Study Evaluating Safety, Tolerability and Clinical Activity of GSK2857916 in Combination With Pembrolizumab in Subjects With Relapsed/Refractory Multiple Myeloma (RRMM)

NCT03848845 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 205207KEYNOTE PN4892018-002816-29
• Study Type: interventional
• Target: 41
• Locations: 4 countries
• Sites: 12

Brief Summary

This is a phase I/II, single arm, open label, two-part study that will assess safety, tolerability and clinical activity of GSK2857916 given in combination with a programmed cell death-1 (PD-1) inhibitor pembrolizumab in subjects with RRMM. This study will enroll adult subjects with RRMM, who have undergone stem cell transplant or who are considered transplant ineligible. Part 1 is a dose escalation phase to evaluate the safety and tolerability of escalating doses of GSK2857916 in combination with 200 milligrams (mg) pembrolizumab to establish the recommended phase 2 dose (RP2D). The following dose levels of GSK2857916 are planned to be studied: 2.5 milligrams per kilograms (mg/kg) (dose level \[DL\] 1) and 3.4 mg/kg (DL2). Part 2 is a dose expansion cohort. Once the RP2D has been identified, an expansion cohort will open for enrolment to confirm the safety profile and to evaluate the clinical activity of the combination. Up to 40 evaluable subjects will be enrolled in this two-part study (up to 12 in Part 1, and 28 in Part 2).

Conditions

Multiple Myeloma

Keywords

GSK2857916, Pembrolizumab, Multiple Myeloma, RP2D

Outcome Measures

Primary Outcomes (12)

• Part 1 - Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE is any untoward medical occurrence in a clinical investigation 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 hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function.

  Up to approximately 31 months

• Part 1 - Number of Participants With Dose Limiting Toxicities (DLTs)

  DLT is an AE that is considered by the investigator to be clinically relevant and attributed to the study therapy during the 21 day DLT period and meets at least one of the DLT criteria: any Grade 4 and 3 non-hematologic toxicity, any Grade 3 or greater non-hematologic laboratory value, hematologic toxicity lasting \>=7 days, except Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia associated with clinically significant bleeding. Grade 3 or greater febrile neutropenia lasting \>48 hours (h) despite adequate treatment, Nephrotoxicity requiring dialysis, Liver toxicity, prolonged delay (\>14 days) in initiating Cycle 2 due to any treatment (pembrolizumab or GSK2857916) related toxicity, any treatment-related toxicity that causes discontinuation of treatment during Cycle 1, any other toxicity considered to be dose-limiting that occurs beyond 21 days and any other event which in the judgment of the investigator and GlaxoSmithKline Medical Monitor is considered to be a DLT.

  Up to 21 days

• Part 1 - Number of Participants With Worst-case Grade Change From Baseline in Hematology Parameters

  Blood samples were collected for the analysis of following hematology parameters: hemoglobin, White blood cells (WBC) count, lymphocytes, neutrophils and platelet count. The laboratory parameters were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Any worst-case post baseline increase in grade along with any increase to a maximum grade of 3 and a maximum grade of 4 are presented.

  Baseline (Day 1) and up to approximately 31 months

• Part 1 - Number of Participants With Worst-case Change Post-baseline in Hematology Parameters

  Blood samples were collected for the analysis of following hematology parameters: basophils, eosinophils, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), erythrocytes, hematocrit, monocytes, neutrophils and reticulocyte. The summaries of worst-case change from baseline with respect to normal range was analyzed for only those laboratory tests that were not gradable by CTCAE version 4.03. The number of participants with decreases to low from baseline, changes to normal or no changes from baseline, and increases to high values have been presented.

  Baseline (Day 1) and up to approximately 31 months

• Part 1 - Number of Participants With Worst-case Grade Change From Baseline in Lab Chemistry Parameters

  Blood samples were collected for the analysis of clinical chemistry parameters: glucose, alanine aminotransferase (ALT), albumin, alkaline phosphatase, aspartate aminotransferase (AST), blood bilirubin, calcium, creatine kinase (CPK), creatinine, gamma glutamyl transferase (GGT), magnesium, phosphate, potassium and sodium. Laboratory parameters were graded according to NCI-CTCAE version 4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Any worst case post baseline increase in grade along with any increase to a maximum grade of 3 and a maximum grade of 4 are presented.

  Baseline (Day 1) and up to approximately 31 months

• Part 1 - Number of Participants With Worst-case Change Post-baseline in Lab Chemistry Parameters

  Blood samples were collected for the analysis of following chemistry parameters: calcium, carbon dioxide, chloride, direct bilirubin, protein, thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3). The summaries of worst case change from baseline with respect to normal range was analyzed for only those laboratory tests that were not gradable by CTCAE version 4.03. The number of participants with decreases to low from baseline, changes to normal or no changes from baseline, and increases to high values have been presented.

