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

NCT ID: NCT03848845

Last Updated: 2024-04-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-14
• Study Completion Date: 2023-06-14

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1: Dose escalation

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.

Group Type: EXPERIMENTAL

belantamab mafodotin

Intervention Type: 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.

Pembrolizumab

Intervention Type: 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 2: Expansion cohort

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.

Group Type: EXPERIMENTAL

belantamab mafodotin

Intervention Type: 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.

Pembrolizumab

Intervention Type: 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.

Interventions

belantamab mafodotin

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.

Intervention Type: DRUG

Pembrolizumab

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.

Intervention Type: DRUG

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.
• 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.
• A female subject 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 120 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.
• 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.

• 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.
• Known active infection requiring antibiotic, antiviral, or antifungal treatment.
• Known Human Immunodeficiency Virus (HIV) infection.
• 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 treatment
• 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 treatment.
• Has received a live-virus vaccination within 30 days of planned start of study therapy.
• Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other chronic form of immunosuppressive therapy within 7 days prior the first dose of study therapy.
• Has known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.
• Has had an allogenic tissue/solid organ transplant

Exclusion Criteria

A subject will NOT be eligible for inclusion in this study if any of the following criteria apply:

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Atlanta, Georgia, United States

GSK Investigational Site

Indianapolis, Indiana, United States

GSK Investigational Site

Charlotte, North Carolina, United States

GSK Investigational Site

Madison, Wisconsin, United States

GSK Investigational Site

Calgary, Alberta, Canada

GSK Investigational Site

Toronto, Ontario, Canada

GSK Investigational Site

Hanover, Lower Saxony, Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Hamburg, , Germany

GSK Investigational Site

Badalona, , Spain

GSK Investigational Site

Pozuelo de Alarcón/Madrid, , Spain

GSK Investigational Site

Salamanca, , Spain

Countries

United States; Canada; Germany; Spain

References

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.

Reference Type: DERIVED

PMID: 38630908 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

KEYNOTE PN489

Identifier Type: OTHER

Identifier Source: secondary_id

2018-002816-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

205207

Identifier Type: -

Identifier Source: org_study_id