Duvelisib/CC-486 + Chemotherapy for Lymphoma

Recruiting at 83 trial locations

Overseen By Neha Mehta-Shah, MD, MSCI

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: Strong CYP3A4 inhibitors, inducers

Disqualifiers: Pregnancy, CNS involvement, HTLV, 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: 6

Duration: 18 weeks

170 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of duvelisib or CC-486 and usual chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone in treating patients with peripheral T-cell lymphoma. Duvelisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as CC-486, cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone, 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. This trial may help find out if this approach is better or worse than the usual approach for treating peripheral T-cell lymphoma.

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

The trial requires that you stop taking any strong CYP3A4 inhibitors or inducers at least 14 days before starting the study treatment. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination used in the Duvelisib/CC-486 + Chemotherapy for Lymphoma trial?

Research shows that adding etoposide to a chemotherapy regimen with cyclophosphamide, doxorubicin, vincristine, and prednisone improved outcomes for young patients with aggressive lymphoma. Additionally, a study found that combining etoposide with doxorubicin resulted in higher complete remission rates in patients with advanced diffuse large cell lymphoma. ^{1 2 3 4 5}

What safety data exists for the chemotherapy drugs used in the Duvelisib/CC-486 + Chemotherapy trial for lymphoma?

Doxorubicin, a drug used in the chemotherapy regimen, can cause serious heart-related side effects, especially in older patients. Liposomal formulations of doxorubicin may have fewer side effects like myelosuppression (reduced ability to produce blood cells) and hair loss compared to conventional doxorubicin, but they can still cause skin reactions. Overall, the chemotherapy regimens have been used with acceptable levels of side effects, but careful monitoring is necessary. ^{6 7 8 9 10}

What makes the Duvelisib/CC-486 + Chemotherapy treatment unique for lymphoma?

The Duvelisib/CC-486 + Chemotherapy treatment is unique because it combines novel agents like Duvelisib, which is a PI3K inhibitor (a drug that blocks a specific enzyme pathway important for cancer cell growth), with traditional chemotherapy drugs. This combination aims to enhance the effectiveness of treatment by targeting lymphoma cells through multiple mechanisms, potentially offering a new option for patients who may not respond well to standard therapies. ^{1 8 11 12 13}

Research Team

Neha Mehta-Shah, MD, MSCI

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

Adults (18+) with peripheral T-cell lymphoma, not including certain subtypes or those with large cell transformation of mycosis fungoides. Participants must have less than 10% CD30 expression in tumors and no active viral infections like HIV or hepatitis B/C unless managed properly. No other concurrent cancers requiring treatment within the last 3 years, except for some localized cases. Must not have had prior systemic therapy for lymphoma, be pregnant/nursing, and should have adequate organ function.

Inclusion Criteria

My lymphoma has been classified based on specific markers.

I do not have an active HIV, hepatitis B, or hepatitis C infection.

Measurable disease as defined by the Lugano criteria

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive chemotherapy with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone, with additional treatment of duvelisib or CC-486 depending on the arm, repeated every 21 days for up to 6 cycles

18 weeks

6 cycles, each with multiple visits

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 6 weeks after cycle 6 day 1, then every 12 weeks for 2 years, then every 24 weeks until 5 years from end of treatment or until documented progression of lymphoma

5 years

Regular follow-up visits

Treatment Details

Interventions

• CC-486
• Cyclophosphamide
• Doxorubicin
• Duvelisib
• Etoposide
• Prednisone
• Vincristine

Trial Overview The trial is testing how well duvelisib or CC-486 works alongside usual chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) in treating peripheral T-cell lymphoma. Duvelisib targets enzymes needed for cancer growth while CC-486 and other chemotherapies aim to kill or stop cancer cells from growing and spreading.