  Baseline (Day 1) and up to 31 months

• Part 1 - Number of Participants With Worst-case Change Post-baseline Urinalysis Results

  Urine samples were collected to assess urine glucose, protein, occult blood and ketones using dipstick method. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Result for urinalysis parameters were recorded as no change/decreased and any increase. Data for worst-case post baseline urinalysis results is presented.

  Baseline (Day 1) and up to approximately 31 months

• Part 1 - Changes From Baseline in Urine Potential of Hydrogen (pH)

  Urine samples were collected from participants to assess urine pH levels. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date.

  Baseline (Day 1) and Week 46

• Part 1 - Changes From Baseline in Urine Specific Gravity

  Urine samples were collected from participants to assess urine specific gravity. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date.

  Baseline (Day 1) and Week 46

• Part 1 - Number of Participants With Worst-case Grade Change From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

  DBP and SBP were measured after resting for at least 5 minutes in a supine or semi-recumbent position. They were graded according to NCI-CTCAE version 4.03. For SBP: Grade 0 (\<=120 millimeter of mercury \[mmHg\]), Grade 1 (121-139 mmHg), Grade 2 (140-159 mmHg), Grade 3 (\>=160 mmHg). For DBP: Grade 0 (\<=80 mmHg), Grade 1 (81-89 mmHg), Grade 2 (90-99 mmHg), Grade 3 (\>=100 mmHg). Higher grade indicates greater severity. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post baseline with any grade increase and a maximum post-baseline grade increase to Grade 3 from their baseline grade are presented.

  Baseline (Day 1) and up to approximately 31 months

• Part 1 - Number of Participants With Worst-case Change From Baseline in Vital Signs: Pulse Rate and Body Temperature

  Vital signs (pulse rate and temperature) were measured after resting for at least 5 minutes in a supine or semi-recumbent position. The abnormal vital sign ranges were: For pulse rate (low \<60 beats per minute \[bpm\] and high \>100 bpm); For body temperature (\<=35 degrees Celsius or \>=38 degrees Celsius). Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst case change from baseline was presented as Baseline to low, Baseline to Normal or No change and Baseline to High.

  Baseline (Day 1) and up to approximately 31 months

• Part 2 - Percentage of Participants With Overall Response Rate (ORR)

  ORR was defined as the percentage of participants with a confirmed partial response (PR) or better (i.e., PR, very good partial response \[VGPR\], complete response \[CR\] and stringent complete response \[sCR\]), according to the International Myeloma Working Group (IMWG) Response Criteria. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component \<100 mg/24 h; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 h.

  Up to approximately 31 months

Secondary Outcomes (74)

• Part 1 - Percentage of Participants With Overall Response Rate (ORR)

  Up to approximately 178 weeks

• Part 2 - Number of Participants With AEs and SAEs

  Up to approximately 178 weeks

• Part 2 - Number of Participants With Worst-case Grade Change From Baseline in Hematology Parameters

  Baseline (Day 1) and up to approximately 178 weeks

• Part 2 - Number of Participants With Worst-case Change Post-baseline in Hematology Parameters

  Baseline (Day 1) and up to approximately 178 weeks

• Part 2 - Number of Participants With Worst-case Grade Change From Baseline in Lab Chemistry Parameters

  Baseline (Day 1) and up to approximately 178 weeks

Study Arms (2)

Part 1: Dose escalation

EXPERIMENTAL

Subjects will receive belantamab mafodotin at escalating doses of 2.5 milligrams per kilograms (mg/kg) and 3.4 mg/kg along with 200 mg pembrolizumab via intravenous (IV) infusion on Day 1 of each 21-day cycle to establish RP2D. There will be maximum of 35 cycles of combination treatment.

Drug: belantamab mafodotin; Drug: Pembrolizumab

Part 2: Expansion cohort

EXPERIMENTAL

Subjects will receive belantamab mafodotin at RP2D along with 200 mg pembrolizumab via IV infusion on Day 1 of each 21-day cycle. There will be maximum of 35 cycles of combination treatment.

Drug: belantamab mafodotin; Drug: Pembrolizumab

Interventions

belantamab mafodotin DRUG

belantamab mafodotin will be available as 20 milligrams per millilitre (mg/mL) solution for IV infusion, supplied as frozen liquid. belantamab mafodotin solution will be diluted in normal 0.9% saline to the appropriate concentration for the dose.

Part 1: Dose escalation; Part 2: Expansion cohort

Pembrolizumab DRUG

Pembrolizumab will be available as 100 mg/4 mL solution that should be stored under refrigeration at 2-8 degree Celsius. Pembrolizumab injection (solution) will be diluted prior to IV administration in 0.9% sodium chloride injection or 5% dextrose injection.

