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Pharmaceutical Solutions

Dexamethasone

Lenalidomide

Daratumumab

Dexamethasone acetate

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Belantamab mafodotin will be administered as a combination therapy as a calculated dose on Day 1 of every other 28-day cycle.

Belantamab mafodotin starting dose:

1. Cohort 1: 1.9 Q8W = 1.9 mg/kg on Day 1 of every other 28-day cycle
2. Cohort 2: 1.4 Q8W = 1.4 mg/kg on Day 1 of every other 28-day cycle

Administration schedule for daratumumab 1800mg SC (fixed dose):

Cycles 1-2: days 1, 8, 15, 22 Cycles 3-6: days 1, 15 Cycles 7+: day 1

Lenalidomide: 25 mg/d on day 1-21 of every 28-day cycle.

Dexamethasone: 40 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants \< 75 years; 20 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants ≥ 75 years

Blmf will be available as 100 mg/vial in single-use vial for reconstitution, supplied as lyophilized powder.

Blmf will be delivered as IV solution over at least 30 minutes.

Belantamab Mafodotin-Blmf

Daratumumab will be administered with subcutaneous injections. On days where Blmf is given together with daratumumab, daratumumab should be performed first.

Lenalidomide will be administered per os.

Dexamethasone will be administered intravenously or per os.

Maria Pagoni, Dr

Athanasios-Meletios Dimopoulos, Professor

Eirini Katodritou, Dr.

Evangelos Terpos, Prof

This is a phase 1/2, open label, study designed to assess the safety and clinical activity of different belantamab mafodotin doses in combination with daratumumab, lenalidomide and dexamethasone.

The study will evaluate different doses of belantamab mafodotin in combination with daratumumab, lenalidomide and dexamethasone in 2 cohorts and will determine the recommended phase 2 dose (RP2D) to be further evaluated for safety and clinical activity in the dose expansion cohort. The RP2D dose will be used for future studies in the transplant ineligible newly diagnosed multiple myeloma setting.

Overall, approximately 36 participants will be enrolled in the study. Participant follow-up will continue up to 3 years after the last participant is randomized. The estimated accrual period will be 12 months corresponding to an approximate total study duration of 4 years.

A Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin in Combination With Daratumumab, Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Transplant Ineligible

A Phase 1/2, Dose and Schedule Evaluation Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin Administered in Combination With Daratumumab, Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Transplant Ineligible (EAE 120)

The number (%) of participants and 95% CI with the DLT in each of the cohorts 1-2, using the DLT evaluable population.

The number (%) of participants with AEs and SAEs in each of the cohorts 1-2, using the DLT evaluable and Safety populations.

Number of participants with ocular toxicity of Grade 2 or higher (per KVA scale).

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 (sCR) (For the 'intention to treat' (ITT) population).

ORR and 95% CI as per IMWG by Investigator Assessment. ORR is defined as the percentage of participants with a confirmed PR, VGPR, CR or sCR.

The RDI is defined as the percentage of the total administered over the total planned lenalidomide dose.

Cumulative belantamab mafodotin dose of (DLT evaluable population, safety population) administered in combination with daratumumab, lenalidomide and dexamethasone, i.e., the total dose of belantamab mafodotin that was administered.

VGPR+ and 95% CI as per IMWG by Investigator Assessment (ITT population) \[Part 1 only\]; ORR is defined as the percentage of participants with a confirmed VGPR, CR or sCR.

TTR as per IMWG by Investigator Assessment (ITT population). TTR is defined as the time (in months) between the date of randomization and the first evidence of confirmed response (PR or better) for participants who achieve a response (i.e., confirmed PR or better).

Descriptive methods will be used for the estimation of the time to response (i.e., mean, standard deviation, median, 1st and 3rd quartiles, minimum value and maximum value).

DoR as per IMWG by Investigator Assessment (ITT population). DoR is defined as the time (months) from first evidence of confirmed PR or better until the earliest date of: documented disease progression (PD) per IMWG response criteria; or death due to PD among participants who achieved a response of PR or better. For alive and progression-free participants, data will be censored at the date of initiation of the subsequent line of treatment or at the last date of follow-up that the participant was known to be alive and progression-free.

The Kaplan-Meier method will be used for the estimation of DoR. The median DoR will be presented along with the respective 95% confidence intervals \[CIs\]) and the 1st and 3rd quartiles.

