Multiple MyelomaPhase 1PKB115125NCT01428492
Ph 1b Study to Evaluate GSK2110183 in Combination With Bortezomib and Dexamethasone in Subjects With Multiple Myeloma
A Phase 1 study testing GSK2110183, Bortezomib and Dexamethasone in people with Multiple Myeloma, run by Novartis at 13 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multiple Myeloma
- What is being tested?
- GSK2110183, Bortezomib and Dexamethasone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 13 sitesin 5 countries
- Study dates
- Dec 2011to Oct 2015
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
13 sites in 5 countries.
13 sites in 5 countries
United States8 sites
Novartis Investigative Site
Atlanta, Georgia, 30322
Novartis Investigative Site
Chapel Hill, North Carolina, 27599-7305
Novartis Investigative Site
Chicago, Illinois, 60637
Novartis Investigative Site
Columbus, Ohio, 43210
Novartis Investigative Site
Duarte, California, 91010
Novartis Investigative Site
Madison, Wisconsin, 53792
Novartis Investigative Site
New York, New York, 10029
Novartis Investigative Site
Scottsdale, Arizona, 85259
Canada2 sites
Novartis Investigative Site
Toronto, Ontario, M5G 2M9
Novartis Investigative Site
Vancouver, British Columbia, V5Z 1M9
About this study
Official 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
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.
Read the detailed description
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.
- Conditions
- Multiple Myeloma
- Being tested
- GSK2110183, Bortezomib, Dexamethasone
- Keywords
- AKT Inhibitor, hematologic malignancies, GSK2110183, bortezomib, multiple myeloma, dexamethasone
- Medical subject headings
- Multiple Myeloma, Hematologic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GSK2110183Drug
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.
BortezomibDrug
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.
DexamethasoneDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Part 1-Dose Escalation | Experimental | GSK2110183 is administered in combination with bortezomib and dexamethasone until MTD is met. Receives: Drug: GSK2110183; Drug: Bortezomib; Drug: Dexamethasone |
| Part 2- Pharmacokinetic/Pharmacodynamics Cohort | Experimental | 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. Receives: Drug: GSK2110183; Drug: Bortezomib; Drug: Dexamethasone |
| Part 2- Safety/Clinical Activity Cohort | Experimental | 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. Receives: Drug: GSK2110183; Drug: Bortezomib; Drug: Dexamethasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Estimation is that each subject may be assessed for up to 48 months.
Secondary outcomes (4)
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.
Measured: 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
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
Measured: 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.
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.
Measured: 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.
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.
Measured: 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).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Sep 2011 (estimated)
- Study startDec 2011
- Primary completionOct 2015
- Study completionOct 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Multiple MyelomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 90 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01428492
- Sponsor's protocol ID
- 115125
- Acronym
- PKB115125
- Status last verified
- Aug 2018
- First submitted
- 11 Aug 2011
- Last updated
- 8 Aug 2018
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT01428492
- Acronym / sponsor ID
- PKB115125 / 115125
- Conditions
- Multiple Myeloma
- Keywords
- AKT Inhibitor, hematologic malignancies, GSK2110183, bortezomib, multiple myeloma, dexamethasone
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 90 participants (actual)
- Lead sponsor
- NovartisIndustry (pharma, biotech, devices)
- Study start
- Dec 2011
- Primary completion
- Oct 2015 (actual)
- Study completion
- Oct 2015 (actual)
- First posted
- 5 Sep 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Part 1-Dose Escalation | Experimental | Drug: GSK2110183, Drug: Bortezomib, Drug: DexamethasoneGSK2110183 is administered in combination with bortezomib and dexamethasone until MTD is met. |
| Part 2- Pharmacokinetic/Pharmacodynamics Cohort | Experimental | Drug: GSK2110183, Drug: Bortezomib, Drug: DexamethasoneOnce 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. |
| Part 2- Safety/Clinical Activity Cohort | Experimental | Drug: GSK2110183, Drug: Bortezomib, Drug: DexamethasoneEnrolment 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- 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)
Key exclusion criteria (26 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GSK2110183The 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. | Drug | Part 1-Dose Escalation, Part 2- Pharmacokinetic/Pharmacodynamics Cohort, Part 2- Safety/Clinical Activity Cohort |
| BortezomibBortezomib (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. | Drug | Part 1-Dose Escalation, Part 2- Pharmacokinetic/Pharmacodynamics Cohort, Part 2- Safety/Clinical Activity Cohort |
| DexamethasoneDexamethasone will be given orally at a fixed dose of 20 mg only on days of bortezomib dosing in both Schedule A and Schedule B. | Drug | Part 1-Dose Escalation, Part 2- Pharmacokinetic/Pharmacodynamics Cohort, Part 2- Safety/Clinical Activity Cohort |
Primary outcome
The recommended Phase II dose (RP2D) and schedule of GSK2110183, bortezomib and dexamethasone dosed in combination.
Time frame: Estimation is that each subject may be assessed for up to 48 months.
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
4 secondary outcomes
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.
Time frame: 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
Clinical activity
Time frame: 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.
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.
Time frame: 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.
Exploratory Translational Research
Time frame: 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).
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Aug 2018.
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Advanced Lymphoma, Advanced Malignant Solid Neoplasm
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
13 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing GSK2110183, Bortezomib and Dexamethasone in people with Multiple Myeloma, run by Novartis at 13 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United States, Canada, Australia, Ireland, Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The recommended Phase II dose (RP2D) and schedule of GSK2110183, bortezomib and dexamethasone dosed in combination. (time frame: Estimation is that each subject may be assessed for up to 48 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Aug 2018.