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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01428492




Registration number
NCT01428492
Ethics application status
Date submitted
11/08/2011
Date registered
5/09/2011
Date last updated
8/08/2018

Titles & IDs
Public title
Ph 1b Study to Evaluate GSK2110183 in Combination With Bortezomib and Dexamethasone in Subjects With Multiple Myeloma
Scientific title
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
Secondary ID [1] 0 0
115125
Universal Trial Number (UTN)
Trial acronym
PKB115125
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 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 - GSK2110183
Treatment: Drugs - Bortezomib
Treatment: Drugs - Dexamethasone

Experimental: Part 1-Dose Escalation - GSK2110183 is administered in combination with bortezomib and dexamethasone until MTD is met.

Experimental: Part 2- Pharmacokinetic/Pharmacodynamics Cohort - Once the MTD(s) has been determined, up to 9 subjects of the total enrolled in Part 2 will be entered in the Pharmacokinetic/Pharmacodynamic Cohort. Subjects will be enrolled in this cohort to explore whether exposure to GSK2110183 at dose identified in Part 1 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 give alone or in combination with GSK2110183.

Experimental: Part 2- Safety/Clinical Activity Cohort - Enrolment into the safety/clinical activity cohort in Part 2 will begin prior to enrollment in the PK/PD cohort. Subjects with relapsed multiple myeloma who are either bortezomib sensitive or naive after failing one line of prior systemic therapy will be enrolled in the Safety/Clinical Activity cohort. "Bortezomib sensitive" is defined as having a response (PR or better) to the last bortezomib-containing therapy lasting at least 60 days beyond the end of therapy. A minimum of 15 subjects and a total of 40 subjects will be enrolled. This expansion cohort will further characterize the safety and clinical activity profile of GSK2110183 to inform the future development of this combination regimen.


Treatment: Drugs: GSK2110183
The oral, once daily dose of GSK2110183 will be dependent on the cohort to which a subject is assigned. Subjects enrolled in Cohort 1 will receive 75 mg GSK2110183 once daily. Dose escalation in Schedule A and Schedule B will follow 25 mg increments in a 3+3 dose escalation procedure up to a maximum of 150mg daily or until MTD is reached, whichever comes first, for each schedule. GSK2110183 will continue at daily dosing until treatment discontinuation criteria is met.

Treatment: Drugs: Bortezomib
Bortezomib (1.0 mg/m2) will be administered on days 1, 4, 8, and 11 of each 21-day cycle for cohort 1 for up to 8 cycles. Bortezomib (1.3 mg/m2) will be administered on days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Bortezomib (1.5 mg/m2) will be administered on days 1, 8, and 15 of each 21-day cycle for up to 8 cycles.

Treatment: Drugs: Dexamethasone
Dexamethasone will be given orally at a fixed dose of 20 mg only on days of bortezomib dosing in both Schedule A and Schedule B.

