MC# 19-22 - A Phase I/II, Open-label, Dose Escalation and Expansion Study to Evaluate Safety, Tolerability, and Clinical Activity of the Antibody-Drug Conjugate GSK2857916 Administered in Combination With Lenalidomide Plus Dexamethasone (Arm A), or Bortezomib Plus Dexamethasone (Arm B) in Participants With Relapsed / Refractory Multiple Myeloma

  • Agent(s): GSK2857916
  • Disease Type(s): Myeloma
  • Phase(s): I, II
  • Drug Classification(s): Bispecific Antibodies
  • Molecular Target(s): BCMA

Mechanism of Action

GSK2857916 is a humanized anti BCMA monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin-F (MMAF), via a stable linker that allows for the release of the cytotoxic agent MMAF inside the cell leading to cell death.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of GSK2857916 can be given with an acceptable level of side effects when given in combination with standard of care regimens
  • The effects of GSK2857916 (good and bad) when given in combination with standard of care regimens
  • How long it takes the body to process and remove GSK2857916 from the blood stream
  • If research tests can be used in the future to predict who will benefit from GSK2857916
Inclusion Criteria
  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
  • Male or female, 18 years or older (at the time consent is obtained)
  • Have confirmed diagnosis of Multiple Myeloma as defined by the International Myeloma Working Group (IMWG) criteria
  • Eastern Cooperative Oncology Group (ECOG) performance status:
    • For Arm A only: 0 to 1
    • For Arm B only: 0 to 2
  • Have undergone autologous SCT, or are considered transplant ineligible
  • Have been previously treated with at least 1 prior line of MM therapy and must have documented disease progression during or after their most recent therapy according to the IMWG criteria
  • Must have at least ONE aspect of measurable disease, defined as one of the following:
    • Urine M-protein excretion ≥200 mg/24 h, or
    • Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or
    • Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain 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:
    • Autologous SCT was >100 days prior to study enrollment
    • No active bacterial, viral, or fungal infection(s) present
    • Participant meets the remainder of the eligibility criteria outlined in this protocol
  • 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 enrollment, except for alopecia.  Patients with Grade 2 neuropathy can be enrolled into Len/Dex treatment arm, but not into Bor/Dex treatment arm.
  • Adequate organ system functions as defined below:
    • Absolute neutrophil count (ANC) ≥1.5 × 109/L
    • Hemoglobin ≥8.0 g/dL
    • Platelets ≥75 × 109/L
    • Total bilirubin ≤1.5 × ULN; (Isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)
    • Alanine aminotransferase (ALT) ≤2.5 × ULN
    • eGFR ≥40 mL/min/1.73 m2
    • Spot urine (albumin/creatinine ratios from spot urine) ≤500 mg/g (56 mg/mmol)
    • Left Ventricular Ejection Fraction (LVEF) by ECHO ≥45%
  • Female participants must not be pregnant or breastfeeding, and must be either:
    • Is not a woman of childbearing potential (WOCBP)
    • 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
  • WOCBP Assigned to Arm A will be eligible if they commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment, during therapy, during dose interruptions and continuing for 120 days following discontinuation of treatment
  • Male participants must be either:
    • Abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
    • 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 from the time of first dose of study until 140 days after the last dose of study treatment
Exclusion Criteria
  • Systemic anti-myeloma therapy (including systemic steroids) within ≤14 days, or plasmapheresis within 7 days prior to the first dose of study drug
  • Use of an investigational drug within 14 days or five half-lives (whichever is longer) 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 allogenic stem cell transplant
    • Participants who have undergone syngeneic transplant will be allowed only if they have no history and no currently active, graft versus host disease (GvHD)
  • Evidence of active mucosal or internal bleeding
  • Any major surgery within the last four weeks
  • 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 fulfill criteria given in Adequate Organ System Function based on Safety Assessments.
  • 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
  • Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, or otherwise stable chronic liver disease per investigator's assessment)
  • Participants with invasive malignancies other than multiple myeloma are excluded, unless the second 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.
    • Note: Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction
  • Evidence of cardiovascular risk including any of the following:
    • QTcF interval > 480 msec (the QT interval values must be corrected for heart rate by Fridericia's formula [QTcF])
    • Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block
    • History of myocardial infarction, 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
    • Uncontrolled hypertension
  • Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to GSK2857916, or any of the components of the study treatment
  • Pregnant or lactating female
  • Active infection requiring treatment
  • Known 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 RNA test result at Screening or within 3 months prior to first dose of study treatment
    • Note: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.  Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
  • Current corneal disease except for mild punctuate keratopathy
    • Note: Participants with mild punctate keratopathy are allowed
  • Additional Exclusion Criteria for Participants Assigned to Arm A (GSK2857916 plus Len/Dex)
    • Participants unable to tolerate antithrombotic prophylaxis must be excluded
    • Discontinuation of prior treatment with lenalidomide due to intolerable adverse events
  • Additional Exclusion Criteria for Participants Assigned to Arm B (GSK2857916 plus Bor/Dex)
    • Unacceptable adverse effects from previous bortezomib treatment
    • Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain from previous bortezomib treatment
    • Intolerance or contraindications to anti-viral prophylaxis

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03544281

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Re: MC# 19-22