Belantamab Mafodotin in patients with relapsed or refractory AL amyloidosis

Phase 1

Conditions: relapsed or refractory AL amyloidosis
MedDRA version: 20.0Level: PTClassification code 10002022Term: AmyloidosisSystem Organ Class: 10021428 - Immune system disorders
Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Registration Number: EUCTR2020-004001-32-DE

Lead Sponsor: Stichting European Myeloma Network – EM

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 35

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.Patients must have had at least two cycles of therapy directed against plasma cell clone. However, patients that have received high dose therapy with melphalan as their only therapy are also eligible.
3.Patients must be 18 years of age or above.
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:
a.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).
b.presence of a monoclonal spike that is =0.5 g/dl.
8.Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system).
9. Patients must have adequate organ function.
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 breast-feeding, and at least one of the following conditions applies:
a.She is not of childbearing potential (WOCBP)
OR
b.She is a WOCBP and using, during the intervention period and for at least 4 months after the last dose of the trial, a contraceptive method that is highly effective (failure rate <1% per year), preferably with low user dependency (as described in Appendix 3). Patient 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 trial intervention.
A WOCBP must have a negative highly sensitive serum-pregnancy test (as required by local regulations) 72 hours before the first dose of the trial intervention.
The investigator is responsible for reviewing the 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):
a.=45 years of age and has not had menses for >1 year
b.Patients who have been amenorrhoeic for <2 years without a history of hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range after screening evaluation
c.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 part

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 > 60% plasma cells in bone marrow.
3.Previous exposure to anti-BCMA agents
4.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.
5.Known repetitive ventricular arrhythmias on 24h Holter Electrocardiograms (ECG) despite anti-arrhythmic treatment. Patient 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, electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities (unless patient has a pacemaker).
•Uncontrolled hypertension or hypotension (i.e., supine SBP< 90 mmHg despite supportive therapy with midodrine)
6.Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to Cycle 1 Day 1.
7.Pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to Cycle 1 Day 1.
8.Ongoing corneal epithelial disease except mild changes in corneal epithelium (mild punctate keratopathy).
9.Current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia (except due to 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 of malignancy is acceptable if otherwise meets entry criteria.
10.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.
11.Patient must not use contact lenses while participating in this trial.
12.Patient must not be simultaneously enrolled in any interventional clinical trial.
13.Use of an investigational drug or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or five half-lives, whichever is shorter, prior to the first dose of trial drug.
14.Plasmapheresis within seven days prior to the first dose of the trial treatment.
15.Treatment with a monoclonal antibody within 30 days prior to the first dose of the trial treatment. Serious conditions unrelated to AL, such as SARS-CoV-2, may be permitted but need to be discussed with the medical doctor and trial-site personnel.
16.Major surgery = 4 weeks prior to initiating trial treatment.
17.Evidence of active mucosal or internal bleeding
18.Known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to blmf or drugs chemically related to blmf, or any of the components of the trial treatment.
19.Active infection