Overview

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

Eligibility

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