A Phase I Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Clinical Activity of the Antibody Drug Conjugate GSK2857916 in Subjects With Relapsed/Refractory Multiple Myeloma and Other Advanced Hematologic Malignancies Expressing BCMA
Overview
- Phase
- Phase 1
- Intervention
- GSK2857916
- Conditions
- Multiple Myeloma
- Sponsor
- GlaxoSmithKline
- Enrollment
- 79
- Locations
- 1
- Primary Endpoint
- Number of Participants With Serious Adverse Events (SAEs) and Common (>=5%) Non-serious Adverse Events- Part 1
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
This study will assess the safety, pharmacokinetic (PK), pharmacodynamic (PD) and the therapeutic potential of GSK2857916 in subjects with multiple myeloma (MM) and lymphomas that express B cell maturation antigen (BCMA). The hypothesis is that GSK2857916 can be safely administered to subjects with MM and with BCMA positive malignancies at doses where target engagement can be demonstrated. This study will determine if adequate target engagement of BCMA receptors translates into clinical benefit for subjects with MM and BCMA positive lymphomas. The study will consists of two parts: a Part 1 dose escalation phase and a Part 2 expansion phase for safety, tolerability, PK, PD, and clinical activity testing. The study will enroll a total of approximately 80-95 subjects with relapsed/refractory MM or BCMA-expressing hematologic malignancies. The maximum dose to be administered in this trial will not exceed 5 milligram/kilogram(mg/kg).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provide signed written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •Male or female, 18 years or older (at the time consent is obtained)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Part 1/dose escalation; Histologically or cytologically confirmed diagnosis of Multiple Myeloma in a subject who fulfills all of the following: has undergone stem cell transplant, or is considered transplant ineligible, has been pretreated with at least the 3 following classes of anti-myeloma drugs: alkylators, proteasome inhibitors and immunomodulators, has demonstrated progression on, or within 60 days of completion of the last therapy.
- •Part 2 /MM cohort; Histologically or cytologically confirmed diagnosis of: Multiple Myeloma in a subject who fulfills all of the following: has undergone stem cell transplant, or is considered transplant ineligible, has been pretreated with at least the 3 following classes of anti-myeloma drugs: alkylators, proteasome inhibitors and immunomodulators, has demonstrated progression on, or within 60 days of completion of the last therapy, and has measurable disease with at least one of the following: serum M-protein \>=0.5 gram (g)/decilitre (dL) (\>=5 g/Litre (L)), urine M-protein \>=200 milligram (mg)/24hour (h).
- •Serum free light chain (FLC) assay: Involved FLC level \>=5 mg/dL (\>=50 mg/L) and an abnormal serum FLC ratio (\<0.26 or \>1.65) and biopsy proven plasmacytoma (should be measured within 28 days of Screening Visit).
- •Part 2/Other BCMA positive Hematologic Malignancies cohort: Subject with one of the following lymphomas: Diffuse Large B-cell Lymphoma (DLBCL) or follicular lymphoma (FL) that exhibits positive BCMA expression on tumor cells as determined by a central laboratory using a validated Immunohistochemistry (IHC) assay. Eligible subjects with BCMA positive malignancies must also fulfill the prior treatment requirements as follows: DLBCL: at least 2 prior lines of systemic therapy containing at least one line of chemo-immunotherapy with anti-CD20 antibody, and either has undergone stem cell transplant or is considered transplant ineligible. FL: at least 2 prior lines of systemic 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 the study protocol.
- •Adequate organ system functions as defined below Absolute neutrophil count\>=1.0x10\^9/L, hemoglobin\>=8.0 g/dL, platelet\>=50x10\^9/L, international normalized ration (INR) \<=1.5, Partial thromboplastin time \<=1.5xupper limit of normal (ULN), total bilirubin \<=1.25xULN, alanine aminotransferase and aspartate aminotransferase\<=1.5 X ULN, serum creatinine or calculated creatinine clearance\<1.2XULN \>=60 mL/min for Part 1;\>=50 mL/minute (min) for Part 2 if data supports loosening criteria, Albuminuria\<=500 mg/24h, left ventricular ejection fraction \>=50%, Troponin\<=1xULN, Calcium\<=1.1xULN
- •A female subject is eligible to participate if she is of: Non-childbearing potential or women of childbearing potential must have a negative serum pregnancy test within 72 hours of first dose of study treatment and agree to use effective contraception during the study and for 60 days following the last dose of study treatment.
