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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01445587




Registration number
NCT01445587
Ethics application status
Date submitted
25/08/2011
Date registered
4/10/2011
Date last updated
26/03/2012

Titles & IDs
Public title
A Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma
Scientific title
An Open-Label, Single Arm, Phase Ib/II Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma
Secondary ID [1] 0 0
115340
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Part 1; Cohort 1
Treatment: Drugs - Part 1; Cohort 2
Treatment: Drugs - Part 2; Stage 1
Treatment: Drugs - Part 2, Stage 2

Experimental: GSK2110183 - The oral dose of GSK2110183 the subjects received will be dependent on when the subject is enrolled to the study. GSK2110183 will be provided in 25mg and 50mg capsules containing the hydrochloride salt form of the API, microcrystalline cellulose, magnesium stearate, and microcrystalline cellulose (optional). They are filled into hard gelatin capsules. The 25mg tablets are opaque, swedish orange, size 2 capsules with no external markings, filled with a white powder. The 50mg tablets are opaque, white, size 1 capsules with no external markings, filled with a white powder.

Other: Bortezomib - Bortezomib salvage therapy will be administered as a 3 to 5 second intravenous (IV) push at 1.3 mg/m2 on Days 1, 8, and 15 in each 21-day cycle until one of the Treatment Discontinuation Criteria is met.


Treatment: Drugs: Part 1; Cohort 1
On Cycle 0, Day -3, three subjects will be enrolled to receive a single oral dose of 125mg GSK2110183. After the 72 hour PK sampling is completed, the subjects will continue the 125mg GSK2110183 dose daily for 21 day cycles. If none of the 3 subjects experience one of the DLTs listed in the protocol during Cycle 1, the dose will be escalated to 150mg GSK2110183 for the subject enrolled to Cohort 2. Alternately, if 1 subject reports a DLT, then 3 more subjects will be enrolled at the same dose. If 2 of 6 subjects report a DLT, then the MTD has been exceeded. Subjects will remain on study until they meet one of the Treatment Discontinuation Criteria.

Treatment: Drugs: Part 1; Cohort 2
For Cohort 2, on Cycle 0, Day -3, three subjects will be enrolled to receive a single oral dose of 150mg GSK2110183. After the 72 hour PK sampling is completed, the subjects will continue the 150mg GSK2110183 dose daily for 21 day cycles. If none of the 3 subjects experience one of the DLTs listed in the protocol during Cycle 1, the MTD will be determined unless the PK and Pharmacodynamic data indicates another dose level should be evaluated. Alternately, if 1 subject reports a DLT, then 3 more subjects will be enrolled at the same dose. If 2 of 6 subjects report a DLT, then the MTD has been exceeded. Subjects will remain on study until they meet one of the Treatment Discontinuation Criteria.

Treatment: Drugs: Part 2; Stage 1
Following the completion of PK sampling and the determination of a Recommended Phase 2 Dose (RP2D) of GSK2110183 in Cohorts 1 and 2, subjects will be enrolled into Part 2, Stage 1 of the study. Twenty subjects will be enrolled in Stage 1. If no subject responds, the study will be stopped; otherwise, the study will continue enrollment of Stage 2.

Treatment: Drugs: Part 2, Stage 2
Twenty subjects will be enrolled in Part 2, Stage 2. If 4 or fewer of the 40 subjects (Stages 1 and 2) respond, the study will not be deemed as a success for GSK2110183 monotherapy. However, those subjects meeting the criteria for progression (as defined by IMWC Panel 1) who also meet the additional eligibility criteria for salvage therapy may proceed to GSK2110183 + bortezomib salvage therapy. GSK2110183 + bortezomib salvage therapy will be continued until one of the Treatment Discontinuation Criteria is met

