Belantamab Mafodotin for AL Amyloidosis

Recruiting at 4 trial locations

Overseen By Donglan Xia

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Texas Southwestern Medical Center

Must be taking: Proteosome inhibitors, Alkylators, CD38 antibodies

Disqualifiers: Multiple myeloma, Corneal disease, Cardiovascular conditions, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called Belantamab Mafodotin to evaluate its safety and effectiveness for people with AL Amyloidosis, a condition where abnormal proteins accumulate in organs. The trial consists of two parts: the first part identifies the optimal dose of the drug, and the second part tests that dose further. Individuals with AL Amyloidosis who have not responded to standard treatments or can no longer tolerate them might be suitable candidates for this trial. As a Phase 1 and Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial group, offering a chance to be among the first to benefit from this potential new therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients must have completed other systemic therapy or investigational drugs more than 28 days before registration, which might imply a need to pause certain treatments. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that Belantamab Mafodotin is likely to be safe for humans?

Research has shown that belantamab mafodotin has been tested for safety in people with AL amyloidosis. In one study, 75% of patients responded well to the treatment. However, some experienced common side effects, such as vision changes. These side effects were usually manageable and did not cause participants to leave the study.

The study available for participation is in the early stages, so researchers are still determining the best dose to use. While the treatment appears promising, some unknown risks may still exist. However, belantamab mafodotin is already used for other conditions, suggesting it is considered safe enough in those cases. Always consult your doctor to decide if joining a trial is right for you. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for amyloidosis?

Unlike the standard treatments for AL Amyloidosis, which often include chemotherapy and stem cell transplants, Belantamab mafodotin stands out due to its unique mechanism of action. This treatment is an antibody-drug conjugate, which specifically targets and delivers a cytotoxic agent directly to the cancerous cells, potentially minimizing damage to healthy cells. Researchers are excited about Belantamab mafodotin because it offers a targeted approach that could result in fewer side effects and improved outcomes for patients. Additionally, its flexible dosing schedule, as seen in the trial, may offer more personalized treatment options tailored to individual patient needs.

What evidence suggests that Belantamab Mafodotin might be an effective treatment for amyloidosis?

This trial will evaluate Belantamab Mafodotin for treating AL amyloidosis. Studies have shown that Belantamab Mafodotin can be effective; one study reported that 89% of patients experienced a very good partial response, and 67% achieved a complete response. This drug targets a protein called BCMA on cancer cells, aiding the immune system in attacking them. It has also been used to treat other blood cancers like multiple myeloma, showing promise in these cases as well. ^{3 5 6 7 8}

Who Is on the Research Team?

Larry Anderson, M.D.

Principal Investigator

UT Southwestern Medical Center

Are You a Good Fit for This Trial?

Adults over 18 with relapsed or refractory AL Amyloidosis, who have tried multiple treatments including a proteasome inhibitor and stem cell transplant. They must have an ejection fraction >35%, stable heart condition, measurable disease, and adequate organ function. Women of childbearing potential need a negative pregnancy test; men agree to contraception rules. Excludes those with recent major surgery, active infections, unstable health conditions, or hypersensitivity to the drug.

Inclusion Criteria

I cannot tolerate or did not respond to previous treatments.

I am a woman who can have children and have a negative pregnancy test taken within the last 3 days.

My AL Amyloidosis affects one or more of my organs.

Exclusion Criteria

My liver and bile ducts are currently stable.

I have a serious heart condition.

Presence of any comorbid or uncontrolled medical condition at screening, which in the opinion of the investigator would increase the potential risk to the subject

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Exploration (Escalation)

This phase will identify and select an appropriate dose of Belantamab mafodotin regarding safety and preliminary evaluation of hematological and organ response.

Up to 18 weeks

Visits every 8-12 weeks depending on dose cohort

Dose Cohort Expansion

This phase will further define the depth and durability of both hematological and organ response at the dose level found to be safe and effective in phase 1.

Up to 2 years

Visits every 4-12 weeks as determined by Part 1 recommended dosage

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years after the last dose

What Are the Treatments Tested in This Trial?

