Clinical trial NCT04398745: A Study of Belantamab Mafodotin Monotherapy in Multiple Myeloma Participants With Normal and Varying Degree of Impaired Renal Function
Official title: A Phase I Study to Evaluate the Pharmacokinetics and Safety of Belantamab Mafodotin Monotherapy in Participants With Relapsed and/or Refractory Multiple Myeloma (RRMM) Who Have Normal and Varying Degrees of Impaired Renal Function (DREAMM 12)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Multiple Myeloma
Keywords: DREAMM12
End-stage renal disease
Normal renal function
Renal impairment
Relapsed and/or refractory multiple myeloma
Belantamab mafodotin
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2020-05-21
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Belantamab mafodotin is an antibody-drug conjugate (ADC) containing humanized anti- B-cell maturation antigen (BCMA) monoclonal antibody (mAb). Renal impairment is a major complication of multiple myeloma (MM) and the majority of MM participants is either at risk or already has renal dysfunction at initial diagnosis. The purpose of this study is to assess the pharmacokinetics (PK), safety, and tolerability of belantamab mafodotin monotherapy in participants with RRMM, who have had at least 3 lines of prior treatment (or at least 2 lines of prior treatment if ineligible for autologous stem cell transplantation ) and have either normal or impaired renal functions. The study will consist of two parts: part 1 will include participants with normal/mildly impaired renal function and severe renal impairment and part 2 will include participants with end-stage renal disease (ESRD), where participants are either not undergoing or require hemodialysis. Participants will be administered belantamab mafodotin at a dose of 2.5 milligram per kilogram (mg/kg) intravenously once in three weeks (Q3W) dosing in Part 1. Based on the Part 1 Safety/Pharmacokinetic (PK) data, Part 2 participants will be administered the dose of either 2.5 mg/kg or 1.9 mg/kg (or other adjusted dose). Participants will be treated with belantamab mafodotin monotherapy until confirmed disease progression, death, unacceptable toxicity, withdrawal of consent, or end of study, whichever occurs first. This study will include a screening phase, treatment phase, follow-up phase and a post analysis continued treatment (PACT) phase . The total duration of the study is approximately up to 48 months.


Eligibility criteria: Inclusion Criteria:

* Participants are capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form.
* Male and/or female participants must be 18 years of age or older, at the time of signing the informed consent. In Republic of Korea, participants must be 19 years of age or older at the time of signing informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
* Participants with histologically or cytologically confirmed diagnosis of MM, as defined in International Myeloma Working Group criteria: 1. Has undergone autologous stem cell transplant (SCT) or is considered transplant-ineligible; 2. Has failed at least 2 prior lines of anti-myeloma treatments, including an immunomodulatory drug (example \[e.g.\], lenalidomide or pomalidomide) and a proteasome inhibitor (e.g., bortezomib, ixazomib or carfilzomib). In Republic of Korea, participants should also have relapsed or refractory disease after treatment with an anti-CD38 antibody, if accessible to patients, or other suitable local standard of care.
* Participants have measurable disease with at least one of the following: Serum M-protein \>=0.5 grams per deciliter (g/dL) (\>=5 grams per liter \[g/L\]); Urine M-protein \>=200 milligrams (mg) per 24 hours (mg/24 h); and Serum free light chain (FLC) assay: Involved FLC level \>=10 milligrams per deciliter (mg/dL) (\>=100 milligrams per liter \[mg/L\]) and an abnormal serum FLC ratio (\<0.26 or \>1.65).
* Participants with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met: 1. Transplant was \>100 days prior to study enrollment, 2. No active infection(s), and 3. Participant meets the remainder of the eligibility criteria outlined in this protocol.
* Participants with adequate organ system functions as defined follows: Absolute neutrophil count \>=1.0 x 10\^9 per liter (/L); Hemoglobin \>=7.0 g/dL or 4.9 millimoles per liter (mmol/L); Platelets \>= 50 x 10\^9/L; Total bilirubin \<=1.5 x Upper limit of normal (ULN) (Isolated bilirubin \>=1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent \[%\]); Alanine aminotransferase \<=2.5 x ULN; iGFR, Group 1: normal/ mildly impaired \>=60milliliter per minute (mL/min); Group 2: severe 15-29 mL/min; Group 3: ESRD (not on dialysis) \<15 mL/min; Group 4: ESRD (on dialysis) \<15 mL/min; and left ventricular ejection fraction by echocardiograms \>=40%.
* Main additional inclusion criteria in Group 1 (matched control participants): Matched to at least one severely renal impaired participant by Baseline body weight (+/-20%) and Baseline albumin levels (+/-10%).
* Female participants: Contraceptive use by 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 \<1% per year), preferably with low user dependency, during the intervention period and for at least 4 months 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 within 72 hours of dosing on Cycle 1 Day 1 and agree to use highly effective contraception during the study and for 4 months after the last dose of study medication. 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.
* Male participants: Contraceptive use by men 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 from the time of first dose of study until 6 months after the last dose of study treatment to allow for clearance of any altered sperm: Refrain from donating sperm and 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 a male condom even if they have undergone a successful vasectomy and female partner to use an additional highly effective contraceptive method with a failure rate of \<1% per year as when having sexual intercourse with a WOCBP (including pregnant females).