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Evaluate the safety and tolerability of GSK2110183 in subjects with proteasome inhibitor refractory MM. - Subjects with proteasome inhibitor refractory MM enrolled into Parts 1 and 2 will be evaluate for safety and tolerability of GSK2110183 by the assessment of adverse events and changes from baseline in safety assessments including laboratory parameters, vital signs, and electrocardiogram (ECG) parameters.
Timepoint [1] 0 0
Subjects will continue on the study from the date of randomization until the date of the first documented progression or when the subjects meet one of the Treatment Discontinuation Criteria and may be assessed on average up to 48 months.
Primary outcome [2] 0 0
Determine a Recommended Phase II Dose (RP2D). - RP2D is defined as a dose that provides adequate pharmacokinetics exposure and biologic activity without exceeding the Maximum Tolerated Dose (MTD) in Multiple Myeloma (MM) subjects as defined in the current study. RP2D will be defined in Part 1 of the study. The specific number of subjects to be enrolled is dependent on the number of Dose Limiting Toxicities (DLTs) reported; however, enrollment of approximately 18 subjects is estimated. The RP2D chosedn in Part 1 will be the dosing regimen used in Part 2.
Timepoint [2] 0 0
Subjects will continue on the study from the date of randomization until the date of the first documented progression or when the subjects meet one of the Treatment Discontinuation Criteria and may be assessed on average up to 48 months.
Primary outcome [3] 0 0
Assess the clinical activity of GSK2110183 in subjects with proteasome inhibitor refractory MM. - Subjects enrolled into Parts 1 and 2 will be assessed for overall response rate of GSK2110183 in subjects with proteasome inhibitor refractory Multiple Myeloma using the 2011 recommendations in the Report of the International Myeloma Workshop Consensus.
Timepoint [3] 0 0
Subjects will continue on the study from the date of randomization until the date of the first documented progression or when the subjects meet one of the Treatment Discontinuation Criteria and may be assessed on average up to 48 months.
Secondary outcome [1] 0 0
Evaluate progression-free survival (PFS), overall survival (OS), time to response, and duration of response. - Subjects enrolled into Parts 1 and 2 will be assessed for PFS, OS, time to response, and duration of response using the 2011 Report of the International Myeloma Workshop Consensus Panel 1. PFS is measured from the date of first dose until the date of disease progression or death due to any cause. OS is defined as the time from the date of first dose until the date of death due to any cause. Duration of response will be defined as the time from the first documented evidence of partial, very good partial, complete, or stringent complete tumor response until date of disease progression or death
Timepoint [1] 0 0
Subjects will continue on the study from the date of randomization until the date of the first documented progression or when the subjects meet one of the Treatment Discontinuation Criteria and may be assessed on average up to 48 months.
Secondary outcome [2] 0 0
Characterize the pharmacokinetics (PK) profile of GSK2110183 in subjects with proteasome inhibitor refractory MM. - To characterize GSK2110183 pharmacokinetic parameters; area of concentration under the curve (AUC), Pre-dose (trough) concentration at the end of the dosing interval (Ct), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax) will be evaluated in the plasma and urine samples. The main PK sampling will take place in Part 1 of the study and Part 2 will have only sparse PK sampling.
Timepoint [2] 0 0
Part 1: plasma PK on C0 (D-3), C1 (D15) pre-dose, 0.5, 1, 2, 3, 4, 5, 8, 10-12, 14-22, 24, 48, and 72. In C2-8 (D1) pre-dose and post-dose. Urine PK on: C0 (D-3) pre-dose and C1 (D15) 24h post. Part 2: plasma PKs on C2-8 (D1) pre-dose and 1-2 hours post
Secondary outcome [3] 0 0
Evaluate the clinical benefit of GSK2110183+bortezomib as salvage therapy for those subjects who progressed on GSK2110183 monotherapy. - In Part 2 of the study, subjects whom bortezomib is added to GSK2110183 due to disease progression on GSK2110183 monotherapy overall response rate (ORR = stringent complete response + complete response + very good partial response + partial response rates), PFS, duration of response, and time-to-next-therapy will be evaluated.
Timepoint [3] 0 0
Subjects will continue on the study from the date of randomization until the date of the first documented progression or when the subjects meet one of the Treatment Discontinuation Criteria and may be assessed on average up to 48 months.
Secondary outcome [4] 0 0
Explore the association of biologic/clinical endpoints with DNA or protein profiles from malignant cells as data permit. - Subjects enrolled into Parts 1 and 2 will have samples collected for analysis of the markers of AKT pathway activation (e.g., pAKT, pPRAS40) in bone marrow biopsy and/or aspirate samples, potential predictive markers of response (e.g., cytogenetics, FISH, Ki67, mutations in NRAS and KRAS) in bone marrow biopsy and/or aspirate samples, and soluble cytokine levels (e.g., VEGF, IL-6, IGF1) in plasma.
Timepoint [4] 0 0
Assessed up to 48 months.