Interventions

• Belantamab mafodotin

Trial Overview The trial is testing different doses of Belantamab Mafodotin (1.9mg/kg or 2.5mg/kg) given every 4, 6 or 8 weeks for safety and effectiveness in treating AL Amyloidosis that has come back or hasn't responded to treatment.

How Is the Trial Designed?

Group I: Cohort Dose Expansion for Part 2 Experimental Treatment 1 Intervention

Cohort Dose expansion for Part 2: Belantamab mafodotin Dose from1.0 mg/kg to 2.5mg/kg every 4 weeks, 6 weeks, 8 weeks, or 12 weeks as determined by Part 1 recommended dosage calculations.

Group II: Cohort (DL 0) for Part 1 Experimental Treatment 1 Intervention

Cohort (DL 0) for Starting Dose : 1.9 mg/kg Belantamab mafodotin intravenously every 8 weeks

Group III: Cohort (DL -3) for Part 1 Experimental Treatment 1 Intervention

Cohort (DL -3) for Dose De-escalation: 1.0 mg/kg Belantamab mafodotin intravenously every 12 weeks

Group IV: Cohort (DL -2) for Part 1 Experimental Treatment 2 Interventions

Cohort (DL -2) for Dose De-escalation: 1.4 mg/kg Belantamab mafodotin intravenously every 12 weeks

Group V: Cohort (DL -1) for Part 1 Experimental Treatment 2 Interventions

Cohort (DL -1) for Dose De-escalation : 1.9 mg/kg Belantamab mafodotin intravenously every 12 weeks

Group VI: Cohort (DL +1) for Part 1 Experimental Treatment 1 Intervention

Cohort (DL +1) for Dose Escalation: 2.5 mg/kg Belantamab mafodotin intravenously every 8 weeks

Belantamab mafodotin is already approved in United States, European Union for the following indications:

Approved in United States as Blenrep for:

• Relapsed or refractory multiple myeloma (approval withdrawn)

Approved in European Union as Blenrep for:

• Relapsed or refractory multiple myeloma

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Published Research Related to This Trial

The combination therapy of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (daratumumab-CyBorD) has become the new standard-of-care for systemic light chain (AL) amyloidosis, showing high rates of hematologic and organ response.

Recent advancements in patient selection and induction regimens have significantly reduced the mortality associated with autologous stem cell transplant (ASCT), while new treatments like venetoclax are proving effective for patients with specific genetic abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the treatment of light chain amyloidosis. Palladini, G., Milani, P.[2023]

In a subset analysis of a phase II trial involving 72 heavily pretreated metastatic breast cancer patients, pemetrexed showed a 26% overall response rate, indicating its potential effectiveness after prior treatments with anthracyclines and taxanes.

Pemetrexed was well tolerated, with a median duration of response of 5.4 months and a median survival of 12.8 months, suggesting it could be a viable option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis. Spielmann, M., Martin, M., Namer, M., et al.[2016]

Gamma-tert-Butylaminopterin (gamma-tBAMT) was synthesized and shown to have similar inhibitory effects on dihydrofolate reductase (DHFR) as gamma-tert-butyl methotrexate (gamma-tBMTX), indicating potential as an effective treatment option.

In vivo studies demonstrated that gamma-tBAMT was nearly as potent as gamma-tBMTX against L1210 leukemia, but gamma-tBAMT was more effective than methotrexate and showed only partial cross-resistance in MTX-resistant cell lines, suggesting it may overcome some resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin. Rosowsky, A., Freisheim, JH., Bader, H., et al.[2019]

Pemetrexed disodium is a multitargeted antifolate that works by inhibiting key enzymes involved in DNA synthesis, making it effective against various solid tumors, including breast cancer.

When combined with gemcitabine, pemetrexed disodium shows promising clinical activity for treating metastatic breast cancer, indicating its potential as a combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and Pemetrexed disodium in treating breast cancer. Adjei, AA.[2022]

AL amyloidosis is a serious condition that can lead to cardiac emergencies, and understanding its pathophysiology is essential for effective treatment, particularly focusing on stabilizing light chains.

Recent advancements in treatment include the approval of daratumumab and ongoing investigations of novel therapies like isatuximab, belantamab, and elotuzumab, which target specific proteins on plasma cells, offering hope for improved management of this complex disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future Developments in Light Chain Amyloidosis Management. Rodriguez, M., Lenihan, D., Merlini, G.[2022]

In a study of 49 patients with relapsed/refractory AL amyloidosis treated with daratumumab, the overall hematologic response rate was 81%, with 64% achieving a very good partial response or better, indicating strong efficacy in this challenging patient population.

