A Study of Belantamab Mafodotin to Investigate Safety, Tolerability, Pharmacokinetics, Immunogenicity and Clinical Activity in Participants With Relapsed/Refractory Multiple Myeloma (RRMM)
Study Details
Study Description
Brief Summary
Multiple myeloma (MM) is a neoplastic plasma cell disorder that is characterized by osteolytic bone lesions, anemia, hypercalcemia and renal failure. belantamab mafodotin was well tolerated in previous studies with at least one dose of belantamab mafodotin in heavily pre-treated participants with relapsed/refractory multiple myeloma (RRMM). This aim of the study is to explore safety, pharmacokinetics (PK), tolerability, immunogenicity and clinical activity of belantamab mafodotin monotherapy in Chinese participants with RRMM who have received at least 2 prior line of anti-myeloma therapy including an alkylator, a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD). This study will include two dose cohorts 2.5 milligram per kilogram (mg/kg) and 3.4 mg/kg. A maximum of 12 participants will be enrolled, 6 each for 2.5 mg/kg cohort and 3.4 mg/kg cohort based on 3+3 design. Participants will be treated until disease progression, intolerable toxicity, end of study or informed consent withdrawal.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Chinese participants with relapsed/refractory multiple myeloma Participants will be administered belantamab mafodotin 2.5 mg/kg or 3.4 mg/kg as an intravenous infusion on Day 1 of each 21-day cycle over 30 minutes. Participants will be treated until disease progression, intolerable toxicity, end of study or informed consent withdrawal. |
Drug: Belantamab mafodotin
Belantamab mafodotin will be available as lyophilized powder 100 mg/vial in single-use vial for reconstitution. It will be administered at a calculated dose of 2.5 mg/kg or 3.4 mg/kg as an IV infusion on Day 1 of each cycle over 30 minutes.
|
Outcome Measures
Primary Outcome Measures
- Number of participants with Adverse events (AEs) [Up to 15 months]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention.
- Number of participants with serious adverse events (SAEs) [Up to 15 months]
An 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; important medical events that may jeopardize the participant or may require medical or surgical intervention; is associated with liver injury and impaired liver function.
- Number of participants with dose limited toxicities (DLTs) [Day 1 to Day 21 (Cycle 1)]
The number of participants with DLTs will be reported.
Secondary Outcome Measures
- Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (Millimeters of mercury) [Baseline and up to 15 months]
SBP and DBP will be measured after 5 minutes of rest at given time point.
- Change from Baseline in temperature (degrees Celsius) [Baseline and up to 15 months]
Temperature will be measured after 5 minutes of rest at given time point.
- Change from Baseline in pulse rate (beats per minute) [Baseline and up to 15 months]
Pulse rate will be measured after 5 minutes of rest at given time point.
- Change from Baseline in hematology parameters: platelet count, absolute white blood cells (WBC), reticulocyte count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils count (Giga cells per Liter) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of hematology parameters.
- Change from Baseline in hematology parameter: Red Blood Cell (RBC) Count (Trillion cells per liter) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of hematology parameters.
- Change from Baseline in hematology parameter: Hematocrit (Proportion of red blood cells in blood) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of hematology parameter.
- Change from Baseline in hematology parameter: Mean Corpuscular Hemoglobin (MCH) (Picograms) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of hematology parameters.
- Change from Baseline in hematology parameter: Mean Corpuscular Volume (MCV) (Femtoliters) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of hematology parameters.
- Change from Baseline in hematology parameter: Hemoglobin, Mean Corpuscular Hemoglobin concentration (MCHC) (Grams per Liter) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of hematology parameters.
- Change from Baseline in chemistry parameters: Blood urea nitrogen (BUN), Creatinine, Glucose, Calcium, Sodium, Potassium, Phosphorous, Chloride, Magnesium, Uric Acid, Carbon dioxide (CO2), Total and direct bilirubin (Millimoles per Liter) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of chemistry parameters.
- Change from Baseline in chemistry parameter: estimated glomerular filtration rate (eGFR) (milliliter per minute per 1.73 meter square) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of chemistry parameters.
