| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/refractory 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1
To determine the safety and tolerability of belantamab mafodotin in combination with DPd and Pd and to establish theRP2R for patients with RRMM and one to three prior lines of treatment who are lenalidomide refractory.
Part 2
To further evaluate the safety and determine the clinical activity of the RP2R in patients with RRMM and one to three prior lines of treatment who are lenalidomide refractory. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of combining belantamab mafodotin with DPd and Pd:
• Assess the efficacy of belantamab mafodotin in combination with DPd and Pd in patients with RRMM and one to three prior lines of treatment who are lenalidomide refractory.
• Evaluate alternate corneal adverse event (AE) management approach using Alternate Dose Modification Guidelines for belantamab mafodotin-related ocular adverse events.
• To evaluate the pharmacokinetic (PK) profile of belantamab mafodotin when administered in combination with DPd and Pd.
• To evaluate vision-related functioning measured by the Vision Related Anamnestic Tool as documented by the investigator.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be ≥18 years.
2. Documented diagnosis of MM as per IMWG criteria.
3. Must have at least ONE aspect of measurable disease, defined as 1 of following:
a. Urine M-protein excretion ≥200 mg/24 hrs (≥0.2 g/24 hrs), or
b. Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or
c. Serum FLC assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65).
4. ECOG performance status of 0–2.
5. Adequate organ system function defined by following assessments.
Hematologic
a. Absolute neutrophil count ≥1.5 X 10^9/L; granulocyte colony stimulating factor use within the past 14 days is NOT permitted.
b. Hemoglobin ≥8.0 g/dL; transfusions within the past 14 days are NOT permitted. Erythropoietin use is allowed.
c. Platelet count ≥50x10^9/L if bone marrow (BM) is >50% involved in myeloma. Otherwise ≥75x10^9/L; transfusions within the past 14 days are NOT allowed to reach this level.
Hepatic
a. Total bilirubin ≤1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
b. Alanine aminotransferase ≤2.5xULN.
Renal
a. Estimate glomerular filtration rate ≥30 mL/min/1.73 m2; calculated using the Modified Diet in Renal Disease formula.
b. Spot urine (albumin/creatinine ratio) ≤500 mg/g (56 mg/mmol)
OR
c. Urine Dipstick: Negative trace; if ≥1+ only eligible if confirmed ≤500 mg/g [56 mg/mmol] by albumin/creatinine ratio.
6. Female participants: contraceptive use should comply with local regulations:
A female participant is eligible if not pregnant or breastfeeding, and at least 1 of the following conditions applies:
• Is not a woman of childbearing potential (WOCBP) defined as follows:
a. ≥45 years and has not had menses for >1 year.
b. Participants who have been amenorrhoeic for <2 years without history of hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range at screening.
c. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the procedure or confirmed by ultrasound. Tubal ligation must be confirmed with medical records of procedure.
OR
• WOCBP and using two methods of reliable birth control (1 method that is highly effective and 1 additional effective [barrier] method), beginning 4 weeks before starting treatment with pomalidomide, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of pomalidomide treatment. WOCBP participants must use 1 method of reliable birth control that is highly effective for 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 pomalidomide or 3 months following discontinuation of daratumumab treatment or 4 months following discontinuation of belantamab mafodotin treatment whichever longer.
WOCBP must have two negative pregnancy tests before starting therapy. First test should be performed within 10–14 days and the second test ≤24 hours before the start of pomalidomide.
Participant should not receive pomalidomide until investigator has verified that results of pregnancy tests are negative. Investigator should evaluate effectiveness of the contraceptive method in relationship to first dose of treatment. Investigator is responsible for a review of medical history, menstrual history, and recent sexual activity to decrease risk for inclusion of woman with a nearly undetected pregnancy.
7. Male participants: contraceptive use should be consistent with local regulations regarding methods of contraception for participants:
Male participants are eligible if they agree to the following during the intervention period and until 28 days after the last dose of pomalidomide or 3 months following discontinuation of daratumumab or 6 months after last dose of belantamab mafodotin, whichever is longer, to allow for clearance of any altered sperm.
• Refrain from donating sperm
+ either:
• Be abstinent from heterosexual intercourse as preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain,
OR
• Must agree to contraception as detailed:
Agree to a male condom, even if they have undergone successful vasectomy, and female partner to use additional highly effective contraceptive method with failure rate of <1% per year as when having sexual intercourse with WOCBP (including pregnant females).
8. Participants must be able to understand the study procedures and agree to participate in study by providing written informed consent and have received 1 to 3 prior lines of therapy (including lenalidomide) and be lenalidomide refractory at any lenalidomide dose.
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| E.4 | Principal exclusion criteria |
1. Peripheral neuropathy or neuropathic pain ≥Grade 2, per NCI CTCAEs V5.
2. Major surgery within 4 weeks before 1st dose.
NOTE: must be clinically stable following major surgery.
NOTE: major surgery shall be defined by Investigator.
3. Presence of active renal condition. Participants with isolated proteinuria resulting from MM are eligible if they fulfil other inclusion criteria.
4. Any serious and/or unstable pre-existing medical or psychiatric disorder, or other conditions that may interfere with participant’s safety, obtaining informed consent or complying to procedures.
5. Active mucosal or internal bleeding uncontrolled by local therapy and unexplained by reversible coagulopathy.
6. Current active unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis (except for Gilbert’s syndrome or asymptomatic gallstones; otherwise, stable non-cirrhotic chronic liver disease; or hepatobiliary involvement of malignancy as per Investigator).
