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A Study of Belantamab Mafodotin in Patients With Relapsed or Refractory AL Amyloidosis (EMN27)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04617925
Recruitment Status : Recruiting
First Posted : November 5, 2020
Last Update Posted : March 3, 2021
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
European Myeloma Network

Brief Summary:

This is an open-label, multicenter, Phase 2 study in subjects with previously treated patients with light chain (AL) amyloidosis in need for therapy.

Approximately 35 subjects will receive therapy with belantamab mafodotin. Subject participation will include a Screening Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term Follow-up Phase.

A safety run-in will be conducted in 6 subjects treated with belantamab mafodotin for at least 1 cycle.

According to the two-stage statistical design of the study, an interim analysis of efficacy will occur. If after 15 patients have been enrolled at least 3 complete or very good partial responses have been recorded, the accrual will continue until all planned patients have been enrolled


Condition or disease Intervention/treatment Phase
AL Amyloidosis Drug: Belantamab mafodotin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Belantamab Mafodotin in Patients With Relapsed or Refractory AL Amyloidosis
Actual Study Start Date : February 26, 2021
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis
Drug Information available for: Belantamab

Arm Intervention/treatment
Experimental: belantamab mafodotin
Belantamab mafodotin will be administered as an IV infusion at a dose of 2.5 mg/kg every six weeks until progression of disease, unacceptable toxicity or subsequent therapy, for a maximum of eight doses (approximately 12 months), according to the response adapted modifications
Drug: Belantamab mafodotin
Belantamab mafodotin will be administered as a monotherapy intravenously at a 2.5 mg/kg calculated dose




Primary Outcome Measures :
  1. response rate [ Time Frame: at 6 months (cycle 4) ]
    Complete Response (CR)/ Very Good Partial Response (VGPR)/ <50 mg/L difference between involved minus uninvolved serum free lights chains (low-dFLC) according to the consensus recommendations for AL amyloidosis treatment response criteria


Secondary Outcome Measures :
  1. Adverse events [ Time Frame: up to 70 days after last dose ]
    Rates of grade 3 or higher AEs related to blmf therapy

  2. Treatment discontinuation [ Time Frame: up to 1 year ]
    Rates of treatment discontinuation due to toxicity related to blmf

  3. Dose reduction [ Time Frame: up to 1 year ]
    Dose reduction due to toxicity of blmf therapy

  4. Hematologic AEs [ Time Frame: up to 70 days after last dose ]
    rates of any hematologic adverse events

  5. Non-hematologic AEs [ Time Frame: up to 70 days after last dose ]
    rates of any non-hematologic adverse events

  6. Ocular toxicity [ Time Frame: up to 1 year ]
    rates of adverse events of special interest

  7. Overall hematologic response rates [ Time Frame: 3 months, 6 months ]
    Complete Response (CR)/ Very Good Partial Response (VGPR)/ <50 mg/L difference between involved minus uninvolved serum free lights chains (low-dFLC)/ Partial Response (PR)

  8. Organ response rates [ Time Frame: 3,6,12,18, and 24 months ]
    Organ response rates per individual organ (heart, kidney, liver) according to International Amyloidosis Consensus Criteria

  9. Duration of response [ Time Frame: approximately up to 9 years ]
    Duration of response is defined as the time between first documentation of response (achievement of at least a PR or lowdFLC response) and PD

  10. Determine time to progression [ Time Frame: approximately up to 9 years ]
    From the date of registration to the date of first disease progression, major organ deterioration or death, whichever occurs first

  11. Overall survival [ Time Frame: approximately up to 9 years ]
    Overall Survival, measured from the date of from randomization to the date the subject's death



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diagnosis of AL amyloidosis, confirmed by histology and typed with immunohistochemistry, immunoelectron microscopy or mass spectrometry or if not available, for patients with biopsy confirmed amyloidosis and cardiac involvement alone, if they also have a negative PYP- or DPD-Tc99m bone scan.
  2. Previous systemic therapy for AL amyloidosis
  3. Patients must be ≥ 18 years of age.
  4. ECOG performance status 0, 1 or 2.
  5. Mayo stage 1 or Mayo stage 2 or Mayo stage 3A1-3 defined as both cTnT < 0.035 ng/mL (or in place of cTnT the cTnI < 0.10 ng/mL or high sensitivity Troponin T < 54 ng/L) AND simultaneous NT-proBNP ≤ 332 ng/L, OR EITHER above threshold, or BOTH above threshold but with NTproBNP < 8500 ng/L (stage 3A disease)
  6. Supine systolic blood pressure ≥ 90 mmHg
  7. Measurable disease defined by at least one of the following:

    1. serum free light chain (FLC) ≥2.0 mg/dL (20 mg/L) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥2mg/dL (20 mg/L).
    2. presence of a monoclonal spike that is ≥0.5 gr/dl.
  8. Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system).
  9. Patient must have adequate organ function, defined as follows:

    System Laboratory Values

    Hematologic:

    Absolute neutrophil count (ANC) ≥1.5 X 109/L Hemoglobin ≥8.0 g/dL Platelets ≥75 X 109/L

    Hepatic:

    Total bilirubin ≤1.5X ULN (Isolated bilirubin ≥1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) ALT ≤2.5 X ULN Renal: eGFR ≥30 mL/min/ 1.73 m2 Cardiac:LVEF (Echo) Clinically asymptomatic patients with ECHO confirmed LVEF ≥25%

  10. Written informed consent in accordance with local and institutional guidelines.
  11. Female patients: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

    A female patient 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 (failure rate of <1% per year), preferably with low user dependency (as described in Appendix 3), during the intervention period and for at least four 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 (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 a nearly undetected pregnancy.

