Loncastuximab Tesirine + Rituximab for Diffuse Large B-Cell Lymphoma

Overseen By Joseph M Tuscano

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Joseph Tuscano

Must not be taking: Immunosuppressives, CAM, others

Disqualifiers: CNS involvement, Severe infections, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 6 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial evaluates whether loncastuximab tesirine and rituximab followed by dose-adjusted doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisone works to treat patients with high risk diffuse large B-cell lymphoma. Loncastuximab tesirine is a monoclonal antibody called loncastuximab, linked to a drug called tesirine. It is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD19 receptors, and delivers tesirine to kill them. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Chemotherapy drugs such as doxorubicin, vincristine, and cyclophosphamide work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Prednisone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving loncastuximab tesirine and rituximab in combination with dose-adjusted doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisone may be more effective at treating high risk diffuse large B-cell lymphoma patients than standard treatments.

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

The trial protocol does not specify if you must stop all current medications. However, you cannot use certain treatments like complementary and alternative medications within 1 week, investigational agents within 3 weeks, or immunosuppressive medications within 14 days before starting the trial. Some exceptions apply, such as steroids and bisphosphonate therapy. It's best to discuss your specific medications with the trial team.

What data supports the idea that Loncastuximab Tesirine + Rituximab for Diffuse Large B-Cell Lymphoma is an effective treatment?

The available research shows that adding rituximab to treatments for diffuse large B-cell lymphoma (DLBCL) has improved outcomes. For example, in one study, patients who received rituximab with their chemotherapy had better progression-free survival compared to those who did not. Another study found that a two-weekly chemotherapy regimen with rituximab led to better survival rates than a three-weekly regimen. While these studies focus on rituximab combined with other drugs, they suggest that rituximab can enhance the effectiveness of treatments for DLBCL, which supports the idea that combining it with Loncastuximab Tesirine could be beneficial. ^{1 2 3 4 5}

What safety data exists for the treatment of Loncastuximab Tesirine + Rituximab for Diffuse Large B-Cell Lymphoma?

The provided research does not directly address the safety data for Loncastuximab Tesirine + Rituximab. The studies focus on antiemetic efficacy and safety of dolasetron and ondansetron during chemotherapy, and the safety of dolasetron in patients receiving doxorubicin and/or cyclophosphamide. These studies do not provide specific safety data for the combination of Loncastuximab Tesirine and Rituximab. ^{6 7 8 9 10}

Is the drug Loncastuximab Tesirine + Rituximab promising for treating Diffuse Large B-Cell Lymphoma?

Yes, the drug Loncastuximab Tesirine + Rituximab shows promise for treating Diffuse Large B-Cell Lymphoma. Research indicates that Loncastuximab Tesirine has notable antitumor activity and an acceptable safety profile, especially for patients who have not responded to other treatments. It has shown encouraging results in improving health-related quality of life and has a good response rate in clinical trials. ^{11 12 13 14 15}

Research Team

Joseph M. Tuscano

Principal Investigator

University of California, Davis

Eligibility Criteria

This trial is for adults with untreated high-risk diffuse large B-cell lymphoma, confirmed by specific criteria. Participants must have measurable disease, be in relatively good health (ECOG <=2), and have a life expectancy of at least 6 months. They should not have had certain previous treatments or conditions that could affect the study results.

Inclusion Criteria

Leukocytes >= 2,500/uL

My kidneys are functioning well enough to clear creatinine.

Life expectancy >= 6 months

Exclusion Criteria

I have a skin condition like eczema, psoriasis, or vitiligo.

Specific timeframes for prior treatments

I have a serious liver condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive rituximab, loncastuximab tesirine, etoposide, doxorubicin, vincristine, prednisone, and cyclophosphamide

6 weeks

Multiple visits (in-person) for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Regular visits (in-person) for CT or PET/CT scans

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin
• Etoposide
• Loncastuximab Tesirine
• Prednisone
• Rituximab
• Vincristine

Trial Overview The trial tests loncastuximab tesirine and rituximab followed by DA-EPOCH-R chemotherapy to see if it's more effective for treating high-risk diffuse large B-cell lymphoma than standard therapies. It combines targeted therapy with traditional chemotherapy.