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

Outcomes
Primary outcome [1] 0 0
The recommended Phase II dose (RP2D) and schedule of GSK2110183, bortezomib and dexamethasone dosed in combination. - 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
Timepoint [1] 0 0
Estimation is that each subject may be assessed for up to 48 months.
Secondary outcome [1] 0 0
Pharmacokinetics of GSK2110183, bortezomib and dexamethasone. Composite (or Profile) of Pharmacokinetics Time Frame: predose, 0, 5 min, 15 min, 1, 2, 3, 4, 6, 8, 10-12, 14-22, and 24 hrs post-dose. - Comparison of GSK2110183 area under the concentration versus time curve (AUC) values when administered alone versus when administered with bortezomib and dexamethasone. Comparison of bortezomib and dexamethasone AUC values when administered alone versus when administered with GSK2110183. Comparison of GSK2110183 maximum concentration (Cmax) values when administered alone versus when administered with bortezomib and dexamethasone. Comparison of bortezomib and dexamethasone Cmax values when administered alone versus when administered with GSK2110183.
Timepoint [1] 0 0
Part 2, PK plasma samples will be collected on Cycle 0 Day 11 and Day 38 and Cycle 1 Day 11 (each day at predose, 5min, 15min, 1, 2, 3, 4, 6, 8, 10-12, 14-22 and 24 hrs). Part 1 and Part 2, 3 PK plasma samples will be collected on Day 1 of Cycles 2 - 8
Secondary outcome [2] 0 0
Clinical activity - The clinical response [ i.e. changes in the M-protein, the serum free light chains (FLC) (kappa/lambda ratio ), the appearance of or the change in the size of plasmacytomas or lytic lesions in bone ] to GSK2110183, bortezomib and dexamethasone in subjects with relapsed/refractory multiple myeloma, as assessed by the International Myeloma Working Group Uniform Response Criteria
Timepoint [2] 0 0
Lab assessment of disease (i.e., quantitative paraprotein, SPEP/UPEP) occurs at beginning of cycles, or every 3 wks. Extramedullary disease assessed every 12 wks by imaging, only as warranted.
Secondary outcome [3] 0 0
Relationships between GSK2110183, Pharmacokinetic (PK), Pharmacodynamic (PD) and clinical activity. Composite (or Profile) of Serial Pharmacokinetics Time Frame: predose, 5 min, 15 min, 1,2,3,4,6,8, 10-12, 14-22, and 24 hours post-dose. - Explore the relationships between GSK2110183 exposure (AUC, Cmax concentration, minimum concentration), PD markers (e.g., changes in phosphorylation of markers of AKT (pAKT) pathway activation in bone marrow (BM) biopsy samples and clinical activity (M Protein levels, clinical response). In Part 2, Serial PK plasma samples collected on 2 days. Parts 1 and 2, samples for PD markers (BM biopsy and/or aspirate, plasma for circulating free DNA (cfDNA) or cytokine and angiogenic factors (CAFs)) collected. Parts 1 and 2, clinical activity (lab assessments, quantitative paraprotein) assessed.
Timepoint [3] 0 0
Part 2, serial PK plasma samples will be collected on Cycle 0 Day 11 and Day 38 and Cycle 1 Day 11. In Part 1 and 2, PD markers (BM biopsy and aspirite, plasma for cfDNA and CAF) will be collected predose, once post dose and at time of relapse.
Secondary outcome [4] 0 0
Exploratory Translational Research - Phosphorylation of markers of AKT pathway activation (i.e., pAKT and pPRAS40) in bone marrow biopsy samples. Exploratory analysis of potential predictive markers of response [i.e., cytogenetics (CD45, CD138, CD38, CD19, CD56, CD20, CD117), FISH [t(4;14), t(14;16), 17p13del, del(13q)], Ki67, mutations in NRAS and KRAS] and soluble cytokine levels (i.e., VEGF, IL-6, IFG1) in plasma. BM biopsy will assess markers of AKT activation. Plasma samples will assess circulating free DNA and CAFs. BM aspirate will assess potential predictive markers of response collected for FISH and cytogenetics.
Timepoint [4] 0 0
BM biopsy for AKT activation markers (predose, once post dose). Plasma for cfDNA and CAFs (predose, once post dose, at time of relapse). BM aspirate to assess potential predictive markers of response: FISH (predose) and cytogenetics (predose and CR).

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, 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.
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 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.

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 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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
Novartis Investigative Site - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
New York
Country [6] 0 0
United States of America
State/province [6] 0 0
North Carolina
Country [7] 0 0
United States of America
State/province [7] 0 0
Ohio
Country [8] 0 0
United States of America
State/province [8] 0 0
Wisconsin
Country [9] 0 0
Canada
State/province [9] 0 0
British Columbia
Country [10] 0 0
Canada
State/province [10] 0 0
Ontario
Country [11] 0 0
Ireland
State/province [11] 0 0
Galway
Country [12] 0 0
Taiwan
State/province [12] 0 0
Taipei

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

Ethics approval
Ethics application status

Summary
Brief summary
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 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. Schedule A - GSK2110183 administered once daily with bortezomib (1.3
mg/m2) and dexamethasone (20 mg) given biweekly. Part 2 will further explore the safety,
tolerability and clinical activity of the MTD(s) identified in Part 1, including a
pharmacokinetic cohort.
Trial website
https://clinicaltrials.gov/show/NCT01428492
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
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
Other publications