- Change from Baseline in chemistry parameters: Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine kinase, Gamma Glutamyl Transferase (GGT), Lactate dehydrogenase (LDH) (International units per Liter) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of chemistry parameters.
- Change from Baseline in chemistry parameters: Albumin, Total Protein (grams per liter) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of chemistry parameters.
- Change from Baseline in chemistry parameter: Albumin/creatinine ratio (ratio) [Baseline and up to 15 months]
Blood samples will be collected at indicated time points for analysis of chemistry parameters.
- Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio) [Baseline and up to 15 months]
Urine samples will be collected at indicated time points for the assessment of specific gravity.
- Change from Baseline in Urinalysis Parameter: Urine potential of hydrogen (pH) [Baseline and up to 15 months]
Urine samples will be collected at indicated time points for the assessment of potential of hydrogen blood.
- Change from Baseline in urinalysis parameter: Glucose and ketones (Millimole per liter) [Baseline and up to 15 months]
Urine samples will be collected at indicated time points for the assessment of urine glucose.
- Change from Baseline in urinalysis parameter: Protein (Grams per liter) [Baseline and up to 15 months]
Urine samples will be collected at indicated time points for the assessment protein.
- Change from Baseline in urinalysis parameter: blood (10^9 cells per liter) [Baseline and up to 15 months]
Urine samples will be collected at indicated time points for the assessment blood in urine.
- Area under the plasma concentration-time curve from time zero to time t (AUC[0-t]) after single dose of belantamab mafodotin (antibody-drug conjugate (ADC)) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- AUC(0-t) after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- AUC(0-t) after single dose of belantamab mafodotin (cys- monomethyl auristatin-F [mcMMAF]) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC[0-infinity]) after single dose of belantamab mafodotin (ADC) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- AUC(0-infinity) after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Maximum observed plasma concentration (Cmax) after single dose of belantamab mafodotin (ADC) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Cmax after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Cmax after single dose of belantamab mafodotin (cys-mcMMAF) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Time to Cmax (tmax) after single dose of belantamab mafodotin (ADC) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- tmax after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- tmax after single dose of belantamab mafodotin (cys-mcMMAF) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Last time point where the concentration is above the limit of quantification (tlast) after single dose of belantamab mafodotin (ADC) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- tlast after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Systemic clearance (CL) after single dose of belantamab mafodotin (ADC) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- CL after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Volume of distribution at steady state (Vss) after single dose of belantamab mafodotin (ADC) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Vss after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Terminal phase elimination rate (Lambda Z) after single dose of belantamab mafodotin (ADC) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Lambda Z after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Terminal phase half-life (t1/2) after single dose of belantamab mafodotin (ADC) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- t1/2 after single dose of belantamab mafodotin (total antibody) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- t1/2 after single dose of belantamab mafodotin (cys-mcMMAF) [Day 1 to Day 21 (Cycle 1)]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Trough concentration (Ctrough) after repeat dose of belantamab mafodotin (ADC) [Day 1 and Up to 15 months]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Ctrough after repeat dose of belantamab mafodotin (total antibody) [Day 1 and Up to 15 months]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Ctrough after repeat dose of belantamab mafodotin (cys-mcMMAF) [Day 1 and Up to 15 months]
Blood samples will be collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin.
- Number of subjects with abnormal ocular findings [Up to 15 months]
Ocular examination for the subjects will include procedures for corrected visual acuity, current glasses, pupillary examination, extra ocular muscular movements, intra-ocular pressure, examination of tear film, and examination of cornea.
- Percentage of participants with Objective Response Rate (ORR) [Up to 15 months]
Objective Response is defined as the confirmed partial response (PR) or better (i.e stringent complete response (sCR), complete response (CR), very good partial response (VGPR), as assessed by International myeloma working group (IMWG) Response Criteria and will be analyzed at given time point.
- Number of participants with Anti-drug antibodies (ADAs) against belantamab mafodotin [Up to 15 months]
Serum samples will be collected at the time points indicated to analyze the titers of antibodies against belantamab mafodotin.
- Titers of ADAs against belantamab mafodotin [Up to 15 months]
Serum samples will be collected at the time points indicated to analyze the titers of antibodies against belantamab mafodotin.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Provide signed written informed consent, which includes compliance with requirements and restrictions listed in the consent form.