Exclusion Criteria
- •Systemic anti-tumor therapy within 14 days, or plasmapheresis within 7 days prior to the first dose of study drug
- •Use of an investigational drug within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drug.
- •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 related to history of autologous stem cell transplant.
- •Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect subject's safety). Subjects with isolated proteinuria resulting from MM are eligible, provided they fulfil the inclusion criteria related to organ system function.
- •Evidence of active mucosal or internal bleeding
- •Any major surgery within the last four weeks.
- •Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
- •Known active infection requiring antibiotic treatment
- •Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal or cardiac disease
- •Subjects with previous or concurrent malignancies are allowed only if the second tumor is not contributing to the subject's illness. The subject must not be receiving active therapy, other than hormonal therapy for this disease and the disease must be considered medically stable for at least 2 years.
Arms & Interventions
Schedule 1 Part 1
Participants will receive GSK2857916 intravenously over 60 minutes (one dose) every 3 weeks (21 day cycle) for a maximum of 16 cycles.
Intervention: GSK2857916
Schedule 2 Part 1
Participants may receive GSK2857916 intravenously over 60 minutes (one dose) once weekly for three consecutive weeks followed by 1 week of rest (28 day cycle) for a maximum of 16 cycles.
Intervention: GSK2857916
Schedule 1 Part 2
Participants will receive the dose and schedule of GSK2857916 evaluated in Part 1 that is selected for further evaluation in Part 2 for up to 16 cycles.
Intervention: GSK2857916
Schedule 2 Part 2
Participants may receive the dose and schedule of GSK2857916 evaluated in Part 1 that is selected for further evaluation in Part 2 for a maximum of 16 cycles.
Intervention: GSK2857916
Outcomes
Primary Outcomes
Number of Participants With Serious Adverse Events (SAEs) and Common (>=5%) Non-serious Adverse Events- Part 1
Time Frame: Up to 23.5 months (maximum duration of follow-up from first dose to last contact or death)
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, other medical events according to medical or scientific judgement and all events of possible study treatment-induced liver injury with hyperbilirubinemia. Part 1 Population comprised of all Part 1 participants (exclusively MM) who received at least one dose of GSK2857916. SAEs and common (\>=5%) non-SAEs is presented.
Number of Participants With SAEs and Common (>=5%) Non-serious Adverse Events- Part 2 (MM)
Time Frame: Up to 35 months (maximum duration of follow-up from first dose to last contact or death)
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, other medical events according to medical or scientific judgement and all events of possible study treatment-induced liver injury with hyperbilirubinemia. Part 2 MM Population comprised of all Part 2 MM participants who received at least one dose of GSK2857916. SAEs and common (\>=5%) non-SAEs is presented.
Number of Participants With SAEs and Common (>=5%) Non-serious Adverse Events- Part 2 (NHL)
Time Frame: Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death)
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, other medical events according to medical or scientific judgement and all events of possible study treatment-induced liver injury with hyperbilirubinemia. Part 2 NHL Population comprised of all Part 2 NHL participants who received at least one dose of GSK2857916. SAEs and common (\>=5%) non-SAEs is presented.
Number of Participants With Dose-limiting Toxicities (DLTs) During the Determinative Period- Part 1
Time Frame: Up to Day 21 (from first dose)
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of the following criteria:albuminuria\>=2000mgper24 hour which has been confirmed by repeat test at least7 days apart and is not considered to be related to disease progression, Grade4 neutropenia (without fever) lasting\>=7 days, febrile neutropenia lasting\>=72 hours, Grade\>=3 thrombocytopenia associated with bleeding where estimated blood loss is\>10 milliliter orGrade4 thrombocytopenia lasting\>7 days and not responding to platelet transfusions, anyGrade3 or greaternon-hematologic toxicity as described in Common National Cancer Institute-Terminology Criteria for Adverse Events version4.0 with the exception of the following Grade3 events that can be controlled within48 hours with routine supportive measures and clinically asymptomatic electrolyte abnormalities which can be corrected within48 hours and liver toxicity meeting pre-specified GSK liver stopping criteria.
