| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple myeloma = cancer of blood cells in the bone marrow |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple myeloma = cancer of blood cells in the bone marrow |
|
| 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 |
|
| 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 examine the ocular AEs associated with single-agent belantamab mafodotin using alternative dosing regimens in participants with
RRMM in Arms B to D compared to Arm A |
|
| E.2.2 | Secondary objectives of the trial |
To further evaluate the ocular safety and tolerability of single-agent belantamab mafodotin in all arms
To evaluate the efficacy of single-agent belantamab mafodotin in all arms
To evaluate the overall safety and tolerability of single-agent belantamab mafodotin in all arms
To assess the pharmacokinetics of single-agent belantamab mafodotin in all arms
To assess anti-drug antibodies against single-agent belantamab mafodotin in all arms |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18 years of age inclusive at the time of signing the Informed Consent Form (ICF).
Type of Participant and Disease Characteristics
2. Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (see Section 10.8).
3. Participant has a histologically- or cytologically-confirmed diagnosis of MM as defined by IMWG criteria [Rajkumar, 2016], and
a. Has undergone stem cell transplant or is considered transplant ineligible, and
b. Has failed at least 3 prior lines of anti-MM therapies, including an anti-CD38 antibody (e.g., daratumumab) alone or in combination, and is refractory to an immunomodulatory agent (e.g., lenalidomide, pomalidomide) and a proteasome inhibitor (e.g., bortezomib, ixazomib, carfilzomib).
4. Participant has measurable disease with at least one of the following criteria:
a. Serum M protein ≥0.5 g/dL (≥5 g/L), or
b. Urine M protein ≥200 mg/24h, or
c. Serum free light chain (FLC) assay: Involved FLC level ≥5 mg/dL (≥50 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65), or
d. Non-irradiated plasmacytoma with ≥1 measurable lesion that has a single diameter of ≥2 cm
5. Participants with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met:
a. Transplant was >100 days before study enrollment, and
b. Participant has no active infection(s), and
c. Participant meets the remainder of the eligibility criteria outlined in this protocol.
6. All prior treatment-related toxicities (defined by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 5.0) must be Grade ≤1 at the time of enrollment, except for alopecia and Grade 2 peripheral neuropathy.
7. Life expectancy of at least 6 months, in the opinion of the investigator.
Sex and Contraceptive/Barrier Requirements
8. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. Female Participants
A female participant is eligible to participate if she is not pregnant or breastfeeding and at least one of the following conditions apply:
• Is not a woman of childbearing potential (WOCBP) as defined in Section 10.9,
or
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency (as described in Section 10.9) during the treatment period and for at least 4 months after the last dose of study treatment 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 treatment.
A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose (Cycle 1 Day 1) of study treatment (see Section 8.2.7). Additional requirements for pregnancy testing during and after study treatment are provided in Section 8.2.7 and the Schedule of Activities (SoA) (Section 1.3). 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 an early undetected pregnancy.
b. Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following conditions from the time of first dose of study treatment until 6 months after the last dose of study treatment to allow for clearance of any altered sperm:
• Refrain from donating sperm, plus either:
o 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
o Must agree to use contraception/barrier as follows: Agree to use a male condom, even if they have undergone a successful vasectomy, with female partner use of an additional highly effective contraceptive method with a failure rate of <1% per year as described in Section 10.9, when having sexual intercourse with a WOCBP (including pregnant females).
Informed Consent
9. Participant is capable of giving signed informed consent as described in Section 10.10 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Other Inclusions
10. Participant meets country-specific inclusion criteria described in Section 10.7, if applicable.
|
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Participant has symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes), or active plasma cell leukemia at the time of screening.
2. Participant currently has corneal epithelial disease, except nonconfluent superficial punctate keratitis (SPK).
3. Participant has evidence of active mucosal or internal bleeding.
4. Participant has presence of an active renal condition (infection, requirement for dialysis, or any other condition that could affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfill adequate organ function inclusion criteria (Exclusion Criteria 24).
5. Participant has any serious and/or unstable pre-existing medical condition, psychiatric disorder, or other conditions (including laboratory abnormalities) that could interfere with the participant’s safety, obtaining informed consent, or compliance with the study procedures.
6. Participant has malignancies other than the disease under study are excluded, except for any other malignancy from which the participant has been disease-free for >2 years and, in the opinion of the principal investigator and GSK medical director, will not affect the evaluation of the effects of the study treatment on the currently targeted malignancy (MM). Participants with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction.
7. Participant has evidence of cardiovascular risk including any of the following criteria:
a. Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram (ECG) abnormalities including second degree (Mobitz Type II) or third degree atrioventricular block, or
b. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting ≤3 months before screening, or
c. Class III or IV heart failure as defined by the New York Heart Association
functional classification system (see Section 10.11).
d. Uncontrolled hypertension.
