Last updated: 11/03/2018 17:50:30

A Study of GSK2110183 in Subjects with Proteasome Inhibitor Refractory Multiple Myeloma

GSK study ID
115340
Clinicaltrials.gov ID
NCT01445587
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Other
Other
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: An Open-Label, Single Arm, Phase Ib/II Study of GSK2110183 in Subjects with Proteasome Inhibitor Refractory Multiple Myeloma
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:

Evaluate the safety and tolerability of GSK2110183 in subjects with proteasome inhibitor refractory MM.

Timeframe: 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.

Determine a Recommended Phase II Dose (RP2D).

Timeframe: 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.

Assess the clinical activity of GSK2110183 in subjects with proteasome inhibitor refractory MM.

Timeframe: 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 outcomes:

Evaluate progression-free survival (PFS), overall survival (OS), time to response, and duration of response.

Timeframe: 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.

Characterize the pharmacokinetics (PK) profile of GSK2110183 in subjects with proteasome inhibitor refractory MM.

Timeframe: 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

Evaluate the clinical benefit of GSK2110183+bortezomib as salvage therapy for those subjects who progressed on GSK2110183 monotherapy.

Timeframe: 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.

Explore the association of biologic/clinical endpoints with DNA or protein profiles from malignant cells as data permit.

Timeframe: Assessed up to 48 months.

Interventions:
  • Drug: Part 1; Cohort 1
  • Drug: Part 1; Cohort 2
  • Drug: Part 2; Stage 1
  • Drug: Part 2, Stage 2
    • Enrollment:
    0
    Primary completion date:
    Not applicable
    Observational study model:
    Not applicable
    Time perspective:
    Not applicable
    Clinical publications:
    Not applicable
    Medical condition
    Cancer
    Product
    afuresertib
    Collaborators
    Not applicable
    Study date(s)
    November 2011 to October 2013
    Type
    Interventional
    Phase
    2

    Participation criteria

    Sex
    Female & Male
    Age
    18+ years
    Accepts healthy volunteers
    No
    • 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.
    • 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.
    Inclusion and exclusion criteria
    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.
    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.

    Trial location(s)

    Location
    Status
    Contact us
    Contact us
    Location
    GSK Investigational Site
    Melbourne, Victoria, Australia, 3004
    Status
    Will Be Recruiting
    Contact us

    Study documents

    No study documents available.

    Results overview

    Study Results yet to be posted

    Recruitment status
    Other
    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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