Exclusion Criteria:

* Participants with active plasma cell leukemia at the time of screening. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, myeloma protein and skin changes), Waldenstroem Macroglobulinemia
* Participants had a prior allogeneic stem cell transplant. . Participants who have undergone a syngeneic bone marrow transplant will be allowed only if there is no history of, or no currently active graft-versus-host-diseases (GvHD).
* Participant has received an investigational drug within 14 days or 5 half-lives whichever is shorter, preceding the first dose of study drug. This includes prior treatment with a monoclonal antibody. The only exception is emergency use of a short course of systemic corticosteroids (equivalent to, or less than: dexamethasone 40 milligrams per day \[mg/day\] for a maximum of 4 days) before treatment.
* Prior belantamab mafodotin therapy.
* Participant has received a strong Organic-anion transporting polypeptide inhibitor within 14 days or 5 half-lives, whichever is shorter, preceding the first dose of study drug.
* Systemic active infection requiring treatment.
* Any unresolved toxicity \>=Grade 2 from previous treatment except for alopecia, or peripheral neuropathy up to Grade 2.
* Plasmapheresis within 7 days prior to the first dose of study drug. Screening laboratory values must be performed after last plasmapheresis.
* Any major surgery within the last 4 weeks prior to Day 1 of Screening.
* Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities except renal impairment) that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures.
* Evidence of active mucosal or internal bleeding.
* 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. (Stable chronic liver disease \[(including Gilbert's syndrome or asymptomatic gallstones\]) or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria)
* Participants with previous or concurrent malignancies other than MM are excluded, unless the prior malignancy has been considered medically stable for at least 2 years. The participant must not be receiving active therapy, other than hormonal therapy for this disease. (Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction)
* Evidence of cardiovascular risk including any of the following: Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram abnormalities such as second degree (Mobitz Type II) or third degree atrioventricular block; History of myocardial infarction (within prior 18 months), acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening; Class III or IV heart failure as defined by the New York Heart Association functional classification system and uncontrolled hypertension.
* Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, or any of the components of the study treatment.
* Known human immunodeficiency virus infection, unless the participant can meet all of the following criteria: Established anti-retroviral therapy (ART) for at least 4 weeks and HIV viral load \<400 copies/mL prior to first dose; CD4+ T-cell (CD4+) counts ≥350 cells/ L and no history of AIDS-defining opportunistic infections within the last 12 months
* Participants with Hepatitis B will be excluded unless the following criteria can be met: If the participant is hepatitis B core antibody (HbcAb) positive or hepatitis B surface antigen (HbsAg) negative, then hepatitis B virus (HBV) deoxyribonucleic acid (DNA) should be undectectable at the time of screening; If HbsAg+ at screening or \<=3 months prior to first dose of study treatment, then HBV DNA should be undetectable, highly effective antiviral treatment should be started ≥4 weeks prior to first dose of study treatment. Participants with cirrhosis are excluded.
* Positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid test result at Screening or within 3 months prior to first dose of study treatment unless the participant can meet the following criteria: RNA test negative and Successful anti-viral treatment (usually 8 weeks duration) is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks prior to first dose.
* Participants with renal impairment due to hepatic disease (hepatorenal syndrome).
* Current corneal epithelial disease except for mild punctuate keratopathy.
* Participant is a woman who is pregnant or breastfeeding.