8. Participant is a pregnant or lactating female.
9. Participant has an active infection requiring antibiotic, antiviral, or antifungal therapy.
10. Participant has known human immunodeficiency virus (HIV) infection, unless the participant can meet all of the following criteria:
a. Established anti-retroviral therapy (ART) for ≥4 weeks and HIV viral load <400 copies/mL, and
b. CD4+ T cell (CD4+) counts ≥350 cells/μL, and
c. No history of acquired immunodeficiency syndrome-defining opportunistic infections within the last 12 months.
Liver Safety
11. Participants with hepatitis B virus (HBV) will be excluded unless the criteria in Table 5 can be met.( please refer to the protocol section 5.2)
12. Participants with a positive hepatitis C antibody test result or a positive hepatitis C virus (HCV) ribonucleic acid (RNA) test result at screening or ≤3 months before the first dose of study treatment will be excluded unless the participant can meet the following criteria:
a. Negative HCV RNA test result
b. Successful antiviral therapy (usually 8 weeks duration), followed by a negative HCV RNA test result after a washout period of ≥4 weeks.
13. Participant has cirrhosis or current unstable liver or biliary disease per investigator assessment, defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice.
14. Participant has alanine aminotransferase (ALT) >2.5× upper limit of normal (ULN).
15. Participants has total bilirubin >1.5×ULN (isolated total bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Prior/Concomitant Therapy
16. Participant has received systemic anti-MM therapy within ≤14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment.
17. Participant has received plasmapheresis ≤7 days before the first dose of study treatment.
18. Participant has received systemic therapy with high dose steroids (equivalent to ≥60 mg prednisone daily for ≥4 days) administered to treat MM or non-MM disease within ≤14 days before the first dose of study treatment.
19. Participant has received a prior allogenic stem cell transplant.
20. Participant has used an investigational drug ≤14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment or has received therapy with a monoclonal antibody ≤30 days before the first dose of study treatment, whichever is shorter.
For 'Other Exclusions' please refer to the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence rate of Grade ≥2 ocular AEs according to the KVA scale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From when the first participant initiated treatment until 9 months after the last participant is randomized into Arms A to D. |
|
| E.5.2 | Secondary end point(s) |
• Cumulative event rate of ocular AEs to Week 16 (KVA scale)
• Incidence rate of ocular AEs by grade (KVA scale)
• Exposure-adjusted incidence rate of ocular AEs by grade (KVA scale)
• Median duration of dose delay
• Percentage of participants requiring dose reductions, dose delays, and study treatment
• discontinuation due to ocular AEs (KVA scale)
• Cumulative incidence of ocular AEs by grade (KVA scale)
•Toxicity Index by assessment/visit
•Duration of ocular AEs (KVA scale)
•Percentage of time on study with ocular AEs (KVA scale)
•Change in BCVA (ΔlogMAR)
•ORR, defined as the percentage of participants with a confirmed PR or better (i.e., PR, VGPR, CR, and sCR)*
•Percentage of participants with a confirmed VGPR or better (i.e., VGPR, CR, and sCR)*
•TTR is defined as the time between the date of randomization and the first documented evidence of response (PR or better), among participants who achieve a response (i.e., confirmed PR or better)*
•DoR in responders, defined as the time from first documented evidence of PR or better until PD or death due to PD*
•TTP, defined as the time from randomization until the earliest date of documented PD or death due to PD*
•PFS, defined as the time from randomization until the earliest date of documented PD or death due to any cause*
•OS, defined as the time from randomization until the date of death due to any cause
•Instance of AEs (including ocular AEs) (CTCAE Version 5.0) and changes in laboratory parameters
•Percentage of participants requiring dose reductions, dose delays, and study treatment
•discontinuation due to any AEs (CTCAE Version 5.0)
•Plasma belantamab mafodotin pharmacokinetic parameters, as data permit
•Incidence and titers of ADAs against belantamab mafodotin and total monoclonal antibody plasma concentration at each ADA time point
* All efficacy endpoints are based on the 2016 IMWG Response Criteria [Kumar, 2016]
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From when the first participant initiated treatment until 9 months after the last participant is randomized into Arms A to D. |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Arm A - approved dosing regimen of 2.5 mg/kg |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 |
| Australia |
| Brazil |
| Canada |
| India |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| Thailand |
| United States |
| France |
| Germany |
| Ireland |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| Argentina |
| Greece |
|
| 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
|
Participants will receive study treatment until PD, unacceptable toxicity (including
meeting stopping criteria for liver chemistry defined in Section 7.1.1), or death. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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