    Nonchildbearing potential is defined as follows (by other than medical reasons):

    • ≥45 years of age and has not had menses for >1 year,
    • Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation,
    • Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
  12. Male Patients : contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

    Male Patients are eligible to participate if they agree to the following during the intervention period and for 6 months after the last dose of study treatment to allow for clearance of any altered sperm:

    • 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, 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 who is not currently pregnant.

  13. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for AEs (NCI-CTCAE), version 5, corneal toxicities are defined according to the Keratopathy Visual Activity [KVA] scale) must be ≤ Grade 1 at the time of enrolment except for alopecia.
  14. Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent

Exclusion Criteria:

  1. Presence of non-AL amyloidosis.
  2. Presence of lytic bone lesions or active myeloma with hypercalcemia, cast nephropathy, anemia due to marrow infiltration or extramedullary disease.
  3. Previously untreated disease: patients must have had at least 2 cycles of therapy directed against the plasma cell clone; however, patients that have received high dose therapy with melphalan as their only therapy are eligible for the study.
  4. Previous exposure to anti-BMCA agents
  5. Cardiac stage IIIB disease: both cTnT > 0.035 ng/mL (or in place of cTnT the cTnI > 0.10 ng/mL or high sensitivity Troponin T > 54 ng/L) AND simultaneous NT-proBNP >8500 ng/L.
  6. Known repetitive ventricular arrhythmias on 24h Holter Electrocardiogram (ECG) in spite of anti-arrhythmic treatment. Patients must not have evidence of cardiovascular risk including any of the following:

    • Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block.
    • History of myocardial infarction, acute coronary syndromes (including unstable or uncontrolled angina), coronary angioplasty, or stenting or bypass grafting within three (3) months of Screening.
    • Class III or IV heart failure as defined by the New York Heart Association functional classification system [NYHA, 1994]
    • Severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless patient has a pacemaker.
    • Uncontrolled hypertension or hypotension (i.e., supine SBPN < 90 mmHg despite supportive therapy with midodrine)
  7. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to Cycle 1 Day 1.
  8. Pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to Cycle 1 Day 1.
  9. Current corneal epithelial disease except mild changes in corneal epithelium.
  10. Current unstable liver or biliary disease defined by the presence of large volume ascites requiring paracentesis, encephalopathy, coagulopathy, hypoalbuminemia (except due to AL related nephrotic syndrome), esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement due to AL amyloidosis is acceptable if otherwise meets entry criteria.
  11. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect the patient's safety) unrelated to AL amyloidosis. Patients with isolated proteinuria resulting from AL are eligible, provided they fulfil other inclusion criteria
  12. Patients must not use contact lenses while participating in this study.
  13. Patients must not be simultaneously enrolled in any interventional clinical trial.
  14. Use of an investigational drug or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug.
  15. Plasmapheresis within 7 days prior to first dose of study treatment.
  16. Treatment with a monoclonal antibody within 30 days of receiving the first dose of study drugs.
  17. Major surgery ≤ 4 weeks prior to initiating study treatment.
  18. Any evidence of active mucosal or internal bleeding.
  19. Known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to blmf or drugs chemically related to blmf, or any of the components of the study treatment.
  20. Active infection requiring treatment.
  21. Known HIV infection (defined by positive testing for human immunodeficiency virus (HIV) antibodies).
  22. Positive test of hepatitis B surface antigen, or hepatitis B core antibody at screening or within 3 months prior to first dose of study treatment.
  23. 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: Patients with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained.

    Note: Hepatitis RNA testing is optional and patients with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.

  24. Invasive malignancies other than disease under study, unless the second malignancy has been medically stable for at least 2 years and, in the opinion of the principal investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy. Patients with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction.
  25. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with the patient's safety, obtaining informed consent or compliance to the study procedures.
  26. Patients must not be pregnant or breast-feeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04617925


Contacts
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Contact: Efstathios European Myeloma Network (EMN), MD +31107033123 sarah.lonergan@emn.life

Locations
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France
Centre hospitalier Universitaire de Limoges - Not yet recruiting
Limoges, France, 87042
Contact: Arnaud Jaccard         
Germany
University Hospital Heidelberg Not yet recruiting
Heidelberg, Germany, 69120
Contact: Stefan Schönland         
Greece
General Hospital of Athens "Alexandra" Recruiting
Athens, Greece, 115 28
Contact: Efstathios Kastritis         
Italy
Fondazione I.R.C.C.S Policlinico "San Matteo" Not yet recruiting
Pavia, Italy, 27100
Contact: Giovanni Palladini         
Netherlands
UMC Utrecht Not yet recruiting
Utrecht, Netherlands, 3584 CX
Contact: Monique Minnema         
United Kingdom
Royal Free Hospital - London, Not yet recruiting
London, United Kingdom
Contact: Ashutosh Wechalekar         
Sponsors and Collaborators
European Myeloma Network
GlaxoSmithKline
Layout table for additonal information
Responsible Party: European Myeloma Network
ClinicalTrials.gov Identifier: NCT04617925    
Other Study ID Numbers: EMN27
First Posted: November 5, 2020    Key Record Dates
Last Update Posted: March 3, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by European Myeloma Network:
Belantamab mafodotin
Additional relevant MeSH terms:
Layout table for MeSH terms
Immunoglobulin Light-chain Amyloidosis
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Paraproteinemias