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Male or female, 18 years or older (at the time consent is obtained).
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Eastern Cooper Oncology Group (ECOG) performance status of 0-2.
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Histological or cytologically confirmed diagnosis of MM as defined according to IMWG criteria and a) Has undergone stem cell transplant or transplant is considered not feasible by local assessment, b) Has failed at least 2 prior lines of anti-myeloma treatments, containing all of the following classes of drugs: alkylating agent, IMID and PI, c) In addition, eligible participant needs to be refractory to an IMiD (i.e.,lenalidomide or pomalidomide), and to a proteasome inhibitor (i.e., bortezomib, ixazomib or carfizomib) as defined by International Myeloma Working Group (IMWG) criteria, d) Participants who failed with cluster of differentiation38 (CD38) antibody (i.e., daratumumab) in previous clinical trials can also be considered to include if they meet the remainder of inclusion criteria in this protocol.
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Has measurable disease with at least one of the following: a) Serum M-protein greater than or equal to 0.5 grams per deciliter (g/dL) (5 g/L) , b) Urine M-protein greater than or equal to 200 mg/24hour, c) Serum Free light chain (FLC) assay: Involved FLC level greater than or equal to10 mg/dL (greater than or equal to 100 mg/L) and an abnormal serum free light chain ratio (less than 0.26 or greater than 1.65)
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Participants with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met: a) Transplant was greater than 100 days prior to study enrolment, b) No active infection(s), c) Participant meets the remainder of the eligibility criteria outlined in this protocol.
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Adequate organ system functions.
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Female Participants: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) or is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of less than 1 percent per year), preferably with low user dependency, during the intervention period and for at least 80 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
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Male Participants: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 140 days: Refrain from donating sperm, plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. or Must agree to use contraception/barrier as detailed below: Agree to use a male condom and female partner to use an additional highly effective contraceptive method with a failure rate of less than 1 percent per year as when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.
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All prior treatment-related toxicities (defined by National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 must be less than or equal to Grade 1 at the time of enrolment except for alopecia and Grade 2 peripheral neuropathy.
Exclusion Criteria:
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Systemic anti-myeloma therapy within less than 14 days, or plasmapheresis within 7 days prior to the first dose of study drug.
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Symptomatic amyloidosis, active polyneuropathy,organomegaly, endocrinopathy, myeloma protein, and skin changes (POEMS) syndrome, active plasma cell leukemia at the time of screening.
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Prior allogeneic stem cell transplant (SCT).
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Current corneal epithelial disease except mild punctate keratopathy.
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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 drugs. Prior B-cell maturation antigen (BCMA) targeted therapy.
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Evidence of active mucosal or internal bleeding.
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Any major surgery within the last four weeks.
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Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil criteria.
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Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures.
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Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
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Malignancies other than disease under study are excluded, except for any other malignancy from which the participant has been disease-free for more than 2 years and, in the opinion of the principal investigators and GSK Medical Monitor, will not affect the evaluation of the effects of this clinical trial treatment on the currently targeted malignancy (MM).
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Evidence of cardiovascular risk including any of the following: a) corrected QT internal Fridericia (QTcF) interval greater than equal to 480 milliseconds (msecs), b) Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block, c) History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within three months of Screening, d) Class III or IV heart failure as defined by the New York Heart Association functional classification system, e) Uncontrolled severe hypertension, e.g. 170/110.
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Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab mafodotin, or any of the components of the study intervention.
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Pregnant or lactating female.
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Active infection requiring antibiotic, antiviral, or antifungal treatment.
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Known human immunodeficiency virus (HIV) infection.
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Presence of hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb at screening or within 3 months prior to first dose of study intervention).
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Positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | GSK Investigational Site | Beijing | China | 100044 | |
| 2 | GSK Investigational Site | Beijing | China | 100191 | |
| 3 | GSK Investigational Site | Jiang Su Province | China | 215006 |
Sponsors and Collaborators
- GlaxoSmithKline
Investigators
- Study Director: GSK Clinical Trials, GlaxoSmithKline
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 208465