Number of Participants With Grade Change From Baseline in Vital Signs-DBP & SBP-Part 1
Time Frame: Baseline and Up to 21.6 months (maximum duration of follow-up from first dose to last contact or death)
Vital signs included systolic blood pressure (SBP), diastolic blood pressure (DBP), temperature (Temp) and heart rate (HR). SBP and DBP were graded using National Cancer Institute-Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. For SBP: Grade 0-\<120 millimeters of mercury\[mmHg\], 120-139 mmHg\[Grade 1\], 140-159 mmHg\[Grade 2\], \>=160 mmHg\[Grade 3\]); For DBP: \<80 mmHg \[Grade 0\], 80-89\[Grade 1\], 90-99\[Grade 2\], \>=100 mmHg\[Grade 3\]). An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline was defined as the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Grade Change From Baseline in Vital Signs-DBP & SBP-Part 2 (MM)
Time Frame: Baseline and Up to 24.2 months (maximum duration of follow-up from first dose to last contact or death)
Vital signs included SBP, DBP, Temp and HR. SBP and DBP were graded using NCI CTCAE version 4.0. For SBP: Grade 0-\<120 mmHg, 120-139 mmHg\[Grade 1\], 140-159 mmHg\[Grade 2\], \>=160 mmHg\[Grade 3\]); For DBP: \<80 mmHg \[Grade 0\], 80-89\[Grade 1\], 90-99\[Grade 2\], \>=100 mmHg\[Grade 3\]). An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline was defined as the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Grade Change From Baseline in Vital Signs-DBP & SBP-Part 2 (NHL)
Time Frame: Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death)
Vital signs included SBP, DBP, Temp and HR. SBP and DBP were graded using NCI CTCAE version 4.0. For SBP: Grade 0-\<120 mmHg, 120-139 mmHg \[Grade 1\], 140-159 mmHg\[Grade 2\], \>=160 mmHg \[Grade 3\]); For DBP: \<80 mmHg \[Grade 0\], 80-89\[Grade 1\], 90-99\[Grade 2\], \>=100 mmHg\[Grade 3\]). An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline was defined as the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Change From Baseline in Heart Rate and Temperature-Part 1
Time Frame: Baseline and Up to 21.6 months (maximum duration of follow-up from first dose to last contact or death)
The following criteria was used to flag vital signs of potential clinical importance: change from Baseline in heart rate (decrease to \<60 beats per minute \[bpm\] and increase to \>100 bpm) and change in temperature from Baseline (increase to \>=38 or decrease to \<=35 degrees celsius). Baseline was defined as the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Change From Baseline in Heart Rate and Temperature-Part 2 (MM)
Time Frame: Baseline and Up to 24.2 months (maximum duration of follow-up from first dose to last contact or death)
The following criteria was used to flag vital signs of potential clinical importance: change from Baseline in heart rate (decrease to \<60 bpm and increase to \>100 bpm) and change in temperature from Baseline(increase to \>=38 or decrease to \<=35 degrees celsius). Baseline was defined as the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Change From Baseline in Heart Rate and Temperature-Part 2 (NHL)
Time Frame: Baseline and Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death)
The following criteria was used to flag vital signs of potential clinical importance: change from Baseline in heart rate (decrease to \<60 bpm and increase to \>100 bpm) and change in temperature from Baseline(increase to \>=38 or decrease to \<=35 degrees celsius). Baseline was defined as the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1
Time Frame: Baseline and Up to 21.6 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following clinical chemistry parameters: albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (T.Bil.), calcium (Ca), creatinine (Creat), creatinine kinase (CK), gamma glutamyl transferase (GGT), glucose (Gl), potassium (Pot), magnesium (Mg), sodium (Sod), phosphate (Ph) and urate. Values(Hyper and hypo)for Gl, Pot, Mg, Sod and Ca is presented. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. All increases are an increase in grade from Baseline. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 2 (MM)
Time Frame: Baseline and Up to 24.2 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following clinical chemistry parameters: albumin,ALP,ALT,AST,T.Bil.,Ca, Creat,CK, GGT,Gl, Pot,Mg, Sod, Ph and urate. Values(Hyper and hypo)for Gl, Pot, Mg, Sod and Ca is presented. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. All increases are an increase in grade from Baseline. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 2 (NHL)
Time Frame: Baseline and Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following clinical chemistry parameters: albumin, ALP, ALT, AST, Bilirubin, Ca, Creat, CK, GGT, Glucose, Pot, Mg, Sod, and Ph. Values(Hyper and hypo)for Glucose, Pot, Mg, Sod and Ca is presented. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. All increases are an increase in grade from Baseline. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Part 1
