Loncastuximab Tesirine + Chemotherapy for Lymphoma

(LONCA Trial)

Recruiting at 2 trial locations

Overseen By Medical College of Wisconsin Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Medical College of Wisconsin

Must not be taking: Antivirals

Disqualifiers: Effusions, Hepatitis, Infections, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

33 Participants Needed

Trial Summary

What is the purpose of this trial?

The overarching hypothesis for this study is that a safe and tolerable dose (i.e., the maximum tolerated dose) will be identified for loncastuximab tesirine in combination with dose-adjusted etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), and rituximab (DA-EPOCH-R) for patients with previously untreated aggressive B-cell lymphoid malignancies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, corticosteroid therapy is allowed without a washout period, and prephase treatment with certain drugs is permitted for symptomatic patients.

What data supports the effectiveness of the drugs used in the Loncastuximab Tesirine + Chemotherapy for Lymphoma trial?

Research shows that etoposide, doxorubicin, and cyclophosphamide are effective in treating various types of lymphoma, with etoposide being particularly useful in different lymphoma subtypes. The CHOP regimen, which includes doxorubicin, cyclophosphamide, vincristine, and prednisone, has been a standard treatment for non-Hodgkin's lymphoma for over 20 years, and adding rituximab has further improved its effectiveness. ^{1 2 3 4 5}

Is the combination of Loncastuximab Tesirine and chemotherapy safe for humans?

The research articles provided do not contain specific safety data for Loncastuximab Tesirine combined with chemotherapy for lymphoma. They focus on the safety of antiemetic drugs used to prevent nausea and vomiting during chemotherapy, which are generally well-tolerated. ^{6 7 8 9 10}

What makes the drug Loncastuximab Tesirine combined with chemotherapy unique for treating lymphoma?

Loncastuximab Tesirine is unique because it is an antibody-drug conjugate that specifically targets CD19, a protein found on many B-cell lymphomas, delivering a toxin directly to cancer cells. This targeted approach, combined with traditional chemotherapy drugs, offers a novel treatment option for patients with relapsed or refractory B-cell non-Hodgkin lymphoma, who have limited alternatives. ^{1 11 12 13 14}

Research Team

Mehdi Hamadani, MD

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

Adults over 18 with specific types of B-cell lymphoma who haven't had multiagent chemotherapy. They can have limited radiation or corticosteroid therapy, and must be physically able to perform daily activities (ECOG 0-3). Their major organs need to function well, they can't be pregnant or breastfeeding, and shouldn't have severe allergies to the study drugs.

Inclusion Criteria

Adequate hematological function: ANC ≥1 × 103/μL and platelet count ≥50 x 10^3/μL

My liver tests are within normal limits, or any high results are due to my condition or Gilbert's syndrome.

I am 18 years old or older.

Exclusion Criteria

Breastfeeding or pregnant

I have chronic hepatitis B but can't or won't take standard antiviral treatments, yet my virus levels are undetectable.

My liver function is severely impaired.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Phase 1a involves a 3+3 dose escalation design to find the maximum tolerated dose (MTD) of loncastuximab tesirine in combination with DA-EPOCH-R.

Up to 21 days per cycle

Cohort Expansion

Phase 1b involves a cohort expansion at the dose level determined to be the recommended phase 2 dose.

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

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

Trial Overview The trial is testing different doses of Loncastuximab Tesirine combined with DA-EPOCH-R chemotherapy in patients with aggressive B-cell lymphomas. The goal is to find the highest dose that's safe and tolerable without causing too many side effects.

Participant Groups

Group I: Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose Experimental Treatment 9 Interventions

The study uses a classic 3+3 dose-escalation design. Three patients will be enrolled into a cohort receiving 0.075 mg/kg by IV. If there is no dose-limiting toxicity (DLT) seen in any of these participants, the trial will enroll additional participants into the next higher dose cohort, which is 0.12 mg/kg by IV. If one patient experiences a DLT at a specific dose, an additional three individuals will be accrued into that same dose cohort. The third dose level is 0.15 mg/kg by IV. DLTs in two or more at a specific dose level indicates that the MTD has been exceeded; dose escalation will not be pursued, and the prior dose level will be expanded to six patients; if there is no more than one patient who experiences a DLT among those six patients, that dose level is considered the MTD. This dose will be added to this record when it is determined.