CRR as per IMWG by Investigator Assessment (ITT population). CRR is defined as the percentage of participants with a confirmed CR or sCR. The denominator will be the total number of participants in each population, cohort and group respectively.

MRD negativity rate (ITT population) is defined as the number (%) of participants who achieve MRD negativity (at or below the threshold of 10-5), assessed via Next Generation Flow (NGF). 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). PFS is defined as the time (in months) from randomization until the earliest date of documented PD per IMWG, or death due to any cause. For participants who neither progress nor die, the PFS will be censored at the date of their last adequate disease assessment. For participants who start a new anti-myeloma treatment, PFS will be censored at the date of the last adequate assessment before the start of the new treatment. For a randomized participant who does not have any post-baseline disease assessments and who has not died, PFS will be censored at the randomization date.

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 is defined as the time from first dose/randomization until death due to any cause. If a participant is not known to have died, survival time will be censored at the date of last contact ("last known date alive").

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 (on ophthalmic exam) (DLT evaluable population, Safety population).

Concentration-time data: linear and semi-logistic unique profiles of concentration-time and the mean and median profiles (as applicable) will be graphically represented for belantamab mafodotin. Belantamab mafodotin concentrations will be presented for each participant and summarized (as applicable) at each PK timepoint and cohort.

PK parameters: Concentration-time data can be presented, considering data from other studies and analyzed using a population PK analysis. The Cmax will be calculated. The results of these analyses can be included in a separate report.

PK parameters will be descriptively summarized using mean, median, standard deviation (SD), and 95% CI, minimum/maximum value, geometric mean and coefficient of variation.

Concentration-time data: linear and semi-logistic unique profiles of concentration-time and the mean and median profiles (as applicable) will be graphically represented for belantamab mafodotin. Belantamab mafodotin concentrations will be presented for each participant and summarized (as applicable) at each PK timepoint and cohort.

PK parameters: Concentration-time data can be presented, considering data from other studies and analyzed using a population PK analysis. The AUC will be calculated. The results of these analyses can be included in a separate report.

PK parameters will be descriptively summarized using mean, median, standard deviation (SD), and 95% CI, minimum/maximum value, geometric mean and coefficient of variation.

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.

KVA events, dose holds, worst post-baseline BCVA and incidence of Grade 4 corneal findings will be descriptively summarized using frequencies and proportions. No statistical comparison will be made between the 2 groups.

GlaxoSmithKline

Hellenic Society of Hematology

Symptoms and General Pathology

Monoclonal Gammopathy of Undetermined Significance

Waldenstrom Macroglobulinemia

Lymphatic Diseases

Hypergammaglobulinemia

Light Chain Deposition Disease

Anti-Infective Agents

Rifaximin

Anti-Bacterial Agents

Patients receive rifaximin PO TID on days 1-14 in the absence of disease progression or unacceptable toxicity.

Madhav Dhodapkar, MD

Bryan Burton

Eduardo Sanabria

This trial studies how well rifaximin works in treating patients with monoclonal gammopathy. Antibiotics, such as rifaximin, may help to kill bacteria in the intestines and reduce the abnormal protein or cells in patients with monoclonal gammopathy.

PRIMARY OBJECTIVE:

I. To evaluate the effect of a 2-week course of rifaximin on clonal immunoglobulin (Ig) in patients with monoclonal gammopathy.

SECONDARY OBJECTIVES:

I. To evaluate safety and tolerability of a 2-week course of rifaximin.

II. To evaluate changes in stool microbiota by 16S ribosomal ribonucleic acid (rRNA) gene (16S) sequencing.

III. To evaluate changes in gammopathy as assessed by changes in clonal Ig and/or plasma cells.

OUTLINE:

Patients receive rifaximin orally (PO) thrice daily (TID) on days 1-14 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 8 weeks.

Rifaximin in Patients With Monoclonal Gammopathy

Pilot Study of Oral Rifaximin in Patients With Monoclonal Gammopathy

Clinical response rate will be calculated as proportion (responders/total patients).

Incidence of adverse events (AEs) occurring during the study will be summarized by system organ class and preferred term. Adverse events will also be summarized by causality and grade. Serious adverse events will be listed separately.