Time Frame: Baseline and Up to 21.6 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following clinical chemistry parameters: direct bilirubin (D.Bil.), chloride, carbon dioxide (CO2), lactate dehydrogenase (LDH), total protein (T.Pro) and urea or blood urea nitrogen (BUN). Baseline was defined as latest pre-dose assessment with a non-missing value, including unscheduled visits. A laboratory value that is outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). If values were unchanged (example: High to High), or whose value became normal, were recorded in the 'To Normal or No Change (NC)' category. Participants were counted twice if the participant "Decreased to low" and "Increased to high" during post-Baseline. Data for worst-case post Baseline is presented.
Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Part 2 (MM)
Time Frame: Baseline and Up to 24.2 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following clinical chemistry parameters: D.Bil., chloride, CO2, LDH, T.Pro and BUN. Baseline was defined as latest pre-dose assessment with a non-missing value, including unscheduled visits.A laboratory value that is outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). If values were unchanged (example: High to High), or whose value became normal, were recorded in the 'To Normal or NC' category. Participants were counted twice if the participant 'Decreased to Low' and 'Increased to High' during post-Baseline.Data for worst-case post Baseline is presented.
Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Part 2 (NHL)
Time Frame: Baseline and Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following clinical chemistry parameters: D.Bil., chloride, CO2, LDH, and T.Pro. Baseline was defined as latest pre-dose assessment with a non-missing value, including unscheduled visits.A laboratory value that is outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). If values were unchanged (example: High to High), or whose value became normal, were recorded in the 'To Normal or NC' category. Participants were counted twice if the participant 'Decreased to Low' and 'Increased to High' during post-Baseline. Data for worst-case post Baseline is presented.
Number of Participants With Grade Change From Baseline in Hematology Data-Part 1
Time Frame: Baseline and Up to 21.6 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following hematology parameters: hemoglobin (Hb), lymphocytes (Lymph), neutrophils (Neutro), platelet count (PC), and leukocytes (leuko). The laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Baseline was defined as latest pre-dose assessment with a non-missing value, including unscheduled visits. An increase is defined as an increase in CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented.
Number of Participants With Grade Change From Baseline in Hematology Data-Part 2 (MM)
Time Frame: Baseline and Up to 24.2 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following hematology parameters: Hb, Lymph, Neutro, PC, and leuko. The laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Baseline was defined as the latest pre-dose assessment with a non-missing value, including unscheduled visits.An increase is defined as an increase in CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented.
Number of Participants With Grade Change From Baseline in Hematology Data-Part 2 (NHL)
Time Frame: Baseline and Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following hematology parameters: Hb, Lymph, Neutro, PC, and leuko. The laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Baseline was defined as the latest pre-dose assessment with a non-missing value, including unscheduled visits. An increase is defined as an increase in CTCAE grade relative to Baseline grade. Data for worst-case post Baseline is presented.
Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Part 1
Time Frame: Baseline and Up to 21.6 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following hematology parameters: basophils (Baso), eosinophils (Eosino), hematocrit (Hct), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), monocytes (Mono), erythrocytes (Erythro) and reticulocytes (Reticu). A laboratory value that was outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). Baseline was defined as latest pre-dose assessment with a non-missing value, including unscheduled visits. If values were unchanged (example: High to High), or whose value became normal, were recorded in the 'To Normal or NC' category. Participants were counted twice if the participant 'Decreased to Low' and 'Increased to High' during post-Baseline.Data at worst-case post Baseline is presented.