Participant Groups

Group I: Treatment (Lonca-R, DA-EPOCH-R) Experimental Treatment 7 Interventions

Patients receive rituximab IV, loncastuximab tesirine IV, etoposide IV, doxorubicin IV, vincristine IV, prednisone PO, and cyclophosphamide IV on study. Patients also undergo collection of blood samples and bone marrow aspiration and biopsy at screening and CT or PET/CT at screening, throughout the study, and during follow up.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Joseph Tuscano

Lead Sponsor

Trials

8

Recruited

180+

ADC Therapeutics

Collaborator

Trials

2

Recruited

20+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

ADC Therapeutics S.A.

Industry Sponsor

Trials

32

Recruited

2,700+

Findings from Research

In a study of 134 patients with diffuse large B-cell lymphoma (DLBCL) involving the testis, the addition of rituximab to standard chemotherapy (R-CHOP) significantly improved progression-free survival and overall survival, with hazard ratios of 0.42 and 0.39 respectively, indicating a strong protective effect.

Despite the benefits of rituximab in reducing lymphoma recurrence, the risk of central nervous system (CNS) relapse remained high, suggesting that additional strategies for CNS prophylaxis are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era. Kridel, R., Telio, D., Villa, D., et al.[2017]

In a study of 112 patients under 65 years old with diffuse large B-cell lymphoma, the combination of rituximab and high-dose sequential chemotherapy led to an impressive 80% clinical remission rate, demonstrating its efficacy in treating this aggressive cancer.

At a median follow-up of 48 months, 78% of patients remained alive and 73% were in continuous remission, indicating that this treatment significantly improves life expectancy compared to conventional chemotherapy for younger patients with higher risk scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Tarella, C., Zanni, M., Di Nicola, M., et al.[2022]

A pilot study involving 80 patients with diffuse large B-cell lymphoma (DLBCL) showed that administering rituximab with chemotherapy every 14 days (R-CHOP-14) is feasible and effective, with 73% of patients achieving complete remission after treatment.

With a median follow-up of 26 months, the study reported a progression-free survival rate of 72% and an overall survival rate of 86% at 30 months, indicating promising long-term outcomes for patients under 70 years old.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study. Rueda, A., Sabin, P., Rifá, J., et al.[2015]

In a study of 20 patients with untreated poor prognosis diffuse large B-cell lymphoma (DLBCL), the two-weekly dose-adjusted EPOCH-like chemotherapy (DA-EDOCH14-R) showed a promising three-year progression-free survival (PFS) rate of 95%, compared to 74% in a previous trial with a three-weekly regimen.

The treatment was well-tolerated with manageable toxicity and no therapy-related deaths, highlighting its safety, especially for patients with a high-risk prognosis (age-adjusted International Prognostic Index of 3), where PFS reached 100% compared to just 30% in the previous trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. García-Suárez, J., Flores, E., Callejas, M., et al.[2015]

The CHOEA-7 chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, etoposide, and ara-C, has shown excellent results in treating patients with CD 20-positive non-Hodgkin's lymphoma.

Adding rituximab to the CHOEA-7 regimen (RCHOEA-7) further enhances treatment efficacy, indicating a promising approach for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. Uzuka, Y., Saitou, Y., Saitou, K., et al.[2015]

In a study involving 197 patients undergoing high-dose chemotherapy, dolasetron and ondansetron were found to be equally effective in preventing nausea and vomiting, with total response rates of 45.7% for dolasetron and 46.9% for ondansetron.

