| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
relapsed or refractory AL amyloidosis
|
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002022 |
| E.1.2 | Term | Amyloidosis |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of blmf in patients with relapsed or refractory AL amyloidosis. |
|
| E.2.2 | Secondary objectives of the trial |
1.The safety of blmf in patients with relapsed or refractory AL amyloidosis.
a.Rates of AEs grade 3 or higher, related to blmf therapy
b.Rates of treatment discontinuation due to toxicity related to blmf
c.Dose reduction due to toxicity of blmf therapy
d.Any grade hematologic AEs
e.Any grade non-hematologic AEs
f.Rates of AEs of special interest
2.Secondary efficacy evaluations:
a.Overall hematologic response rates
b.Organ response rates per individual organ
c.Time to first hematologic response
d.Time to at least a very good hematologic response
e.Time to at least a low-dFLC response
f.Duration of hematologic response (time from first response to hematologic progression, for those who achieved at least a hematologic PR or low-dFLC response)
g.Time to a subsequent therapy, either due to progression or inadequate response
h.Time to hematologic progression or major organ deterioration or death
i.Overall survival
j.Quality of life
3. Characterization of the blmf PK profile |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 breastfeeding, 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 study, 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 study
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
study 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 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:
a.Refrain from donating sperm
PLUS, either:
b.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
c.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 agrees to use an additional highly
effective contraceptive method with a failure rate of <1% per year as
when having sexual intercourse with a woman of childbearing potential
who is not pregnant.
13. All toxicities related to previous treatment (defined by National
Cancer Institute- Common Toxicity Criteria for Adverse Events [NCICTCAE], 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. Patient must be able to understand the study procedures and agree
to participate in the study by providing written informed consent.
|
|
| E.4 | Principal 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.
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 study.
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 study drug.
14.Plasmapheresis within seven days prior to the first dose of the study
treatment.
15.Treatment with a monoclonal antibody within 30 days prior to the
first dose of the study treatment. Serious conditions unrelated to AL,
such as SARS-CoV-2, may be permitted but need to be discussed with
the medical doctor and study-site personnel.
16.Major surgery ≤ 4 weeks prior to initiating study 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 study treatment.
19.Active infection requiring treatment.
20.Known HIV infection (defined as positive testing for human
immunodeficiency virus [HIV] antibodies).
21.Positive test for hepatitis B surface antigen (HBsAg), or hepatitis B
core antibody (HBcAb) at screening or within 3 months prior to the first
dose of study treatment.
22.Positive test for hepatitis C antibody hepatitis C RNA at screening or
within 3 months prior to the first dose of the study treatment.
23.Invasive malignancies other than the 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 the clinical trial treatments of the currently targeted
malignancy. Patients with curatively treated non-melanoma skin cancer
may be enrolled without a 2-year restriction.
24.Any serious and/or unstable pre-existing medical, psychiatric
disorder, or other conditions (including lab abnormalities) that could
interfere with the patient's safety, informed consent or compliance to
the study procedures.
25.Patients must not be pregnant or breast-feeding.
26.Participant must not have received a live or live-attenuated vaccine
within 30 days prior to first dose of belantamab mafodotin. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary end point of the study is the CR/VGPR/low-dFLC response rate at 6 months/ 4 cycles from start of therapy with blmf, according to consensus response criteria
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
at 6 months/ 4 cycles from start of therapy with blmf
|
|
| E.5.2 | Secondary end point(s) |
•Evaluation of safety (grade 3 or higher adverse events rates related to blmf therapy, treatment discontinuation rates, any grade hematologic adverse events, any grade non-hematologic adverse events) and
•Further evaluation of efficacy (Overall hematologic response rates at 6 months (CR+VGPR+low-dFLC response+ PR), Organ response rates per individual organ (heart, kidney, liver) at 3, 6, 12, 18 and 24 months from start of therapy, Time to first hematologic response (PR or better), Time to at least a very good hematologic response (VGPR or better), Time to at least a low-dFLC response, Duration of hematologic response (time from first response to hematologic progression, for those who achieved at least a hemPR or low-dFLC response), Time to a subsequent therapy, either due to progression or inadequate response, Time to hematologic progression or major organ deterioration or death, overall survival and quality of life).
•Derived PK parameter values for belantamab mafodotin as data permit.
Exploratory Endpoints:
•Relation between baseline bone marrow BCMA expression
levels/soluble BCMA (sBCMA) levels AND clinical response.
•Change from baseline of sBCMA levels.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
for the entire duration of the study
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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