Summary

This phase II trial studies the effect of adding duvelisib or CC-486 to the usual chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone vs. chemotherapy alone in treating patients with peripheral T-cell lymphoma. Duvelisib is in a class of medications called kinase inhibitors. It works by blocking the signals that cause cancer cells to multiply. This helps to stop the spread of cancer cells. Chemotherapy drugs, such as CC-486, cyclophosphamide, doxorubicin, vincristine, etoposide, 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. Prednisone is used to reduce inflammation and lower the body's immune response to help reduce the side effects of chemotherapy drugs. This trial will help to determine whether adding duvelisib or CC-486 to the usual chemotherapy is better than chemotherapy alone in treating peripheral T-cell lymphoma.

Objectives

PRIMARY OBJECTIVE:
I. To compare the complete remission (CR) rates by fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) using the Lugano 2014 criteria following completion of treatment with duvelisib-cyclophosphamide (C) doxorubicin (H) vincristine (O) (etoposide [E]) prednisone (P) versus (vs) CHO(E)P and with CC-486-CHO(E)P vs CHO(E)P in previously untreated peripheral T-cell lymphomas that have < 10% expression of CD30.

SECONDARY OBJECTIVES:
I. To determine the toxicity and tolerability of the treatment regimens.
II. To determine the CR rates by FDG PET/CT or CT alone using the Lugano 2014 criteria.
III. To determine the overall response rate (ORR), duration of response, progression free survival (PFS), event free survival (EFS), and overall survival (OS) of each treatment regimen.
IV. To determine whether designation of follicular helper T-cell phenotype is correlated with response to therapy, PFS, EFS, and OS.
V. To assess the toxicity profile of the experimental regimens in untreated CD30 negative peripheral T-cell lymphomas using Common Terminology Criteria for Adverse Events (CTCAE) and patient reported outcomes (PRO)-CTCAE.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive cyclophosphamide intravenously (IV) on day 1, doxorubicin IV on day 1, vincristine IV on day 1, etoposide (given only to patients =< 60 years old) IV on day 1 or days 1-3 or orally (PO) once daily (QD) on days 2-3, and prednisone PO QD on days 1-5. Patients also receive duvelisib PO twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive cyclophosphamide IV on day 1, doxorubicin IV on day 1, vincristine IV on day 1, etoposide (given only to patients =< 60 years old) IV on day 1 or days 1-3 or PO QD on days 2-3, 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.

ARM C: Patients receive cyclophosphamide IV on day 1, doxorubicin IV on day 1, vincristine IV on day 1, etoposide (given only to patients =< 60 years old) IV on day 1 or days 1-3 or PO QD on days 2-3, 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.

All patients undergo bone marrow biopsy during screening and on the trial. Patients also undergo positron emission tomography (PET)/ computed tomography (CT) throughout the trial. Additionally, patients undergo blood sample collection on the trial and during follow up.

After completion of study treatment, patients are followed up every 12 weeks for 2 years, every 24 weeks until 5 years or until documented progression of lymphoma. After documented progression of lymphoma, patients are followed up every 6 months until 5 years from end of treatment.

Eligibility

1. Histologically confirmed diagnosis of peripheral T-cell lymphoma (PTCL) with < 10% CD30 expression by immunohistochemistry in the following subtypes: nodal T-cell lymphoma with T-follicular helper (TFH) phenotype (TFH-PTCL), follicular T-cell lymphoma, PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma * Patients with expression of CD30 in >= 10% of the tumor (based on local immunohistochemistry review) regardless of histology will not be permitted * Patients with a diagnosis of other PTCL subtype histologies other than those specified in the inclusion criteria are excluded including large cell transformation of mycosis fungoides * Patients will be stratified by presence or absence of TFH phenotype (i.e. diagnosis of AITL, TFH-PTCL, follicular T-cell lymphoma) based on local review of pathology. Determination of TFH phenotype can be defined by expression of two or more of the following markers CD10, BCL6, CXCL13, ICOS, and PD1 by immunohistochemistry
2. Measurable, fluorodeoxyglucose (FDG) avid disease as defined by the Lugano criteria
3. No prior systemic therapy or radiation therapy for T-cell lymphoma (excluding corticosteroids)
4. Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 7 days prior to registration is required
5. Age >= 18 years
6. Eastern Cooperative Oncology Group (ECOG) performance status =< 2
7. Platelet count >= 75,000/mm^3 (>= 50,000/mm^3 if secondary to bone marrow involvement from lymphoma per investigator assessment; the first 12 patients on each arm of the study must have platelets >= 75,000/mm^3 regardless of bone marrow involvement)
8. Absolute neutrophil count (ANC) >= 1,000/mm^3
9. Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3.0 x upper limit of normal (ULN) * Except in subjects in the expansion phase with documented liver involvement by lymphoma; In the safety lead in and safety check phases of the study, subjects with documented liver involvement may have AST/SGOT and ALT/SGPT =< 5.0 x ULN
10. Calculated creatinine clearance >= 30 mL/min by Cockcroft-Gault formula
11. Total bilirubin =< 2.0 x ULN * Except in cases of Gilbert’s Syndrome or documented liver or pancreatic involvement by lymphoma in the expansion phase
12. Archival tissue must be available for submission
13. Patients known to have human T-lymphotropic virus-1/2 (HTLV 1/2) are excluded
14. Patients with known central nervous system involvement are excluded
15. No active viral infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Those who are seropositive (e.g. hepatitis B core antibody [Ab] positive) are permitted if they are negative by polymerase chain reaction (PCR). Those who are seropositive for hepatitis B and are negative for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) by PCR must receive concomitant hepatitis B directed antiviral therapy. Those who have hepatitis C Ab positivity who have completed curative therapy for hepatitis C with negative hepatitis C PCR are eligible
16. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
17. No active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment). Patients with Epstein-Barr virus (EBV) viremia related to their lymphoma are permitted
18. No concurrent malignancy requiring active therapy within the last 3 years with the exception of basal cell carcinoma limited to the skin, squamous cell carcinoma limited to the skin, carcinoma in situ of the cervix, breast or localized prostate cancer. Adjuvant hormonal therapy for cancer previously treated for curative intent is permitted
19. Patients must have documented left ventricular ejection fraction of >= 45%
20. No significant active cardiac disease within the previous 6 months including: * New York Heart Association (NYHA) class III or IV congestive heart failure * Unstable angina or angina requiring surgical or medical intervention; and/or * Myocardial infarction
21. No contraindication to any drug in the chemotherapy regimen, including neuropathy >= grade 2
22. Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment

Treatment Sites in Georgia