16S sequencing will be used to compare changes in stool microbiota.

Changes in clonal Ig will be used to assess changes in gammopathy.

Emory University

Principal Investigator

Pomalidomide

Belantamab mafodotin will be administered by intravenous infusion as a combination therapy as a calculated dose on Day 1 of every other 28-day cycle.

Belantamab mafodotin starting dose for Part 1:

* Cohort 1: 1.4 Q8W = 1.4 mg/kg on Day 1 of every other 28-day cycle
* Cohort 2: 1.9 Q8W = 1.9 mg/kg on Day 1 of every other 28-day cycle

Daratumumab 1800mg SC (fixed dose) on:

Cycles 1-2: days 1, 8, 15, 22 Cycles 3-6: days 1, 15 Cycles 7+: day 1

Pomalidomide: 4 mg/d on days 1-21 of every 28-day cycle.

Dexamethasone: 40 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants \< 75 years; 20 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants ≥ 75 years.

Blmf will be available as 100 mg/vial in single-use vial for reconstitution, supplied as lyophilized powder. Blmf will be delivered as IV solution over at least 30 minutes

Pomalidomide will be administered per os.

This is a phase 1/2, open label, single-center study designed to assess the safety and preliminary clinical activity of different belantamab mafodotin doses in combination with daratumumab, pomalidomide, and dexamethasone (DPd) in patients with Relapsed/ Refractory Multiple Myeloma (RRMM) previously treated with one line of therapy who are lenalidomide refractory.

This will be a 2-Part study. Part 1 will evaluate the safety of belantamab mafodotin in combination with DPd in 2 cohorts and determine the Recommended Phase 2 Dose (RP2D). In the dose expansion phase (Part 2) an expansion cohort will be treated with the RP2D. The expansion cohort will randomize participants (1:1) in two groups to evaluate two alternate dose modification guidelines for corneal AEs. Part 2 will further evaluate the safety and assess the preliminary clinical activity of the belantamab mafodotin RP2D in combination with DPd.

Overall, approximately 48 participants will be enrolled in the study. Participant follow-up will continue up to 3 years after the last participant is randomized. The estimated accrual period will be 12 months corresponding to an approximate total study duration of 4 years.

A Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin in Combination With Daratumumab, Pomalidomide and Dexamethasone in Patients With Relapsed/ Refractory Multiple Myeloma Previously Treated With One Line Therapy Who Are Lenalidomide Refractory

A Phase 1/2, Dose and Schedule Evaluation Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin Administered in Combination With Daratumumab, Pomalidomide and Dexamethasone in Patients With Relapsed/ Refractory Multiple Myeloma Previously Treated With One Line of Therapy Who Are Lenalidomide Refractory.

The number (percent) of participants with DLTs using the DLT evaluable population.

The number (percent) of participants with AEs and SAEs using the DLT evaluable and Safety populations.

The number (percent) of participants with Grade ≥2 ocular toxicity per Keratopathy Visual Acuity (KVA) scale.

Cumulative belantamab mafodotin dose of (DLT evaluable population, safety population) administered in combination with daratumumab, pomalidomide and dexamethasone, i.e., the total dose of belantamab mafodotin that was administered.

ORR and 95% CI as per IMWG by Investigator Assessment (ITT population); ORR is defined as the percentage of participants with a confirmed PR, VGPR, CR or sCR.

VGPR+ and 95% CI as per IMWG by Investigator Assessment (ITT population);ORR is defined as the percentage of participants with a confirmed VGPR, CR or sCR.

TTR as per IMWG by Investigator Assessment (ITT population). TTR is defined as the time (in months) between the date of randomization and the first evidence of confirmed response (PR or better) for participants who achieve a response (i.e., confirmed PR or better).

DoR as per IMWG by Investigator Assessment (ITT population). DoR is defined as the time (months) from first evidence of confirmed PR or better until the earliest date of: documented disease progression (PD) per IMWG response criteria; or death due to PD among participants who achieved a response of PR or better. For alive and progression-free participants, data will be censored at the date of initiation of the subsequent line of treatment or at the last date of follow-up that the participant was known to be alive and progression-free.

CRR as per IMWG by Investigator Assessment (ITT population). CRR is defined as the percentage of participants with a confirmed CR or sCR. The denominator will be the total number of participants in each population and group respectively.