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.96 mg/kg
Time Frame: Baseline and Day 1 (Cycle 2, 3, 4, 5, 6)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Part 2 (MM)
Time Frame: Baseline and Up to 24.2 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following hematology parameters: Baso, Eosino, Hct, MCHC, MCH, MCV, Mono, Erythro and Reticu. A laboratory value that was outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). Baseline was defined as latest pre-dose assessment with a non-missing value, including unscheduled visits. If values were unchanged (example: High to High), or whose value became normal, were recorded in the 'To Normal or NC' category. Participants were counted twice if the participant 'Decreased to Low' and 'Increased to High' during post-Baseline.Data at worst-case post Baseline is presented.
Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Part 2 (NHL)
Time Frame: Baseline and Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death)
Blood samples were collected for the analysis of following hematology parameters: Baso, Eosino, Hct, MCHC, MCH, MCV, Mono, Erythro and Reticu. A laboratory value that was outside the reference range was considered either high abnormal (value above the upper limit of the reference range) or low abnormal (value below the lower limit of the reference range). Baseline was defined as latest pre-dose assessment with a non-missing value, including unscheduled visits. If values were unchanged (example: High to High), or whose value became normal, were recorded in the 'To Normal or NC' category. Participants were counted twice if the participant 'Decreased to Low' and 'Increased to High' during post-Baseline. Data at worst-case post Baseline is presented.
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.24 mg/kg
Time Frame: Baseline and Day 1 (Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13,14, 15)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method -Part 1
Time Frame: Baseline and Up to 21.6 months (maximum duration of follow-up from first dose to last contact or death)
Urine samples were collected to assess urine occult blood (OB) and urine protein (Pro). The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as no change/decreased, increase to small (indicated by trace and 1+), increase to moderate (indicated by 2+) and increase to large (indicated by 3+ and above) for urine OB and no change/decreased, increase to trace, increase to 1+, increase to 2+ and increase to 3+ for urine Pro indicating proportional concentrations in the urine sample. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method -Part 2 (MM)
Time Frame: Baseline and Up to 24.2 months (maximum duration of follow-up from first dose to last contact or death)
Urine samples were collected to assess urine OB and urine Pro. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as no change/decreased, increase to small (indicated by trace and 1+), increase to moderate (indicated by 2+) and increase to large (indicated by 3+ and above) for urine OB and no change/decreased, increase to trace, increase to 1+, increase to 2+ and increase to 3+ for urine Pro indicating proportional concentrations in the urine sample. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method -Part 2 (NHL)
Time Frame: Baseline and Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death)
Urine samples were collected to assess urine OB and urine Pro. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as no change/decreased, increase to small (indicated by trace and 1+), increase to moderate (indicated by 2+) and increase to large (indicated by 3+ and above) for urine OB. For Urine Pro., results were reported as no change/decreased, increase to trace, increase to 1+, increase to 2+ and increase to 3+ indicating proportional concentrations in the urine sample. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Data for worst-case post Baseline is presented.
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.06 mg/kg
Time Frame: Baseline and Day 1 (Cycle 2 and 3)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.03 mg/kg and 0.12 mg/kg
Time Frame: Baseline and Day 1 (Cycle 2)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.48 mg/kg
Time Frame: Baseline and Day 1 (Cycle 2, 3, 5, 6, 7, 8)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 1.92 mg/kg
Time Frame: Baseline and Day 1 (Cycle 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 16)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 2.50 mg/kg
Time Frame: Baseline and Day 1 (Cycle 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 3.40 mg/kg and 4.60 mg/kg
Time Frame: Baseline and Day 1 (Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 2 (MM)
Time Frame: Baseline and Day 1 (Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
Urine samples were collected to assess urine Pro. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Pro. excretion (24 hour) is presented
Change From Baseline in Urine Protein Excretion (24 Hour)-Part 2 (NHL)
Time Frame: Baseline and Day 1 (Cycle 2)
Urine samples were collected to assess urine Protein. Baseline was the latest pre-dose assessment with a non-missing value, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in urine Protein excretion (24 hour) is presented.