Both dolasetron and ondansetron were well-tolerated by patients, indicating that they are safe options for managing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, multicenter, open-label comparison of the antiemetic efficacy of dolasetron versus ondansetron for the prevention of nausea and vomiting during high-dose myeloablative chemotherapy. Mandanas, RA., Beveridge, R., Rifkin, RM., et al.[2020]

In a study involving 307 cancer patients, dolasetron mesylate effectively prevented nausea and vomiting during chemotherapy, with a significant increase in complete response rates from 44.7% at 25 mg to 82.5% at 200 mg.

All doses of dolasetron were well tolerated, with the most common side effects being headache and dizziness, indicating a favorable safety profile for this antiemetic treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral dolasetron mesylate in patients receiving moderately emetogenic platinum-containing chemotherapy. Oral Dolasetron Dose Response Study Group. Grote, TH., Pineda, LF., Figlin, RA., et al.[2013]

In a study of 304 Chinese breast cancer patients undergoing doxorubicin-cyclophosphamide chemotherapy, adding olanzapine to an aprepitant-based antiemetic regimen significantly improved the complete response rate and quality of life compared to a standard doublet regimen.

The netupitant/palonosetron/dexamethasone combination was found to be more effective than the aprepitant/ondansetron/dexamethasone regimen, indicating that the choice of antiemetic can greatly impact patient outcomes during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of optimal contemporary antiemetic prophylaxis for doxorubicin-cyclophosphamide chemotherapy in Chinese cancer patients: post-hoc analysis of 3 prospective studies. Yeo, W., Li, L., Lau, TK., et al.[2021]

In a pilot study involving 69 cancer patients, intravenous dolasetron was found to be safe and effective in preventing nausea and vomiting caused by doxorubicin and/or cyclophosphamide, with 61% of patients achieving complete control of emesis.

The study indicated that while increasing doses of dolasetron did not significantly improve antiemetic efficacy, factors like age, gender, and type of chemotherapy were important predictors of treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide. Hesketh, PJ., Gandara, DR., Hesketh, AM., et al.[2019]

A systematic review of 299 studies involving 58,412 patients found that 5-HT3 receptor antagonists are generally safe and effective for reducing nausea and vomiting in chemotherapy patients, with no significant differences in cardiac risks among the agents compared.

However, dolasetron combined with dexamethasone was associated with a higher risk of QTc prolongation compared to ondansetron combined with dexamethasone, indicating a potential safety concern with this combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative safety and effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a systematic review and network meta-analysis. Tricco, AC., Blondal, E., Veroniki, AA., 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 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 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 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]

An integrated pharmacokinetic model for loncastuximab tesirine in treating relapsed/refractory B cell non-Hodgkin lymphoma showed that the drug's exposure is significantly associated with better overall response rates and overall survival, based on data from 328 patients.

Factors like low albumin levels and mild to moderate liver impairment were linked to reduced drug exposure and poorer outcomes, but the study suggests maintaining the current dosing schedule without increases, despite these challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety Exposure-Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma. Hess, B., Townsend, W., Ai, W., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era. [2017]

2. England pubmed.ncbi.nlm.nih.gov

Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). [2022]

3. England pubmed.ncbi.nlm.nih.gov

R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. [2015]

5. Japan pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

A randomized, multicenter, open-label comparison of the antiemetic efficacy of dolasetron versus ondansetron for the prevention of nausea and vomiting during high-dose myeloablative chemotherapy. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Oral dolasetron mesylate in patients receiving moderately emetogenic platinum-containing chemotherapy. Oral Dolasetron Dose Response Study Group. [2013]

8. China pubmed.ncbi.nlm.nih.gov

Identification of optimal contemporary antiemetic prophylaxis for doxorubicin-cyclophosphamide chemotherapy in Chinese cancer patients: post-hoc analysis of 3 prospective studies. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Comparative safety and effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a systematic review and network meta-analysis. [2022]

11. United States 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. [2022]

12. England 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. [2021]

13. United States 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. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. [2022]

15. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety Exposure-Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma. [2022]