Participant Groups

Group I: Arm B (CC-486, CHO[E]P) Experimental Treatment 6 Interventions

Patients receive cyclophosphamide IV on day 1, doxorubicin IV on day 1, vincristine IV on day 1, etoposide IV on day 1 or days 1-3 or PO QD on days 2-3 for patients =\< 60 years old, and prednisone PO QD on days 1-5. Patients also receive CC-486 PO QD on days -6 to 0 of cycle -1 and days 8-21 of cycles 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (duvelisib, CHO[E]P) Experimental Treatment 6 Interventions

Patients receive cyclophosphamide IV on day 1, doxorubicin IV on day 1, vincristine IV on day 1, etoposide IV on day 1 or days 1-3 or PO QD on days 2-3 for patients =\< 60 years old, and prednisone PO QD on days 1-5. Patients also receive duvelisib PO BID on days 1-21. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group III: Arm C (CHO[E]P) Active Control 5 Interventions

Patients receive cyclophosphamide IV on day 1, doxorubicin IV on day 1, vincristine IV on day 1, etoposide IV on day 1 or days 1-3 or PO QD on days 2-3 for patients =\< 60 years old, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

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?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 389 young patients with good-prognosis aggressive lymphoma, the high dose of CHOEP-21 did not improve event-free or overall survival compared to the standard CHOEP-21 regimen, indicating no clinical benefit from the increased dosage.

The high CHOEP regimen was associated with significantly higher toxicity, including increased rates of severe leukocytopenia, thrombocytopenia, infections, and therapy-related deaths, suggesting that the risks may outweigh any potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Pfreundschuh, M., Zwick, C., Zeynalova, S., et al.[2020]

In a study of 81 patients with advanced diffuse large cell lymphoma, the epipodophyllotoxin VP-16-213 alone achieved a complete remission rate of 55%, while its combination with doxorubicin also showed a high remission rate of 62%, indicating that VP-16-213 is an effective treatment option.

The combination of VP-16-213 with cyclophosphamide was found to be inferior, with a complete remission rate of only 29%, suggesting that this combination may not be beneficial for patients with this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VP-16-213 in the treatment of stage III and IV diffuse large cell lymphoma. Jacobs, P., King, HS., Dent, DM., et al.[2019]

The intensified chemotherapy regimen for children with advanced B-cell malignancies resulted in a high overall complete remission rate of 93%, with 66 out of 74 patients with B-ALL and 57 out of 59 patients with stage IV SNCCL achieving remission.

The 4-year event-free survival rates were promising, at 65% for B-ALL and 79% for stage IV SNCCL, indicating that the intensified treatment may significantly improve long-term outcomes for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a pediatric oncology group study. Bowman, WP., Shuster, JJ., Cook, B., et al.[2017]

The CyclOBEAP regimen, which adds etoposide and bleomycin to a standard CHOP-like treatment, achieved an 88% complete response rate in 121 patients with aggressive lymphoma over a 12-week period, indicating its efficacy.

The 5-year overall survival rate was 72% and the progression-free survival rate was 62%, with no treatment-related deaths reported, suggesting that the regimen is safe while enhancing the effectiveness of traditional CHOP therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II study of the CyclOBEAP (CHOP-like + etoposide and bleomycin) regimen for patients with poor-prognosis aggressive lymphoma. Niitsu, N., Okamoto, M., Aoki, S., et al.[2015]

A new regimen combining doxorubicin and paclitaxel has been developed that is both well-tolerated and highly effective, utilizing bolus administration of doxorubicin and a 3-hour infusion of paclitaxel, overcoming previous schedule-dependent toxicity issues.

Paclitaxel has shown promising results when combined with fluorouracil and folinic acid in patients with extensive prior chemotherapy, and adding mitoxantrone to this combination appears to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-based combination chemotherapy for breast cancer. Hortobagyi, GN.[2015]

The CEOP chemotherapy regimen, which substitutes epirubicin for doxorubicin, demonstrated a high efficacy with a complete remission rate of 64.3% in 186 patients with intermediate- or high-grade non-Hodgkin lymphoma, particularly benefiting elderly patients.

Long-term follow-up showed that 79.8% of patients who achieved complete remission remained disease-free at a median of 86.9 months, indicating that CEOP is not only effective but also well-tolerated, with no deaths from cardiac toxicity reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of patients with intermediate or high-grade non-Hodgkin lymphoma treated with a combination of cyclophosphamide, epirubicin, vincristine, and prednisone. Rossini, F., Terruzzi, E., Perego, D., et al.[2015]

In a study of 47 elderly women with high-risk breast cancer, the combination of Non-Pegylated Liposomal Doxorubicin (NPL-DOX) and Cyclophosphamide followed by weekly Paclitaxel showed a low rate of cardiac toxicity over a median follow-up of 76 months, with only one case of grade 3 congestive heart failure reported.