Part 1: Dose escalation; Part 2: Expansion cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Subjects must: have histologically or cytologically confirmed diagnosis of Multiple myeloma (MM), as defined by IMWG, 2014 and has undergone stem cell transplant or is considered transplant ineligible, and has been treated with at least 3 prior lines of prior anti-myeloma treatments including an immunomodulatory imide drug (IMiD) (eg. lenalidomide or pomalidomide), a proteasome inhibitor (eg. bortezomib, ixazomib or carfilzomib) and an anti-CD38 antibody alone or in combination. Line of therapy are defined by consensus panel of the International Myeloma Workshop, Has measurable disease defined as one the following: a) Serum M-protein \>=0.5 grams per deciliter (g/dL) (\>=5 grams per liter \[g/L\]). b) Urine M-protein ≥200 mg/24h. c) 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 free light chain ratio (\<0.26 or \>1.65).
• Subjects with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met: a) transplant was \> 100 days prior to study enrolment. b) no active infection(s). c) subject meets the remainder of the eligibility criteria.
• Adequate organ system functions as defined by the laboratory assessments.
• All prior treatment-related toxicities (defined by National Cancer Institute-Common Toxicity Criteria for Adverse Events \[NCI-CTCAE\], version 4.03, 2010) must be \<= Grade 1 at the time of enrolment except for alopecia and Grade 2 neuropathy.
• Male subjects are eligible to participate if they agree to the following during the intervention period and for at least 140 days after the last dose of study intervention. Male subjects should 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 a male condom and female partner to use an additional highly effective contraceptive method with a failure rate of \<1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.

You may not qualify if:

• Systemic anti-myeloma therapy or an investigational drug \<=14 days or five half-lives, whichever is shorter, preceding the first dose of study drug
• Plasmapheresis within 7 days prior to the first dose of study drug
• Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drugs
• Has received prior therapy with an anti-PD-1, anti-Programmed cell death Ligand 1 (PD-L1), or anti-Programmed cell death Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated antigen 4 \[CTLA-4\], OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune related adverse event (irAE)
• Current corneal epithelial disease except mild punctate keratopathy
• Any major surgery within the last four weeks prior to the first dose of study therapy
• 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.
• Has received prior radiotherapy within 2 weeks of start of study therapy. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (\<=2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
• History of (non-infectious) pneumonitis that required steroids, or current pneumonitis
• Current active liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
• Malignancies other than disease under study are excluded, except for any other malignancy from which the subject 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 (RRMM). Subjects with curatively treated non-melanoma skin cancer are allowed.
• Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study therapy
• Evidence of cardiovascular risk including any of the following: a) corrected for heart rate by Fridericia's formula (QTcF) interval ≥470 msecs. b) Evidence of current clinically significant uncontrolled arrhythmias; i. including clinically significant ECG abnormalities including 2nd degree (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 six months of Screening. d) Class III or IV heart failure as defined by the New York Heart Association functional classification system. e) Uncontrolled hypertension. f) Presence of cardiac pacemaker (or defibrillator) with a predominantly ventricular paced rhythm, limiting ECG/QTcF analysis. g) 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 pembrolizumab, or any of the components of the study treatment.
• Pregnant or lactating female.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (12)

GSK Investigational Site

Atlanta, Georgia, 30322, United States

Location

GSK Investigational Site

Indianapolis, Indiana, 46202, United States

Location

GSK Investigational Site

Charlotte, North Carolina, 28204, United States

Location

GSK Investigational Site

Madison, Wisconsin, 53792, United States

Location

GSK Investigational Site

Calgary, Alberta, T2N 2T9, Canada

Location

GSK Investigational Site

Toronto, Ontario, M5G 2M9, Canada

Location

GSK Investigational Site

Hanover, Lower Saxony, 30625, Germany

Location

GSK Investigational Site

Berlin, 12200, Germany

Location

GSK Investigational Site

Hamburg, 20246, Germany

Location

GSK Investigational Site

Badalona, 08916, Spain

Location

GSK Investigational Site

Pozuelo de Alarcón/Madrid, 28223, Spain

Location

GSK Investigational Site

Salamanca, 37007, Spain

Location

Related Publications (1)

• Suvannasankha A, Bahlis N, Trudel S, Weisel K, Koenecke C, Oriol A, Voorhees PM, Alonso AA, Callander NS, Mateos MV, Reddy N, Hakim S, LaMacchia J, Patel N, Williams D, Jewell RC, Zhou X, Gupta I, Opalinska J, Nooka AK. Safety and efficacy of belantamab mafodotin with pembrolizumab in patients with relapsed or refractory multiple myeloma. Cancer. 2024 Aug 1;130(15):2629-2641. doi: 10.1002/cncr.35319. Epub 2024 Apr 17.

  PMID: 38630908 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

belantamab mafodotin; pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: This will be an open-label study. Hence, there will be no masking.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects will receive GSK2857916 at escalating doses along with pembrolizumab on Day 1 of each 21-day Cycle to establish RP2D during the Part 1 of the study. Subjects will receive GSK2857916 at RP2D along with pembrolizumab on Day 1 of each 21-day Cycle in Part 2 of the study.

Study Record Dates

• First Submitted: February 19, 2019
• First Posted: February 21, 2019
• Study Start: March 14, 2019
• Primary Completion: October 18, 2021
• Study Completion: June 14, 2023
• Last Updated: April 9, 2024
• Results First Posted: December 23, 2022

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

CA (2); US (4); DE (3); ES (3)