7. Participants with previous or concurrent malignancies other than MM are excluded, except surgically treated cervical carcinoma in situ, or any other malignancy that has been considered medically stable for ≥2 years. The participant must not receive therapy, other than hormonal.
NOTE: Participants with cured non-melanoma skin cancer are allowed without restriction.
8. Evidence of cardiovascular risk including any of the following:
• Current clinically significant untreated arrhythmias, including clinically significant electrocardiogram (ECG) abnormalities, second degree or third degree atrioventricular block.
• Screening 12-lead ECG showing a baseline QT interval >470msec.
• History of myocardial infarction, acute coronary syndromes, coronary angioplasty, or stenting or bypass grafting within 3 months of Screening.
• Class III/IV heart failure per NYHA functional classification system.
• Uncontrolled hypertension.
9. Participant has known chronic obstructive pulmonary disease (COPD; defined as a forced expiratory volume in 1 second [FEV1] <50% of predicted normal), persistent asthma, or history of asthma within ≤2 years.
10. Active infection requiring therapy.
11. Known HIV infection, unless participant meets all following:
• Established anti-retroviral therapy (ART) for ≥4 weeks and HIV viral load <400 copies/mL.
• CD4+ T-cell count ≥350 cells/uL.
• No history of acquired immunodeficiency syndrome-defining opportunistic infections within the last year.
12. To be seropositive for hepatitis B at screening or ≤3 months prior to first study drug dose.
NOTE: Participants with resolved infection must be screened using real-time polymerase chain reaction (PCR), except PCR positive.
NOTE: Presence of antiHBs indicating previous vaccination will not constitute an exclusion criterion.
13. Positive hepatitis C virus (HCV) antibody test result or HCV RNA test result at screening or ≤3 months before the first dose of study drug unless participant meets the following:
• RNA test negative
• Successful anti-viral treatment (8 weeks), following negative HCV RNA test after ≥4 weeks.
14. Current corneal epithelial disease except for mild punctate keratopathy.
NOTE: Mild punctate keratopathy allowed.
15. Intolerance or contraindications to anti-viral prophylaxis.
16. Intolerant to antithrombotic prophylaxis.
17. Active or history of venous thromboembolism within ≤3 months.
18. AL amyloidosis, active POEMS syndrome or active plasma cell leukemia at screening.
19. Prior allogeneic stem cell transplantation.
20. Clinical signs or history of meningeal or central nervous system involvement by MM.
21. Intolerance, 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. Investigational drug within 14 days or 5 half-lives (whichever shonrter) preceding first study drug.
23. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drug.
24. Participant who has received prior treatment with pomalidomide, belantamab mafodotin or other BCMA targeted agent are excluded.
25. Plasmapheresis within 7 days before the first dose of study drug.
26. Participants with uncontrolled skin disease.
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.
Because of the embryo-fetal risk of pomalidomide, all participants must adhere to the pomalidomide Pregnancy Prevention Program applied in their region as per label.
The Sponsor will review and approve the participant eligibility data submitted by the investigational site before dosing. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints
Part 1
• Number of participants with dose-limiting toxicities (DLTs).
• Number of participants with AEs and serious adverse events (SAEs).
• Number of participants with ocular toxicity of Grade ≥2 (per KVA scale).
Part 2
• Overall Response Rate (ORR) as per IMWG by Investigator Assessment.
• Number of participants with AEs and SAEs.
• Number of participants with ocular toxicity of Grade ≥2 (per KVA scale).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the whole study duration. |
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| E.5.2 | Secondary end point(s) |
Part 1 & 2
• Cumulative administered dose of belantamab mafodotin in combination with daratumumab, pomalidomide, and dexamethasone or in combination with pomalidomide and dexamethasone.
• ORR as per IMWG (secondary endpoint for Part 1)
• Very Good Partial Response (VGPR) or better (VGPR+) rate.
• Time to Response (TTR) as per IMWG by Investigator assessment.
• Duration of Response (DoR) as per IMWG by Investigator assessment.
• Complete Response Rate (CRR) as per IMWG by Investigator assessment.
• Minimal residual disease (MRD) negativity rate in the BM, Negative MRD is defined as the absence of tumor plasma cells in minimum 100,000 (105) BM cells. MRD will be assessed via next-generation flow (NGF) cytometry in participants with VGPR or better response.
• Progression-Free Survival (PFS) as per IMWG by Investigator assessment.
• Overall Survival (OS).
• Number of participants with abnormal ocular findings (on ophthalmic exam).
• Belantamab mafodotin dose holds.
• Belantamab mafodotin observed plasma concentrations.
• Number and proportion of participants with changes from baseline in ocular symptoms and related impacts as measured by the Vision Related Anamnestic Tool (only for Part 2).
Exploratory Endpoints
• Relation between baseline bone marrow B-Cell Maturation Antigen (BCMA) expression levels/soluble BCMA (sBCMA) levels AND clinical response.
• Change from baseline of sBCMA levels.
• Derived PK parameter values for belantamab mafodotin.
• Belantamab mafodotin exposure (e.g., concentration, Cmax, or AUC) vs. efficacy and/or safety endpoints (e.g., ORR, CRR, ocular events), as data permit.
• Concordance between the visual acuity score produced by the Peak Acuity app and the best corrected visual acuity score of the ophthalmic exam |
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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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| 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.8.3 |
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 | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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