MRD negativity rate (ITT population); defined as the number (percent) of participants who achieve MRD negativity (at or below the threshold of 10-5), assessed via NGF in participants with CR or better response. The denominator will be the total number of participants in each population group respectively.

VGPR or better as per IMWG by Investigator Assessment (ITT population). VGPR or better rate is defined as the percentage of participants with a confirmed VGPR, CR or sCR. The denominator will be the total number of participants in each population, and group respectively.

PFS as per IMWG by Investigator Assessment (ITT population, Safety population). PFS is defined as the time (in months) from randomization until the earliest date of documented PD per IMWG, or death due to any cause. For participants who neither progress nor die, the PFS will be censored at the date of their last adequate disease assessment. For participants who start a new anti-myeloma treatment, PFS will be censored at the date of the last adequate assessment before the start of the new treatment. For a randomized participant who does not have any post-baseline disease assessments and who has not died, PFS will be censored at the randomization date.

OS (ITT population, Safety population). OS is defined as the time from first dose/randomization until death due to any cause. If a participant is not known to have died, survival time will be censored at the date of last contact ("last known date alive").

Number (percent) of participants with abnormal ocular findings (on ophthalmic exam) (DLT evaluable population, Safety population).

Concentration-time data: linear and semi-logistic unique profiles of concentration-time and the mean and median profiles (as applicable) will be graphically represented for belantamab mafodotin. Belantamab mafodotin concentrations will be presented for each participant and summarized (as applicable) at each PK timepoint.

Number of participants with within-participant meaningful change in ocular symptoms and related impacts as measured by the Vision Related Anamnestic Tool.

Proportion of participants with within-participant meaningful change in ocular symptoms and related impacts as measured by the Vision Related Anamnestic Tool.

No statistical comparison will be made between the 2 groups.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin in Combination With Daratumumab, Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Transplant Ineligible	NCT05280275	Multiple Myelom... Neoplasms Neoplasms, Plas... Gammopathy, Mon... Paraproteinemia... Blood Protein D... Haematologic Di... Corneal Disease	Belantamab Mafo... Daratumumab Lenalidomide Dexamethasone	18 Years -	Hellenic Society of Hematology
Rifaximin in Patients With Monoclonal Gammopathy	NCT03820817	IgA Monoclonal ... IgG Monoclonal ... IgM Monoclonal ... Light Chain Dep... Monoclonal Gamm... Smoldering Wald... Waldenstrom Mac... Gammopathy, Mon... Gammopathy Igg	Rifaximin	18 Years -	Emory University
Rifaximin in Patients With Monoclonal Gammopathy	NCT03820817	IgA Monoclonal ... IgG Monoclonal ... IgM Monoclonal ... Light Chain Dep... Monoclonal Gamm... Smoldering Wald... Waldenstrom Mac... Gammopathy, Mon... Gammopathy Igg	Rifaximin	18 Years -	Emory University
A Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin in Combination With Daratumumab, Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Transplant Ineligible	NCT05280275	Multiple Myelom... Neoplasms Neoplasms, Plas... Gammopathy, Mon... Paraproteinemia... Blood Protein D... Haematologic Di... Corneal Disease	Belantamab Mafo... Daratumumab Lenalidomide Dexamethasone	18 Years -	Hellenic Society of Hematology
A Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin in Combination With Daratumumab, Pomalidomide and Dexamethasone in Patients With Relapsed/ Refractory Multiple Myeloma Previously Treated With One Line Therapy Who Are Lenalidomide Refractory	NCT05581875	Multiple Myelom... Multiple Myelom... Neoplasms Gammopathy, Mon... Paraproteinemia... Blood Protein D... Haematologic Di... Corneal Disease Neoplasms, Plas...	Belantamab Mafo... Daratumumab Pomalidomide Dexamethasone	18 Years -	Hellenic Society of Hematology
A Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin in Combination With Daratumumab, Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Transplant Ineligible	NCT05280275	Multiple Myelom... Neoplasms Neoplasms, Plas... Gammopathy, Mon... Paraproteinemia... Blood Protein D... Haematologic Di... Corneal Disease	Belantamab Mafo... Daratumumab Lenalidomide Dexamethasone	18 Years -	Hellenic Society of Hematology

Spots Global Cancer Trial Database for gammopathy, monoclonal