Group II: Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV. Experimental Treatment 7 Interventions

The study uses a classic 3+3 dose-escalation design. Three patients will be enrolled into a cohort receiving 0.075 mg/kg by IV. If there is no dose-limiting toxicity (DLT) seen in any of these participants, the trial will enroll additional participants into the next higher dose cohort, which is 0.12 mg/kg by IV. If one patient experiences a DLT at a specific dose, an additional three individuals will be accrued into that same dose cohort. The third dose level is 0.15 mg/kg by IV. DLTs in two or more at a specific dose level indicates that the MTD has been exceeded; dose escalation will not be pursued, and the prior dose level will be expanded to six patients; if there is no more than one patient who experiences a DLT among those six patients, that dose level is considered the MTD.

Group III: Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV. Experimental Treatment 7 Interventions

The study uses a classic 3+3 dose-escalation design. Three patients will be enrolled into a cohort receiving 0.075 mg/kg by IV. If there is no dose-limiting toxicity (DLT) seen in any of these participants, the trial will enroll additional participants into the next higher dose cohort, which is 0.12 mg/kg by IV. If one patient experiences a DLT at a specific dose, an additional three individuals will be accrued into that same dose cohort. The third dose level is 0.15 mg/kg by IV. DLTs in two or more at a specific dose level indicates that the MTD has been exceeded; dose escalation will not be pursued, and the prior dose level will be expanded to six patients; if there is no more than one patient who experiences a DLT among those six patients, that dose level is considered the MTD.

Group IV: Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV. Experimental Treatment 7 Interventions

The study uses a classic 3+3 dose-escalation design. Three patients will be enrolled into a cohort receiving 0.075 mg/kg by IV. If there is no dose-limiting toxicity (DLT) seen in any of these participants, the trial will enroll additional participants into the next higher dose cohort, which is 0.12 mg/kg by IV. If one patient experiences a DLT at a specific dose, an additional three individuals will be accrued into that same dose cohort. The third dose level is 0.15 mg/kg by IV. DLTs in two or more at a specific dose level indicates that the MTD has been exceeded; dose escalation will not be pursued, and the prior dose level will be expanded to six patients; if there is no more than one patient who experiences a DLT among those six patients, that dose level is considered the MTD.

Group V: Dose Expansion Phase Experimental Treatment 9 Interventions

Subjects will receive the recommended phase 2 dose (RP2D) identified from dose-escalation phase. This dose will be added to this record when it is determined.

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?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Findings from Research

Etoposide is a key drug in treating malignant lymphomas and Hodgkin's disease, showing broad activity across various subtypes and demonstrating single-agent efficacy comparable to older treatments like alkylating agents and doxorubicin.

The drug works by inhibiting protein synthesis and topoisomerase II, allowing it to provide effective cytotoxicity without cross-resistance, and is integrated into multiple treatment protocols, enhancing the overall management of these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of etoposide in the management of lymphomas and Hodgkin's disease. O'Reilly, SE., Klimo, P., Connors, JM.[2019]

In a study of 415 patients with low-grade lymphoma treated with doxorubicin-containing therapy (CHOP), the median survival duration was 6.9 years, with significant factors affecting survival including age, sex, and histology.

The study found that doxorubicin-containing treatment did not improve overall median survival compared to less aggressive treatment options, and maintenance therapy did not extend survival for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. Dana, BW., Dahlberg, S., Nathwani, BN., et al.[2017]

A novel chemotherapy regimen for treating intermediate and high-grade non-Hodgkin's lymphoma resulted in a high complete response rate of 77% among 56 previously untreated patients, indicating its efficacy in a population with a poor prognosis.

Despite the promising response rates, the treatment was associated with significant myelosuppression, with severe leukopenia occurring in all patients and a 9% rate of toxic deaths, highlighting the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of treatment with high intensity, brief duration chemotherapy in poor prognosis non-Hodgkin's lymphoma. McMaster, ML., Greer, JP., Wolff, SN., et al.[2019]

In a study of 22 patients with non-Hodgkin's lymphoma, the LEMP regimen (oral lomustine, i.v. etoposide, methotrexate, and prednisone) resulted in 5 complete remissions and 12 partial remissions, demonstrating its efficacy in patients who had previously undergone chemotherapy.

