Duvelisib/CC-486 + Chemotherapy for Lymphoma

Not currently recruiting at 96 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding either duvelisib or CC-486 to standard chemotherapy can more effectively treat peripheral T-cell lymphoma, a type of blood cancer. Duvelisib aims to stop cancer cell growth by blocking certain enzymes, while CC-486 (an oral form of the chemotherapy drug azacitidine) and the chemotherapy drugs work by killing cancer cells or preventing their spread. Suitable candidates for this trial have a confirmed diagnosis of peripheral T-cell lymphoma, have not received previous systemic treatment for it, and face daily challenges due to their condition. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants, offering a chance to contribute to important findings.

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.

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

Research has shown that both duvelisib and CC-486 have been tested in previous studies, providing insights into their safety.

For CC-486, studies found that most patients handled the treatment well, with 88% completing all treatment cycles. However, some patients experienced serious side effects. About 64% faced severe issues like low white blood cell counts, which can weaken the body's ability to fight infections.

Duvelisib has been used for other conditions and showed promising results with a manageable safety profile. Some studies reported that patients tolerated the treatment, but concerns arose about a higher risk of serious side effects. The FDA issued a warning about a possible increased risk of death compared to other treatments.

Overall, both treatments have shown potential benefits and risks. Participants should consider these factors and discuss any concerns with their healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for lymphoma because they introduce new ways to potentially improve patient outcomes. Duvelisib, used in one arm of the trial, is a PI3K inhibitor that targets specific pathways cancer cells use to grow, offering a different mechanism compared to traditional chemotherapy. CC-486, used in another trial arm, is an oral form of azacitidine that may enhance the effect of chemotherapy by modifying gene expression. These innovative approaches could provide better responses and possibly fewer side effects compared to standard chemotherapy regimens.

What evidence suggests that this trial's treatments could be effective for peripheral T-cell lymphoma?

Research has shown that duvelisib, one of the treatments in this trial, can help treat certain types of T-cell lymphoma when combined with standard chemotherapy. It has an overall response rate of 48% and a complete response rate of 33%, indicating that many patients experience a reduction or disappearance of their cancer for a period of time. Another treatment arm in this trial involves CC-486 combined with CHOEP (a type of chemotherapy), which has response rates similar to CHOP-based treatments, with overall response rates between 60% and 80%. Both treatments in this trial offer hope for better management of peripheral T-cell lymphoma. ^{6 7 8 9 10}

Who Is on the Research Team?

Neha Mehta-Shah, MD, MSCI

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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 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 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]

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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10356559/

Multicenter phase 2 study of oral azacitidine (CC-486) plus ...

With the exception of anaplastic large cell lymphoma (ALCL), CHOP typically delivers a overall response rate (ORR) of 60% to 80%, complete response (CR) of 30% ...

2.

clinical-lymphoma-myeloma-leukemia.com

clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(23)02197-3/fulltext

Real-world Effectiveness of Azacitidine in Treatment-Naive ...

Results from randomized phase III trials demonstrate improved hematologic responses (complete remission [CR] rate for AZA, 7%-17%), delayed ...

3.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.20.02619

Phase III, Randomized, Placebo-Controlled Trial of CC-486 ...

In interim survival analysis (median follow-up 13.3 months), the estimated median OS was 17.3 months in the CC-486 arm and 16.2 months in the ...

4.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0006497124044306

Multicenter, Open-Label, Phase I Study of Azacitidine- ...

Complete response (CR) rates with CHOP-based chemotherapy range from 30-40%, with limited evidence suggesting significant improvements from ...

5.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38216397/

Real-world Effectiveness of Azacitidine in Treatment-Naive ...

This retrospective study with patient chart review evaluated AZA effectiveness in 382 treatment-naive patients with HR-MDS from a US electronic health record ( ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9211445/

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in ...

With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming ...

7.

lymphomahub.com

lymphomahub.com/medical-information/safety-and-efficacy-of-oral-azacitidine-cc-486-plus-r-chop-in-patients-with-previously-untreated-intermediate-to-high-risk-dlbcl-a-phase-i-study

Safety and efficacy of oral azacitidine (CC-486) plus R- ...

A total of 88% of patients treated in both dose-escalation and expansion phases completed all cycles of CC-486, while 92% completed six cycles ...

8.

ashpublications.org

ashpublications.org/blood/article/141/18/2194/494499/Multicenter-phase-2-study-of-oral-azacitidine-CC

Multicenter phase 2 study of oral azacitidine (CC-486) plus ...

Key Points. Addition of oral azacitidine to CHOP as initial therapy is safe, and induces high rates of CR in patients with PTCL-TFH.

9.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03703375?id=%22NCT01120834%22OR%22NCT01983969%22OR%22NCT02701673%22OR%22NCT03161223%22OR%22NCT03450343%22OR%22NCT03703375%22OR%22NCT04899414%22OR%22NCT05075460%22&rank=3

Efficacy and Safety of Oral Azacitidine (CC-486) Compared ...

A safety run-in will be conducted to confirm the tolerability of oral azacitidine at doses of 100 mg and 200 mg QD in Asian patients.

10.

sciencedirect.com

sciencedirect.com/science/article/pii/S0006497119807097

A Phase I, Open Label, Multicenter Trial of Oral Azacitidine ...

Grade 3/4 treatment-related AEs occurred in 21 (64%) pts; most common (≥10%) were neutropenia (58%) and febrile neutropenia (21%). Serious AEs (SAEs) occurred ...