309
GSK Investigational Site Raleigh, North Carolina  27609
GSK Investigational Site Akron, Ohio  44304
GSK Investigational Site Green Bay, Wisconsin  54301
GSK Investigational Site Savannah, Georgia  31405
GSK Investigational Site Park Ridge, Illinois  60068
GSK Investigational Site New York, New York  10021