Daratumumab was found to be safe and well tolerated, with no patients discontinuing treatment due to toxicity, and it demonstrated significant cardiac and renal responses (74% and 73%, respectively), supporting its use in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab for relapsed AL amyloidosis-When cumulative real-world data precedes clinical trials: A multisite study and systematic literature review. Shragai, T., Gatt, M., Lavie, N., et al.[2021]

In a phase II trial involving 31 patients with relapsed/refractory AL amyloidosis, 57% achieved a partial hematologic response or better after treatment with bendamustine and dexamethasone, indicating significant efficacy.

The treatment was well tolerated, with no grade 5 adverse events reported, although 65% of patients experienced grade 3-4 adverse events, primarily myelosuppression, fatigue, and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. Lentzsch, S., Lagos, GG., Comenzo, RL., et al.[2021]

Chemically self-assembled antibody nanorings (CSANs) can effectively target CD3+ T-leukemia cells, showing rapid internalization and stability for several hours, which allows for monitoring their cellular behavior using fluorescence.

The CSANs demonstrated significantly higher cytotoxicity (GI(50) = 0.5-1.5 μM) compared to the bis-methotrexate ligand alone (GI(50) > 20 μM), indicating their potential as effective tissue-selective drug carriers while remaining nontoxic to the cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemically self-assembled antibody nanostructures as potential drug carriers. Fegan, A., Kumarapperuma, SC., Wagner, CR.[2021]

Alimta, a multitargeted antifolate, has shown promising results as a single agent for treating malignant pleural mesothelioma (MPM), a rare and aggressive cancer with no proven standard chemotherapy.

A recent phase III trial demonstrated that combining Alimta with cisplatin significantly improves treatment efficacy compared to cisplatin alone, and vitamin supplementation can help reduce side effects without affecting the drug's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of Alimta in the treatment of malignant pleural mesothelioma: an overview of preclinical and clinical trials. Hanauske, AR.[2015]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38171355/

Real-world efficacy of single-agent belantamab mafodotin ... The best haematological overall response rate was 71%, and the complete/very good partial response was 58%. Sixty-eight percent had keratopathy ...

2. ashpublications.org ashpublications.org/blood/article/146/16/1874/547615/BCMA-BeCoMing-a-new-hope-for-AL-amyloidosis

BCMA: BeCoMing a new hope for AL amyloidosis | Blood All patients achieved rapid (median, 9 days) hematologic responses, 89% at least hematologic VGPR, and 67% hematologic complete response (CR), ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05145816

Phase 1/2a Study of Belantamab Mafodotin in Relapsed or ... The goal of this study is to test the safety of drug, Belantamab Mafodotin, and see what effects (good and bad) it has on people who take it and amyloidosis ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S295032802500038X

Belantamab mafodotin in patients with relapsed/refractory ... Belantamab mafodotin showed ORR 45%, PFS 3.8 months, and OS 17.2 months in relapsed/refractory multiple myeloma in a real-world setting. · ORR was 29% in heavily ...

5. nature.com nature.com/articles/s41408-022-00717-2

High response rates with single-agent belantamab ... We report our results using belantamab mafodotin monotherapy for the treatment of patients with relapsed refractory AL amyloidosis including those with CKD.

6. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1927/531239/Efficacy-and-Safety-of-Belantamab-Mafodotin

Efficacy and Safety of Belantamab Mafodotin Monotherapy in ... We present updated safety and efficacy data from the EMN27 study, assessing belamaf monotherapy in pts with RR AL amyloidosis.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39357511/

Belantamab Mafodotin in Relapsed/Refractory AL ... The overall hematological response rate (ORR) was 75% (9/12), including 5 complete responses. Six of the 10 evaluable patients had organ ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124046743

Efficacy and Safety of Belantamab Mafodotin Monotherapy ... Herein, we present updated safety and efficacy data from the EMN27 study, assessing belamaf monotherapy in pts with RR AL amyloidosis. METHODS. The ongoing, ...