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

- Male or female who is at least 18 years of age or older.

- Histologically confirmed diagnosis of secretory MM (must have measurable M protein in
serum or urine) with one or more of the following:

Serum M-protein count greater than or equal to 1 g/dL Urinary M-protein greater than or
equal to 200 mg/24 hours Serum free light chain (FLC) assay: involved FLC level greater
than or equal to 10 mg/dL (greater than or equal to 100 mg/L) and a serum FLC ratio outside
of normal range. Biopsy proven plasmacytoma

- Relapsed after 2 or more lines of systemic therapy including at least one proteasome
inhibitor (i.e., bortezomib, carfilzomib) and at least one immunomodulatory agent
(i.e., lenalidomide, pomalidomide) AND refractory to proteasome inhibitor therapy.
Subjects will be considered refractory to proteasome inhibitor therapy if they
experienced stable disease or progressive disease as the best response on their last
proteasome inhibitor containing therapy OR progressed within 60 days following two or
more cycles of proteasome inhibitor therapy. A line of therapy is generally separated
by disease progression from a preceding line of therapy; therefore, 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 more than 100 days prior to study enrolment No active infection Subject
meets the remainder of the eligibility criteria

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

- Able to swallow and retain oral medication.

- Fasting serum glucose less than126 mg/dL (<7 mmol/L). Subjects diagnosed previously
with diabetes mellitus type 2 must also meet the additional following criteria:

Diagnosis of diabetes greater than 6 months prior to enrollment Glycosylated hemoglobin A1c
(HbA1c) less than 8% at screening

- A female subject is eligible to participate if she is of the following:

Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) defined
as premenopausal 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 greater than 40 MlU/ml and
estradiol less than 40 pg/ml (less than 147 pmol/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 listed 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 to 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.

Childbearing potential, has a negative serum pregnancy test during the screening period,
and agrees to use adequate contraception (methods listed in the protocol) from screening
until four weeks after the last dose of GSK2110183. Note: Oral contraceptives are not
reliable due to potential drug-drug interaction.

- Male subjects with female partners of childbearing potential must have had a prior
vasectomy or agree to use adequate contraception from the time of the first dose of
GSK2110183 until 3 months after the last dose of GSK2110183.

- Adequate organ function as defined by laboratory results within specific value ranges
listed in the protocol.

Inclusion criteria: Salvage Therapy with GSK2110183 and Bortezomib:

- Platelet count greater than or equal to 70 X 10^9/L

- A subject whose ANC is greater than 1000/mm^3 before GSK2110183 monotherapy but whose
ANC decreases below 1000/mm^3 at the time of transitioning to the salvage therapy is
allowed up to 14 days following interruption of GSK2110183 dosing for ANC to recover
to greater than or equal to 1000/mm^3.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Chemotherapy, radiotherapy, immunotherapy, or other anti-myeloma therapy within 14
days prior to the first dose of GSK2110183. In addition, any drug-related toxicity,
except for alopecia, should have recovered to Grade 1 or less.

- Use of an investigational drug within 14 days or 5 half-lives, whichever is longer,
preceding the first dose of GSK2110183.