The treatment was well tolerated with minimal toxicity, showing no alopecia or cardiotoxicity, and no treatment-related deaths, suggesting it could be a safer option for patients unable to handle more intensive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lomustine, etoposide, methotrexate and prednisone (LEMP) therapy for relapsed and refractory non-Hodgkin's lymphoma. Dorigo, A., Mansberg, R., Kwan, YL.[2019]

Anthracyclines, particularly doxorubicin, are crucial in treating non-Hodgkin's lymphoma (NHL), with the CHOP regimen being the standard for over 20 years, but they carry a risk of cardiotoxicity as a late side effect.

Using liposome-encapsulated doxorubicin has shown to be effective in treating NHL while significantly reducing the risk of cardiotoxicity, making it a safer option for patients, especially those at higher risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving forward with new data and approaches: a fresh look at anthracyclines in non-Hodgkin's lymphoma. Amadori, D.[2023]

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 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 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 study involving 319 cancer patients, dolasetron mesylate was shown to be effective in preventing nausea and vomiting after chemotherapy, with higher doses leading to better outcomes.

No serious side effects were reported, and the most common adverse effect was a mild headache, indicating that dolasetron mesylate is a safe option for managing chemotherapy-induced nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Oral Dolasetron Dose-Response Study Group. Rubenstein, EB., Gralla, RJ., Hainsworth, JD., et al.[2013]

In a study of 83 breast cancer patients undergoing chemotherapy with doxorubicin-cyclophosphamide, both aprepitant (APT) and olanzapine (OLP) were effective in preventing chemotherapy-induced nausea and vomiting, with complete response rates of 81% for APT and 85% for OLP in the acute period.

OLP showed a lower incidence of severe vomiting compared to APT, with 50% of OLP patients experiencing severe vomiting versus 81% in the APT group, suggesting that OLP may provide a safer profile for managing nausea and vomiting in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine versus aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving doxorubicin-cyclophosphamide regimen: A prospective, nonrandomized, open-label study. Shivaprakash, G., Udupa, KS., Sarayu, V., et al.[2018]

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]

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 of 35 adults with relapsed or refractory B-cell acute lymphoblastic leukemia, loncastuximab tesirine, an antibody-drug conjugate targeting CD19, showed promising preliminary clinical activity with 3 patients achieving complete responses at different doses.

The treatment was generally well-tolerated, with common side effects including nausea and febrile neutropenia, but no treatment-related deaths were reported, indicating a favorable safety profile despite a high incidence of grade ≥3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia. Jain, N., Stock, W., Zeidan, A., et al.[2023]

In a study of 91 people living with HIV and Burkitt lymphoma, adding rituximab to CODOX-M/IVAC chemotherapy did not increase severe treatment-related toxicities, indicating it is a safe option for this population.

The addition of rituximab significantly improved both overall survival (72% vs. 55%) and progression-free survival (81% vs. 55%) compared to chemotherapy alone, suggesting it enhances treatment efficacy without added risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding rituximab to CODOX-M/IVAC chemotherapy in the treatment of HIV-associated Burkitt lymphoma is safe when used with concurrent combination antiretroviral therapy. Alwan, F., He, A., Montoto, S., et al.[2022]

References

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

The evolving role of etoposide in the management of lymphomas and Hodgkin's disease. [2019]

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

Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. [2017]

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

Results of treatment with high intensity, brief duration chemotherapy in poor prognosis non-Hodgkin's lymphoma. [2019]

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

Lomustine, etoposide, methotrexate and prednisone (LEMP) therapy for relapsed and refractory non-Hodgkin's lymphoma. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Moving forward with new data and approaches: a fresh look at anthracyclines in non-Hodgkin's lymphoma. [2023]

6. 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]

7. 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]

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

Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Oral Dolasetron Dose-Response Study Group. [2013]

10. India pubmed.ncbi.nlm.nih.gov

Olanzapine versus aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving doxorubicin-cyclophosphamide regimen: A prospective, nonrandomized, open-label study. [2018]

11. 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]

12. 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]

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

Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia. [2023]

14. England pubmed.ncbi.nlm.nih.gov

Adding rituximab to CODOX-M/IVAC chemotherapy in the treatment of HIV-associated Burkitt lymphoma is safe when used with concurrent combination antiretroviral therapy. [2022]