Primary outcomes:
measure: Part 1: Maximum observed plasma concentration (Cmax) of GSK2857916
timeFrame: Up to Day 85
measure: Part 1: Time to Cmax (Tmax) of GSK2857916
timeFrame: Up to Day 85
measure: Part 1: Concentration of GSK2857916 at the end of infusion (C-EOI)
timeFrame: Cycle 1 up to Cycle 3: end infusion (EOI) (each cycle is 21 days)
measure: Part 1: Predose plasma concentration (Ctrough) of GSK2857916
timeFrame: Predose on Cycle 1 and up to Cycle 3 (each cycle is 21 days)
measure: Part 1: AUC over the dosing interval (AUC[0-tau]) of GSK2857916
timeFrame: Up to Day 85
measure: Part 1: Last time point where the concentration is above the limit of quantification (Tlast) of GSK2857916
timeFrame: Up to Day 85
measure: Part 1: Cmax of total monoclonal antibody (mAb)
timeFrame: Up to Day 85
measure: Part 1: Tmax of total mAb
timeFrame: Up to Day 85
measure: Part 1: Ctrough of total mAb
timeFrame: Predose on Cycle 1 and up to Cycle 3 (each cycle is 21 days)
measure: Part 1: C-EOI of total mAb
timeFrame: Cycle 1 up to Cycle 3: end infusion (EOI) (each cycle is 21 days)
measure: Part 1: AUC(0-tau) of total mAb
timeFrame: Up to Day 85
measure: Part 1: Tlast of total mAb
timeFrame: Up to Day 85
measure: Part 1: Cmax of Cys Monomethyl Auristatin F (cys-mcMMAF)
timeFrame: Up to Day 85
measure: Part 1: Tmax of cys-mcMMAF
timeFrame: Up to Day 85
measure: Part 1: C-EOI of cys-mcMMAF
timeFrame: Cycle 1 up to Cycle 3: end infusion (EOI) (each cycle is 21 days)
measure: Part 1: AUC(0-168 hours) of cys-mcMMAF
timeFrame: Predose and up to 168 hours
measure: Part 1: Tlast of cys-mcMMAF
timeFrame: Up to Day 85
measure: Part 2: Cmax of GSK2857916
timeFrame: Up to Day 85
measure: Part 2: Tmax of GSK2857916
timeFrame: Up to Day 85
measure: Part 2: C-EOI of GSK2857916
timeFrame: Cycle 1 up to Cycle 3: end infusion (EOI) (each cycle is 21 days)
measure: Part 2: Ctrough of GSK2857916
timeFrame: Predose on Cycle 1 and up to Cycle 3 (each cycle is 21 days)
measure: Part 2: AUC(0-tau) of GSK2857916
timeFrame: Up to Day 85
measure: Part 2: Tlast of GSK2857916
timeFrame: Up to Day 85
measure: Part 2: Cmax of total mAb
timeFrame: Up to Day 85
measure: Part 2: Tmax of total mAb
timeFrame: Up to Day 85
measure: Part 2: C-EOI of mAb
timeFrame: Cycle 1 up to Cycle 3: end infusion (EOI) (each cycle is 21 days)
measure: Part 2: Ctrough of total mAb
timeFrame: Predose on Cycle 1 up to Cycle 3 (each cycle is 21 days)
measure: Part 2: AUC(0-tau) of total mAb
timeFrame: Up to Day 85
measure: Part 2: Tlast of total mAb
timeFrame: Up to Day 85
measure: Part 2: Cmax of cys-mcMMAF
timeFrame: Up to Day 85
measure: Part 2: Tmax of cys-mcMMAF
timeFrame: Up to Day 85
measure: Part 2: C-EOI of cys-mcMMAF
timeFrame: Cycle 1 up to Cycle 3: end infusion (EOI) (each cycle is 21 days)
measure: Part 2: AUC(0-168 hours) of cys-mcMMAF
timeFrame: Predose and up to 168 hours
measure: Part 2: Tlast of cys-mcMMAF
timeFrame: Up to Day 85
Secondary outcomes:
measure: Part 1 and Part 2: Change from Baseline in Vital Signs- Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) (millimeter of mercury [mmHg])
timeFrame: Baseline and up to 48 months
measure: Part 1 and Part 2: Change from Baseline in Vital Sign- Heart rate (beats per minute)
timeFrame: Baseline and up to 48 months
measure: Part 1 and Part 2: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to 48 months
measure: Part 1 and Part 2: Number of participants with toxicity grading for clinical laboratory parameters
timeFrame: Up to 48 months
measure: Part 1 and Part 2: Change from baseline in physical examination parameter
timeFrame: Baseline and up to 48 months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Beverly Hills
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Plantation
country: United States
facility: GSK Investigational Site
state: Florida
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Westwood
country: United States
facility: GSK Investigational Site
state: Kansas
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: The Woodlands
country: United States
facility: GSK Investigational Site
state: Texas
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Busan
country: Korea, Republic of
facility: GSK Investigational Site
city: Incheon
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Singapore
country: Singapore
facility: GSK Investigational Site
city: Singapore
country: Singapore
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: