Loncastuximab Tesirine Combinations for Non-Hodgkin's Lymphoma

Recruiting at 39 trial locations

Overseen By Contact ADC Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: ADC Therapeutics S.A.

Must not be taking: Immunosuppressants, Corticosteroids, Antivirals, others

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: 34

Duration: Up to 1 year

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of the drug loncastuximab tesirine (an antibody-drug conjugate) when combined with other medications for treating non-Hodgkin's lymphoma, a cancer affecting the lymphatic system. The main goal is to determine the safety of these combinations and identify the best dose for patients. Individuals with non-Hodgkin's lymphoma that has recurred or not responded to previous treatments may be suitable candidates, particularly if they have undergone at least two different treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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 you should not have had certain treatments recently, like chemotherapy or immunosuppressive medication, within a specific time before starting the study. It's best to discuss your current medications with the study team to get a clear answer.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the FDA has approved loncastuximab tesirine for treating diffuse large B-cell lymphoma, a type of blood cancer. This approval indicates prior testing for human safety. When combined with other drugs like mosunetuzumab, studies have found it has a manageable safety profile, meaning side effects are usually expected and manageable.

For the combination of loncastuximab tesirine with glofitamab, research indicates a safety profile similar to each drug individually, with side effects aligning with existing medical understanding.

Studies have also examined loncastuximab tesirine combined with polatuzumab vedotin, showing these combinations are generally well-tolerated, meaning most people can handle the treatment without serious issues.

This study is in an early phase, so researchers are still determining the best doses and safety of these combinations. However, existing data from previous studies provide a good starting point, suggesting these combinations are relatively safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Loncastuximab tesirine is unique because it combines an antibody with a cytotoxic drug, specifically targeting cancer cells in non-Hodgkin's lymphoma (NHL). Unlike standard therapies like R-CHOP or BR (bendamustine and rituximab), loncastuximab tesirine works by delivering a potent toxin directly into the cancer cells, minimizing damage to healthy cells. Researchers are excited about its potential to improve treatment outcomes by directly attacking malignant cells with precision, potentially leading to fewer side effects and improved efficacy. Additionally, its combination with other novel agents like mosunetuzumab, glofitamab, and polatuzumab vedotin in this trial suggests a strategic approach to enhance the therapeutic impact against NHL.

What evidence suggests that this trial's treatments could be effective for Non-Hodgkin's Lymphoma?

Research shows that combining the drug loncastuximab tesirine with mosunetuzumab, one of the treatment arms in this trial, yields promising results for treating diffuse large B-cell lymphoma (DLBCL). Another trial arm involves loncastuximab tesirine with glofitamab, which earlier studies found led to a high overall response rate (ORR) of 94% and a complete response (CR) rate of 72%. In another study, this combination achieved a 93.3% ORR in patients whose DLBCL had returned or was not responding to treatment. Additionally, a separate trial arm will test loncastuximab tesirine combined with polatuzumab vedotin, which has shown similar effectiveness to using each treatment alone, but with potentially better safety. These findings suggest that combining these treatments could effectively treat non-Hodgkin's lymphoma. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

Adults with relapsed or refractory B-cell non-Hodgkin Lymphoma who've had at least two prior treatments can join this trial. They must have measurable disease, adequate organ function, and agree to use effective contraception. Exclusions include significant health issues, recent other cancer therapies, live vaccines, certain infections like HIV/HBV/HCV, CNS lymphoma involvement, known drug hypersensitivities.

Inclusion Criteria

BL (for Arm C only)

I can provide a tissue sample from my tumor.

My B-cell non-Hodgkin Lymphoma has come back or didn't respond to treatment, and I've tried at least two treatments.

Exclusion Criteria

I have chronic hepatitis B and can't or won't take standard antiviral therapy.

History of Stevens-Johnson syndrome, toxic epidermal necrolysis, or macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH)

Breastfeeding or pregnant

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive loncastuximab tesirine in combination with other anti-cancer agents in 21-day cycles

Up to 1 year

Every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Approximately every 12 weeks (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Gemcitabine
• Glofitamab
• Lenalidomide
• Loncastuximab Tesirine
• Mosunetuzumab
• Polatuzumab Vedotin
• Umbralisib

Trial Overview

The study tests the safety and anti-cancer effects of Loncastuximab Tesirine combined with Polatuzumab Vedotin, Glofitamab or Mosunetuzumab in patients. It aims to find the highest dose patients can tolerate without severe side effects (MTD) and suggest a dose for further trials (RDE).

How Is the Trial Designed?

Group I: Part 2 (Dose Expansion): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C) Experimental Treatment 2 Interventions

Participants with B-NHL will receive loncastuximab tesirine in combination with polatuzumab vedotin at the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) if favorable results of Part 1 are received.

Group II: Part 2 (Dose Expansion): Loncastuximab Tesirine + Mosunetuzumab (Arm F) Experimental Treatment 2 Interventions

Participants with B-NHL will receive loncastuximab tesirine in combination with mosunetuzumab at the MTD and/or RDE if favorable results of Part 1 are received.

Group III: Part 2 (Dose Expansion): Loncastuximab Tesirine + Glofitamab (Arm E) Experimental Treatment 3 Interventions

Participants with B-NHL will receive loncastuximab tesirine in combination with glofitamab at the MTD and/or RDE if favorable results of Part 1 are received. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1.

Group IV: Part 1 (Dose Escalation): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C) Experimental Treatment 2 Interventions

Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day (D) 1 of each cycle (where each cycle is 21 days). Participants will also receive polatuzumab vedotin at a dose of 1.8 mg/kg on D1 of each cycle, infusion will be started one hour after end of loncastuximab tesirine infusion.

Group V: Part 1 (Dose Escalation): Loncastuximab Tesirine + Mosunetuzumab (Arm F) Experimental Treatment 2 Interventions

Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day (D) 1 of each cycle (where each cycle is 21 days). Participants will also receive mosunetuzumab 5 mg on C1 D1, 45 mg for C1 D8, C1 D15 and cycles 2-8 D1.

Group VI: Part 1 (Dose Escalation): Loncastuximab Tesirine + Glofitamab (Arm E) Experimental Treatment 3 Interventions

Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on D2 of Cycle (C) 1 and then D1 of all other cycles (where each cycle is 21 days). Participants will also receive glofitamab 2.5 mg on C1 D8, 10 mg on C1 D15 and 30 mg for cycles 2-12 D1. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1.

Gemcitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

ADC Therapeutics S.A.

Lead Sponsor

Trials

32

Recruited

2,700+

Published Research Related to This Trial

Loncastuximab tesirine is an antibody-drug conjugate that targets B cell lymphomas, specifically approved for relapsed/refractory diffuse large B cell lymphoma (DLBCL) after two or more lines of treatment.

The drug works by using an anti-CD19 antibody to deliver a DNA-alkylating agent directly to B cells, enhancing its efficacy in targeting cancer cells while minimizing damage to healthy cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab Tesirine: First Approval. Lee, A.[2021]

In a phase 2 trial involving 145 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), loncastuximab tesirine demonstrated a significant overall response rate of 48.3%, indicating its effectiveness as a treatment option for this challenging patient population.

The treatment was associated with an acceptable safety profile, with serious adverse events occurring in 39% of patients, but none were directly linked to loncastuximab tesirine, suggesting it may be a safe option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Caimi, PF., Ai, W., Alderuccio, JP., et al.[2021]

In a study analyzing overall survival (OS) for treatments of relapsed/refractory B-cell lymphomas, tafasitamab combined with lenalidomide showed superior survival outcomes compared to polatuzumab, selinexor, and loncastuximab tesirine, with hazard ratios indicating a significantly lower risk of death.

The analysis utilized reconstructed patient-level data from published survival graphs, providing a comprehensive comparison of these therapies, although the comparisons were indirect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatments for relapsed-refractory diffuse large B-cell lymphoma: comparison of overall survival outcomes observed with four novel agents. Messori, A., Caccese, E.[2022]

In a phase II study involving 145 patients with relapsed or refractory diffuse large B-cell lymphoma, loncastuximab tesirine demonstrated significant improvements in health-related quality of life, with a notable increase in overall health scores over treatment cycles.

The treatment was well-tolerated, with over 60% of patients reporting minimal bother from side effects, indicating a favorable safety profile alongside its antitumor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life, Symptoms, and Tolerability of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Spira, A., Zhou, X., Chen, L., et al.[2022]

In a study involving 80 patients from the LOTIS-2 trial, loncastuximab tesirine (Lonca) demonstrated a significantly higher overall response rate (53.4%) compared to chemoimmunotherapy (CIT) treatments (40.3%) for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).

Lonca also showed improved overall survival, with a median survival of 10.8 months compared to 6.4 months for CIT, indicating it may be a more effective treatment option for patients with R/R DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted Indirect Comparison of the Efficacy of Loncastuximab Tesirine Versus Treatment in the Chemoimmunotherapy Era for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Hamadani, M., Chen, L., Song, Y., et al.[2022]

In a study analyzing overall survival (OS) for five treatments of relapsed-refractory diffuse large B-cell lymphoma (DLBCL), tafasitamab plus lenalidomide showed the best OS with a median of 26.5 months and a hazard ratio of 0.514 compared to glofitamab, indicating it may be a more effective option.

Despite glofitamab's advanced mechanism as a bispecific antibody, it did not demonstrate a significant OS advantage over the other treatments, with a median survival of 11.7 months, suggesting that other therapies may be more beneficial for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatments for Relapsed-Refractory Diffuse Large B-cell Lymphoma: A Preliminary Evaluation of the Place in Therapy of Glofitamab, a Bispecific Monoclonal Antibody. Messori, A., Rivano, M., Mengato, D., et al.[2023]

Loncastuximab tesirine-lpyl, an anti-CD19 antibody-drug conjugate, has shown a 48.3% overall response rate in patients with relapsed, refractory diffuse large B-cell lymphoma during the phase II LOTIS-2 trial, indicating its efficacy as a treatment option.

The drug demonstrated a tolerable safety profile with common side effects including neutropenia and thrombocytopenia, and no new safety concerns were identified in the phase II trial, suggesting it is safe for further testing in various non-Hodgkin lymphoma subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab tesirine for diffuse large B-cell lymphoma. Zurko, J., Hamadani, M.[2021]

Loncastuximab tesirine-lpyl, an anti-CD19 antibody-drug conjugate, has shown a 48.6% overall response rate in patients with relapsed, refractory diffuse large B-cell lymphoma, indicating its efficacy as a treatment option.

The drug has a tolerable safety profile, with common side effects including neutropenia and thrombocytopenia, leading to its recent FDA approval for treating this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma: a review of clinical data. Furqan, F., Hamadani, M.[2022]

In the phase III AUGMENT trial, lenalidomide combined with rituximab significantly improved progression-free survival in patients with relapsed or refractory follicular lymphoma compared to placebo, showing particular benefit for elderly patients.

Lenalidomide has an acceptable safety profile, although it can cause more frequent cases of severe neutropenia, which can be managed with dosage adjustments and growth factor support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. Blair, HA.[2021]

In a phase 1 study involving 183 patients with relapsed or refractory B-cell non-Hodgkin lymphoma, loncastuximab tesirine demonstrated a promising overall response rate of 45.6%, with 26.7% achieving complete responses, indicating its potential as an effective treatment option.

The study established a recommended dose of 150 µg/kg for phase 2 trials, with an acceptable safety profile characterized by manageable hematologic toxicities, suggesting that loncastuximab tesirine could be a viable alternative to current therapies for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Hamadani, M., Radford, J., Carlo-Stella, C., et al.[2022]

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