| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| newly diagnosed multiple myeloma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
Part 1 – Dose finding
To determine the safety and tolerability of belantamab mafodotin in combination with daratumumab, lenalidomide, and dexamethasone to establish a recommended dose for participants with TI NDMM.
Part 2 – Dose expansion
To further evaluate the safety and determine the preliminary clinical activity of belantamab mafodotin RP2D in combination with daratumumab, lenalidomide, and dexamethasone.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of combining belantamab mafodotin with daratumumab, lenalidomide, and dexamethasone:
•Assess the efficacy of belantamab mafodotin in combination with daratumumab, lenalidomide, and dexamethasone in TI NDMM.
•Evaluate alternate corneal AE management approaches using visual acuity changes for belantamab mafodotin dose modifications.
•To further characterize the pharmacokinetic (PK) profile of belantamab mafodotin when administered in combination with daratumumab, lenalidomide, and dexamethasone
•To evaluate symptomatic AEs measured by the Ocular Surface Disease Index (OSDI) questionnaire as documented by the investigator.
Exploratory objectives:
•To investigate the relationship between biological characteristics and clinical response.
•To explore the exposure-response relationship of belantamab mafodotin with clinical endpoints.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age ≥ 18 years
2.Monoclonal plasma cells in the BM ≥10% or presence of a biopsy proven plasmacytoma and documented MM satisfying at least 1 of the
CRAB criteria: -Hypercalcemia:serum calcium >0.25 mmol/L higher than ULN or >2.75 mmol/L. - Renal insufficiency:CrCl <40mL/min or serum creatinine >177 μmol/L. -Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL. - Bone lesions: 1 or more osteolytic lesions on skeletal radiography, CT or PET-CT OR
Biomarkers of Malignancy: - Clonal BM plasma cell ≥60% - Involved: uninvolved serum FLC ratio ≥100 - More than 1 focal lesion on MRI studies 3.Must have at least 1 aspect of measurable disease, defined as one of the below Urine M-protein excretion ≥200 mg/24 hours or
Serum M-protein concentration ≥0.5 g/dL or Serum FLC assay: involved FLC level ≥10 mg/dL and an abnormal serum FLC ratio <0.26 or >1.65
4.Not a candidate for high-dose chemotherapy with ASCT due to the presence of significant comorbid condition(s) that are likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. The participants will be assessed by the IMWG frailty index that is recommended by ESMO guidelines. Participants with IMWG frailty index score 1 or 2 will be considered transplant ineligible
5.ECOG performance status: 0–2
6.Adequate organ system function as defined by the below laboratory assessments.
oANC ≥1.25 X 109/L; GCSF use within the past 14 days is NOT permitted
Hemoglobin ≥ 8.0 g/dL; transfusions within the past 14 days are NOT permitted
PLT ≥ 50 x 109/L if BM is >50% involved in myeloma. Otherwise ≥75 x 109/L; transfusions within the past 14 days are NOT allowed to reach this level
Total bilirubin ≤1.5xULN
ALT ≤ 2.5xULN
eGFR ≥30 mL/min/1.73 m2
Spot urine < 500 mg/g (56 mg/mmol) OR
Urine Dipstick: Negative trace; if ≥ 1+ only eligible if confirmed < 500 mg/g [56 mg/mmol] by albumin/creatinine ratio
7.Female participants are eligible to participate if she is not pregnant or breastfeeding and at least 1 of the following conditions applies:
Is not a WOCBP defined as follows:
a.Age≥ 45 years with no menses for > 1 year
b.Participants who have been amenorrhoeic for < 2 years without a history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon 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. OR
•Is a WOCBP and using 2 methods of reliable birth control, beginning 4 weeks before initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide treatment. Thereafter, WOCBP must use 1 method of reliable birth control that is highly effective for a further 4 months following discontinuation of belantamab mafodotin or 3 months following the discontinuation of daratumumab. WOCBP must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during treatment, during dose interruptions and for 28-days following the last dose of lenalidomide or 3 months following discontinuation of daratumumab treatment or 4 months following discontinuation of belantamab mafodotin treatment whichever is longer.
A WOCBP must have 2 negative pregnancy tests before therapy initiation. The 1st test should be performed within 10-14 days and the 2nd test within 24h before the start of lenalidomide therapy. The participant should not receive lenalidomide until the investigator has verified that the results of these tests are negative and evaluate the effectiveness of the contraceptive method in relation to the 1st dose of study treatment. The investigator is responsible for reviewing the medical and menstrual history and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy
8.Male participants are eligible to participate if they agree to the following during the intervention period and until 28 days after the last dose of lenalidomide or 3 months following the discontinuation of daratumumab or 6 months after the last dose of belantamab mafodotin whichever is longer 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 and agree to remain abstinent OR
•Must agree to use contraception/barrier as below:
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 as when having sexual intercourse with a woman of childbearing potential
•Participants must be able to understand the study procedures and agree to participate in the study by providing written ICF
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| E.4 | Principal exclusion criteria |
1.Prior systemic therapy for MM or SMM.
2.Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI CTCAE Version 5.
3.Major surgery within 2 weeks before the first dose of study drug
4.Presence of active renal condition. Participants with isolated proteinuria resulting from MM are eligible, provided that they fulfil the other inclusion criteria.
5.Any serious and/or unstable pre-existing medical or psychiatric disorder, or other conditions (including laboratory abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures.
6.Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not explained by reversible coagulopathy.
7.Current active unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
8.Participants with previous or concurrent malignancies other than MM are excluded. Exceptions are surgically treated cervical carcinoma in situ, or any other malignancy that 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.
9.Evidence of cardiovascular risk including any of the following:
•Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities, second degree or third degree AV block.
