Phase 1
Completed N=38
Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Clinical Activity of GSK2857916
Source: ClinicalTrials.gov NCT02064387 ↗Enrolled (actual)
38
Serious AEs
41.8%
Results posted
Sep 2019
Primary outcomePrimary: Number of Participants With Serious Adverse Events (SAEs) and Common (>=5%) Non-serious Adverse Events- Part 1 — 1; 1; 4; 4 Participants
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).
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Serious Adverse Events (SAEs) and Common (>=5%) Non-serious Adverse Events- Part 1 |
1; 1; 4; 4; 3; 3 | — |
| PRIMARY Number of Participants With SAEs and Common (>=5%) Non-serious Adverse Events- Part 2 (MM) |
35; 17 | — |
| PRIMARY Number of Participants With SAEs and Common (>=5%) Non-serious Adverse Events- Part 2 (NHL) |
6; 3 | — |
| PRIMARY Number of Participants With Dose-limiting Toxicities (DLTs) During the Determinative Period- Part 1 |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Vital Signs-DBP & SBP-Part 1 |
0; 1; 2; 1; 2; 3 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Vital Signs-DBP & SBP-Part 2 (MM) |
30; 31 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Vital Signs-DBP & SBP-Part 2 (NHL) |
5; 5 | — |
| PRIMARY Number of Participants With Change From Baseline in Heart Rate and Temperature-Part 1 |
0; 0; 2; 1; 0; 0 | — |
| PRIMARY Number of Participants With Change From Baseline in Heart Rate and Temperature-Part 2 (MM) |
9; 17; 10; 1; 29; 5 | — |
| PRIMARY Number of Participants With Change From Baseline in Heart Rate and Temperature-Part 2 (NHL) |
3; 2; 1; 0; 5; 1 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 |
0; 0; 1; 1; 4; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 2 (MM) |
19; 0; 0; 1; 0; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 2 (NHL) |
2; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Part 1 |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Part 2 (MM) |
2; 20; 8; 7; 25; 4 | — |
| PRIMARY Number of Participants With Change From Baseline in Clinical Chemistry Data With Respect to Normal Range-Part 2 (NHL) |
0; 2; 0; 1; 2; 2 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Hematology Data-Part 2 (MM) |
1; 0; 0; 18; 7; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Hematology Data-Part 2 (NHL) |
0; 0; 0; 2; 0; 0 | — |
| PRIMARY Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Part 1 |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Part 2 (MM) |
0; 33; 2; 7; 26; 2 | — |
| PRIMARY Number of Participants With Change From Baseline in Hematology Data With Respect to Normal Range-Part 2 (NHL) |
0; 6; 0; 0; 6; 0 | — |
| PRIMARY Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method -Part 1 |
1; 1; 3; 3; 1; 2 | — |
| PRIMARY Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method -Part 2 (MM) |
18; 14; 1; 0; 15; 11 | — |
| PRIMARY Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method -Part 2 (NHL) |
4; 0; 0; 1; 3; 1 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.06 mg/kg |
-0.0; 0.3 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.03 mg/kg and 0.12 mg/kg |
0.4 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.24 mg/kg |
-0.0; -0.0; 88.1; -0.1; -0.0; -0.0 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.48 mg/kg |
0.0; 0.8; 0.1; 0.1; 0.1; 0.1 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 0.96 mg/kg |
0.2; -0.1; -0.1; 0.0; 0.2 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 1.92 mg/kg |
-0.1; -30.3; -22.4; 0.2; -0.6; -0.6 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 2.50 mg/kg |
0.8; -0.2; -0.2; 0.0; -0.2; 0.2 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 1: GSK2857916 3.40 mg/kg and 4.60 mg/kg |
-0.6; 0.0; -0.6; -0.0; -0.7; -0.1 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 2 (MM) |
-0.5; -0.7; -0.7; -0.7; -0.8; -0.9 | — |
| PRIMARY Change From Baseline in Urine Protein Excretion (24 Hour)-Part 2 (NHL) |
0.0 | — |
| SECONDARY 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 |
215803.06; 767285.51; 632339.28; 2991509.97; 9235256.20; 18469186.92 | — |
| SECONDARY AUC[0-infinity] of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY 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 |
200467.82; 633446.78; 729443.84; 2389114.19; 4448319.69; 9892863.42 | — |
| SECONDARY AUC[0-tau] of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY 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 |
44260.79; 178485.20; 637783.48; 694825.13; 2170746.96; 4492292.65 | — |