While there was a gradual decline in left ventricular ejection fraction (LVEF) over time, it remained above 50% and did not lead to any significant clinical symptoms, indicating that the treatment is relatively safe for cardiac health in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study. Coltelli, L., Finale, C., Musettini, G., et al.[2023]

In a study of 125 patients with advanced stage diffuse large cell non-Hodgkin's lymphoma, the MACOP-B chemotherapy regimen achieved a high complete response rate of 84%, indicating its efficacy in treating this aggressive cancer.

The overall toxicity of the MACOP-B treatment was manageable, with only 4.8% of patients experiencing treatment-related deaths, and the most common side effects were mucocutaneous, suggesting that while effective, there is still room for improvement in reducing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated clinical experience with MACOP-B. Klimo, P., Connors, JM.[2017]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

Epirubicin, which has lower cardiotoxicity than doxorubicin, allows for higher cumulative doses and is effective in treating metastatic breast cancer, making it a safer option for patients.

A phase III trial is set to compare the effectiveness of a concurrent epirubicin/taxane regimen against a sequential epirubicin/cyclophosphamide followed by taxane treatment in patients with operable node-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of a phase III trial of adjuvant sequential epirubicin/ cyclophosphamide and taxane versus concurrent epirubicin/taxane in operable node-positive breast cancer. Perez, EA.[2019]

In a study of 348 patients with diffuse large B-cell lymphoma treated with various chemotherapy regimens, those receiving more than 90% of the average relative dose intensity (ARDI) had a median survival of 7.08 years, significantly better than those with lower ARDI.

The findings suggest that maintaining optimal chemotherapy intensity is crucial for improving patient outcomes, as dose reductions due to hematological toxicities negatively impacted treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Bosly, A., Bron, D., Van Hoof, A., et al.[2022]

In a study of 70 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone), the treatment showed comparable outcomes in terms of time to progression and disease-specific survival when matched against a control group of 140 patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Although R-CEOP demonstrated similar progression-free and disease-specific survival rates, it was associated with a lower overall survival rate (30% vs 49% for R-CHOP), likely due to the higher comorbidities and frailty in the R-CEOP group, indicating that while R-CEOP is a viable alternative for patients who cannot tolerate anthracyclines, it may not be as effective overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines. Moccia, AA., Schaff, K., Freeman, C., et al.[2021]

In a study of 46 elderly patients (aged 69 and older) with aggressive non-Hodgkin's lymphoma, the chemotherapy regimen (CTVP) combined with granulocyte colony-stimulating factor (G-CSF) resulted in a 74% objective response rate and a 46% complete response rate, demonstrating its efficacy.

The use of G-CSF helped reduce severe neutropenia complications, with only 22% experiencing grade 3 or 4 neutropenia, allowing for outpatient treatment without negatively impacting overall survival (47%) or event-free survival (28%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of granulocyte colony-stimulating factor administration in elderly patients with aggressive non-Hodgkin's lymphoma treated with a pirarubicin-combination chemotherapy regimen. Groupe d'Etudes des Lymphomes de l'Adulte. Guerci, A., Lederlin, P., Reyes, F., et al.[2020]

References

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

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). [2020]

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

VP-16-213 in the treatment of stage III and IV diffuse large cell lymphoma. [2019]

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

Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a pediatric oncology group study. [2017]

4. Germany pubmed.ncbi.nlm.nih.gov

Multicenter phase II study of the CyclOBEAP (CHOP-like + etoposide and bleomycin) regimen for patients with poor-prognosis aggressive lymphoma. [2015]

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

Paclitaxel-based combination chemotherapy for breast cancer. [2015]

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

Long-term follow-up of patients with intermediate or high-grade non-Hodgkin lymphoma treated with a combination of cyclophosphamide, epirubicin, vincristine, and prednisone. [2015]

7. Italy pubmed.ncbi.nlm.nih.gov

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study. [2023]

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

Updated clinical experience with MACOP-B. [2017]

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

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. [2022]

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

Rationale and design of a phase III trial of adjuvant sequential epirubicin/ cyclophosphamide and taxane versus concurrent epirubicin/taxane in operable node-positive breast cancer. [2019]

11. Germany pubmed.ncbi.nlm.nih.gov

Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. [2022]

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

Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Effect of granulocyte colony-stimulating factor administration in elderly patients with aggressive non-Hodgkin's lymphoma treated with a pirarubicin-combination chemotherapy regimen. Groupe d'Etudes des Lymphomes de l'Adulte. [2020]