- History of an allogeneic stem cell transplant. Subjects with a history of an
autologous stem cell transplant are NOT excluded if they meet Inclusion Criterion 5
(Subjects with a history of autologous stem cell transplant are eligible for...).

- Current use of a prohibited medication.

- Current use of oral corticosteroids, with the exception of inhaled or topical
corticosteroids.

- Anticoagulants (e.g., warfarin, low molecular weight heparin, direct thrombin
inhibitors) at therapeutic doses or at low doses (e.g., prophylactic) are permitted
only if the subject meets the partial thromboplastin time (PTT) and international
normalization ratio (INR) entry criteria. Anticoagulant use must be monitored in
accordance with local institutional practice.

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

- Any major surgery within the last 14 days.

- Unresolved toxicity (except alopecia) greater than or equal to Grade 2 National Cancer
Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4)
from previous anticancer therapy.

- Presence of greater than Grade 1 peripheral neuropathy.

- Type 1 diabetes mellitus.

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

- Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
respiratory, hepatic, renal, or cardiac disease, unstable hypertension).

- History of known human immunodeficiency virus infection.

- Subjects with a positive test for hepatitis B surface antigen or a positive test for
hepatitis C antibody are excluded, regardless of the viral load. If hepatitis C
antibody is positive, a confirmatory RIBA test may be performed. If the RIBA test is
negative, the subject is eligible for the study.

- Primary or metastatic malignancy of the central nervous system.

- Diagnosis of or treatment for another malignancy within 2 years of enrollment, with
the exception of complete resection of basal carcinoma or squamous cell carcinoma of
the skin, or an in situ malignancy.

- QTC interval greater than or equal to 470 msec. NOTE: If initial result is prolonged,
eligibility will be based on the average of manually calculated QTcF value from 3 ECGs
(e.g., obtain 2 more ECGs at least 5 minutes apart and calculate the average of
triplicate ECGs).

- Other clinically significant ECG abnormalities including 2nd degree (Type II) 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 6
months.

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

- Known hypersensitivity to GSK2110183, bortezomib, boron, and/or mannitol.

- Pregnant or lactating female.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a single arm, open-label, Phase Ib/II study to evaluate the safety, pharmacokinetics,
pharmacodynamics, and efficacy of the oral AKT inhibitor, GSK2110183, when administered to
subjects with proteasome inhibitor refractory multiple myeloma (MM). During Part 1 of the
study, GSK2110183 will be administered to subjects in sequential Pharmacokinetic (PK) Cohorts
on a continuous daily dosing schedule in 21-day cycles until one of the Treatment
Discontinuation Criteria is met. The PK Cohorts will characterize the PK of GSK2110183 in
plasma and urine as well as determine the Recommended Phase 2 Dose (RP2D) of GSK2110183. The
RP2D will be that dose that provides adequate PK exposure and biologic activity without
exceeding the maximum tolerated dose (MTD) in MM subjects as defined in the current study. In
Part 2 of the study, the RP2D will be further evaluated using a flexible 2-stage design with
a stopping rule to allow for early termination based on lack of efficacy at the end of Stage
1. The first stage will accrue 20 subjects who will receive GSK2110183 at the RP2D. If a
clinical response is observed in at least 1 subject in Stage 1, the study will proceed to
Stage 2 and 20 additional subjects will be enrolled. GSK2110183 will be administered in Part
2 (Stage 1 and Stage 2) on a continuous daily dosing schedule in 21 day cycles until
International Myeloma Working Group criteria for progression are met, at which point the
subject will proceed to GSK 2110183 + bortezomib salvage therapy provided they meet the
additional eligibility criteria for this phase of the study. GSK2110183 and bortezomib will
be continued until one of the Treatment Discontinuation Criteria is met.

Exploratory PK/PD analyses may be performed to examine the potential relationships between
GSK2110183 pharmacokinetics and pharmacodynamic biomarkers.
Trial website
https://clinicaltrials.gov/show/NCT01445587
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT01445587