Secondary Outcomes
- Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC[0-infinity]) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1(Pre-dose, 30 minutes post start of infusion (SOI), at end of infusion (EOI), 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- AUC[0-infinity] of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- AUC[0-tau] of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Area Under the Concentration-time Curve From Zero to Time of Last Quantifiable Concentration (AUC[0-tlast]) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- AUC[0-tlast]) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Clearance (CL) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- CL of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Maximum Observed Concentration (Cmax) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- Cmax of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Trough Plasma Concentration (Ctrough) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1), Pre-dose and EOI of Day 1 (Cycle 2 and Cycle 4))
- Ctrough of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1, Cycle 2 and Cycle 4))
- Terminal Half-life (t1/2) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- t1/2 of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Volume of Distribution at Steady State (Vss) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- Vss of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Time to Reach Maximum Observed Concentration (Tmax) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- Tmax of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Ctrough of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM-Part 2(Pre-dose and EOI of Day 1 (Cycle 1, Cycle 2 and Cycle 4))
- Ctrough of GSK2857916 Following IV Dose in Participants With NHL-Part 2(Pre-dose and EOI of Day 1 (Cycle 1, Cycle 2 and Cycle 3))
- AUC(0-tlast) of Cys Monomethyl Auristatin F (Cys-mcMMAF) Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- AUC(0-tlast) of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Cmax of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- Cmax of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Ctrough of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1), Pre-dose and EOI of Day 1 (Cycle 2 and Cycle 4))
- Ctrough of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1, Cycle 2 and Cycle 4))
- Tmax of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1(Pre-dose, 30 minutes post-SOI, at EOI, 1, 3, 8 and 24 hours post-EOI of Day 1 (Cycle 1))
- Tmax of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM-Part 1: GSK2857916 2.50 mg/kg(Pre-dose and EOI of Day 1 (Cycle 1))
- Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-drug Antibody Result- Part 1(Up to 21.6 months (maximum duration of follow-up from first dose to last contact or death))
- Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-drug Antibody Result- Part 2 (MM)(Up to 24.2 months (maximum duration of follow-up from first dose to last contact or death))
- Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-drug Antibody Result- Part 2 (NHL)(Up to 7.2 months (maximum duration of follow-up from first dose to last contact or death))
- Number of Participants With Antibodies to GSK2857916 in Serum Over Time- Part 1(Baseline, Day 1 (Cycle 2, 3, 4, 6, 9, 12, 16), End of study (within 30 days [+ 7 days of last treatment or prior to the start of new anti-cancer treatment], whichever is earlier) (1 cycle=21 days))
- Number of Participants With Antibodies to GSK2857916 in Serum Over Time- Part 2 (MM)(Baseline, Day 1 (Cycle 2, 3, 6, 7, 9, 11, 12, 16), End of study (within 30 days [+ 7 days of last treatment or prior to the start of new anti-cancer treatment], whichever is earlier) (1 cycle=21 days))
- Number of Participants With Antibodies to GSK2857916 in Serum Over Time - Part 2 (NHL)(Baseline, Day 1 (Cycle 2, 3), End of study (within 30 days [+ 7 days of last treatment or prior to the start of new anti-cancer treatment], whichever is earlier) (1 cycle=21 days))
- Overall Response Rate (ORR)- Part 1(From the Start of Treatment (at First Dose) up to the earlier of disease progression or the start of new anti-cancer therapy (maximum duration of follow-up is 21.6 months))
- ORR-Part 2 (MM)(From the Start of Treatment (at First Dose) up to the earlier of disease progression or the start of new anti-cancer therapy (maximum duration of follow-up is 24.2 months))
- ORR-Part 2 (NHL)(From the Start of Treatment (at First Dose) up to the earlier of disease progression or the start of new anti-cancer therapy (maximum duration of follow-up is 7.2 months))
- Clinical Benefit Rate (CBR)- Part 1(From the Start of Treatment (at First Dose) up to the earlier of disease progression or the start of new anti-cancer therapy (maximum duration of follow-up is 21.6 months))
- CBR- Part 2(From the Start of Treatment (at First Dose) up to the earlier of disease progression or the start of new anti-cancer therapy (maximum duration of follow-up is 24.2 months))