•Screening 12-lead ECG showing a baseline QT interval >470 msec
•History of myocardial infarction, acute coronary syndromes, 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.
10.Participant has known COPD
11.Active infection requiring treatment.
12.Known HIV infection, unless the participant can meet all of the following criteria:
•Established ART for at least 4 weeks and HIV viral load <400 copies/mL.
•CD4+ T-cell (CD4+) count ≥350 cells/uL.
•No history of AIDS-defining opportunistic infections within the last 12 months.
13.To be seropositive for hepatitis B at screening or within 3 months prior to first dose of study treatment.
14.Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before the first dose of study treatment unless the participant can meet the following criteria:
•RNA test negative
•Successful anti-viral treatment is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks.
15.Current corneal epithelial disease except for mild punctate keratopathy.
16.Intolerance or contraindications to anti-viral prophylaxis.
17.Unable to tolerate antithrombotic prophylaxis.
18.Active or history of venous thromboembolism within past 3 months.
19.AL amyloidosis (light chain amyloidosis), active POEMS syndrome or active plasma cell leukemia at the time of screening.
20.Exhibiting clinical signs of or with a known history of meningeal or central nervous system involvement by MM.
21.Known intolerance or immediate or delayed hypersensitivity reaction or idiosyncratic reaction to: drugs chemically related to belantamab mafodotin, or any of the components of the study treatment; daratumumab SC or to any of its excipients; or infused protein products, sucrose, histidine, and polysorbate 80.
22.Use of an investigational drug within 14 days or 5 half-lives (whichever is longer) preceding the first dose of study drug.
23.Plasmapheresis within 7 days before the first dose of study drug.
24.Participants with uncontrolled skin disease.
25.Participants with concomitant administration of a strong or moderate CYP3A4 inhibitor or inducer
26.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.
27.Participant must not have received a live or live-attenuated vaccine within 30 days prior to first dose of belantamab mafodotin.
28.Participant should not use contact lenses while receiving belantamab mafodotin.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints
Part 1:
•The number (%) of participants and 95% CI with the dose-limiting toxicity (DLTs) in each of the cohorts 1-2, using the DLT evaluable population.
•The number (%) of participants with AEs and serious adverse events (SAEs) in each of the cohorts 1-2, using the DLT evaluable and Safety populations.
Part 2:
•Overall Response Rate (ORR) as per IMWG by Investigator assessment; defined as the percentage of participants with a confirmed partial response (PR), very good partial response (VGPR), complete response (CR) or stringent CR (intenetion-to-treat [ITT] set).
•Number (%) of participants with AEs and SAEs (Safety set).
Both endpoints will be presented separately for Groups A and B.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| First cycle of study treatment (4 weeks-28 days) |
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| E.5.2 | Secondary end point(s) |
•Lenalidomide RDI; DLT evaluable population, safety population
•Cumulative belantamab mafodotin dose of (DLT evaluable population, safety population) administered in combination with daratumumab, lenalidomide and dexamethasone. The total dose for each participant will be calculated as the sum of all administrated doses
•ORR and 95% CI as per IMWG by Investigator Assessment (ITT population) Part 1 only
•VGPR+ and 95% CI as per IMWG by Investigator Assessment (ITT population) Part 1 only
•TTR as per IMWG by Investigator Assessment (ITT population)
•DoR as per IMWG by Investigator Assessment (ITT population). The median DoR will be presented along with the respective 95% CIs and the 1st and 3rd quartiles.
•CRR as per IMWG by Investigator Assessment (ITT population).The denominator will be the total number of participants in each population, cohort and group respectively.
•MRD negativity rate (ITT population). The denominator will be the total number of participants in each population, cohort and Group respectively.
•PFS as per IMWG by Investigator Assessment (ITT population, Safety population). The median PFS will be analyzed with the Kaplan Meier method and presented along with the respective 95% CI and the 1st and 3rd quartiles.
•OS (ITT population, Safety population). The median OS will be analyzed using the Kaplan-Meier method and will be presented with the respective 95% CI and the 1st and 3rd quartiles.
•Number (%) of participants with abnormal ocular findings (DLT evaluable population, Safety population).
•PK analysis (PK population)
Concentration-time data: linear and semi-logistic unique profiles of concentration-time and the mean and median profiles will be graphically represented for belantamab mafodotin.
PK parameters: Concentration-time data can be presented, considering data from other studies and analyzed using a population PK analysis. Further, the Cmax and AUC will be calculated.
•Number of participants with changes from baseline and proportion of participants with within-participant meaningful change in self reported ocular symptoms and related impacts as measured by the OSDI questionnaire.
•Alternate corneal AE management: KVA events, dose holds, worst post-baseline BCVA and incidence of Grade 4 corneal findings will be descriptively summarized using frequencies and proportions.
Exploratory Endpoints
Part 1 & 2
•The relation between baseline BM BCMA expression levels/sBCMA levels AND clinical response will be evaluated, using descriptive statistics. The baseline BCMA expression levels/sBCMA levels will be presented by best response and in 2 groups. Exploratory non-parametric statistical comparisons might also be presented to quantify the gratitude of the respective potential relation (ITT population).
•Mean maximum change from baseline of sBCMA levels overall and by best response will be presented to evaluate the change from baseline of sBCMA levels. Exploratory non-parametric statistical tests may also be implemented (ITT population).
•Furthermore, the mean SD sBCMA value overtime; overall and by best response will be estimated. Exploratory non-parametric statistical tests might also be performed (ITT population).
Belantamab mafodotin exposure will be presented in several, as data permit. Exploratory non-parametric statistical comparisons might be also presented to quantify the extent of the respective potential relation between the belantamab mafodotin exposure and the response and safety profile (PK population)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the whole study duration |
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| 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 | Yes |
| 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 | Yes |
| 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 | 2 |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| 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 |
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