| SECONDARY AUC[0-tlast]) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Clearance (CL) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1 |
28.27; 10.53; 25.01; 15.10; 8.46; 11.68 | — |
| SECONDARY CL of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Maximum Observed Concentration (Cmax) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1 |
429.00; 1323.00; 2956.77; 4548.10; 11876.46; 23050.05 | — |
| SECONDARY Cmax of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Trough Plasma Concentration (Ctrough) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1 |
NA; 381.95; 1331.11; 4307.00; 3720.27; 11420.61 | — |
| SECONDARY Ctrough of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg |
3726.78; 11352.94; 11121.73 | — |
| SECONDARY Terminal Half-life (t1/2) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1 |
126.18; 188.20; 117.82; 198.48; 264.93; 308.39 | — |
| SECONDARY t1/2 of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Volume of Distribution at Steady State (Vss) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1 |
5239; 2900; 4286; 4388; 3224; 5156 | — |
| SECONDARY Vss of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Time to Reach Maximum Observed Concentration (Tmax) of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1 |
2.080; 4.080; 1.185; 3.085; 1.000; 2.050 | — |
| SECONDARY Tmax of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM - Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Ctrough of GSK2857916 Following IV Dose in Participants With Relapsed/Refractory MM-Part 2 |
3486.49; 5799.89; 6184.46 | — |
| SECONDARY Ctrough of GSK2857916 Following IV Dose in Participants With NHL-Part 2 |
0.0; 3761.8; 8401.0 | — |
| SECONDARY AUC(0-tlast) of Cys Monomethyl Auristatin F (Cys-mcMMAF) Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1 |
1157.46; 1623.87; 14681.62; 20787.48; 72608.00; 119177.30 | — |
| SECONDARY AUC(0-tlast) of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Cmax of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1 |
51.50; 91.49; 260.62; 488.29; 1054.02; 1199.86 | — |
| SECONDARY Cmax of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Ctrough of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Ctrough of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1: GSK2857916 2.50 mg/kg |
NA; NA; NA | — |
| SECONDARY Tmax of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM- Part 1 |
49.130; 23.875; 24.730; 9.050; 8.750; 23.700 | — |
| SECONDARY Tmax of Cys-mcMMAF Following IV Dose of GSK2857916 in Participants With Relapsed/Refractory MM-Part 1: GSK2857916 2.50 mg/kg |
— | — |
| SECONDARY Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-drug Antibody Result- Part 1 |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-drug Antibody Result- Part 2 (MM) |
— | — |
| SECONDARY Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-drug Antibody Result- Part 2 (NHL) |
— | — |
| SECONDARY Number of Participants With Antibodies to GSK2857916 in Serum Over Time- Part 1 |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants With Antibodies to GSK2857916 in Serum Over Time- Part 2 (MM) |
2; 28; 0; 2; 21; 3 | — |
| SECONDARY Number of Participants With Antibodies to GSK2857916 in Serum Over Time - Part 2 (NHL) |
0; 5; 5; 0; 4; 4 | — |
| SECONDARY Overall Response Rate (ORR)- Part 1 |
0; 0; 0; 0; 0; 1 | — |
| SECONDARY ORR-Part 2 (MM) |
21 | — |
| SECONDARY ORR-Part 2 (NHL) |
— | — |
| SECONDARY Clinical Benefit Rate (CBR)- Part 1 |
0; 0; 0; 1; 1; 1 | — |
| SECONDARY CBR- Part 2 |
21 | — |
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 1.
- 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 ( 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) =60 mL/min for Part 1;>=50 mL/minute (min) for Part 2 if data supports loosening criteria, Albuminuria =50%, Troponin =470 millisecond, evidence of current clinically significant uncontrolled arrhythmias, 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 functional classification system, uncontrolled hypertension, subjects with intra-cardiac defibrillators or permanent pacemakers, abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2857916 or any of the components of the study treatment.
- Pregnant or lactating female.
- Known human immuno virus infection.
- Subjects with positive test for Hepatitis B surface (HBS-Ag) or Hepatitis B core (HBc)antigen
- Subjects with positive test for hepatitis C (HCV) infection are excluded regardless of viral loa
Data sourced from ClinicalTrials.gov (NCT02064387). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.