Testing the Addition of Duvelisib or CC-486 to the Usual Treatment for Peripheral T-Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To compare the complete remission (CR) rates by positron emission tomography (PET)/computed tomography (CT) following completion of treatment with duvelisib-cyclophosphamide (C) doxorubicin (H) vincristine (O) (etoposide [E]) prednisone (P) versus (vs) CHO(E)P and with oral azacitidine (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 overall response rate (ORR), duration of response, progression free survival (PFS), event free survival (EFS), and overall survival (OS) of each treatment regimen. III. To determine whether designation of follicular helper T-cell phenotype is correlated with response to therapy, PFS, EFS, and OS. IV. 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 IV on days 1-3 or etoposide IV on day 1 and orally (PO) once daily (QD) on days 2-3 for patients <=60 years old, 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 IV on days 1-3 or etoposide IV on day 1 and orally (PO) once daily (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. ARM C: Patients receive cyclophosphamide IV on day 1, doxorubicin IV on day 1, vincristine IV on day 1, etoposide IV on days 1-3 or etoposide IV on day 1 and orally (PO) once daily (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. After completion of study treatment, patients are followed 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. After documented progression of lymphoma, patients are followed up every 6 months until 5 years from end of treatment.

Official Title
-----------------
A Randomized Phase II Study of CHO(E)P vs CC-486-CHO(E)P vs Duvelisib-CHO(E)P in Previously Untreated CD30 Negative Peripheral T-Cell Lymphomas

Conditions
-----------------
Angioimmunoblastic T-cell Lymphoma, Enteropathy-Associated T-Cell Lymphoma, Follicular T-Cell Lymphoma, Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma, Nodal Peripheral T-Cell Lymphoma With TFH Phenotype, Peripheral T-Cell Lymphoma, Not Otherwise Specified

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone
* Drug: Etoposide
* Drug: Duvelisib
* Drug: Oral azacitidine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed diagnosis of peripheral T-cell lymphoma (PTCL) with < 10% CD30 expression by immunohistochemistry in the following subtypes (by local review): 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 Measurable disease as defined by the Lugano criteria No prior systemic therapy for lymphoma (excluding corticosteroids) 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 Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status =< 2 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) Absolute neutrophil count (ANC) >= 1,000/mm^3 Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3.0 x upper limit of normal (ULN) * Except in subjects with documented liver involvement by lymphoma Calculated creatinine clearance >= 30 mL/min by Cockcroft-Gault formula Total bilirubin =< 2.0 x ULN * Except in cases of Gilbert's Syndrome or documented liver or pancreatic involvement by lymphoma Archival tissue must be available for submission Patients known to have HTLV 1/2 are excluded Patients with known central nervous system involvement are excluded 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 Patients with history of HIV are eligible if they have an undetectable viral load for at least 6 months 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 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 Patients must have documented left ventricular ejection fraction of >= 45% 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 No contraindication to any drug in the chemotherapy regimen, including neuropathy >= grade 2 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (duvelisib, CHO[E]P)<br>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. | Drug: Cyclophosphamide<br>* Given IV<br>Drug: Doxorubicin<br>* Given IV<br>Drug: Vincristine<br>* Given IV<br>Drug: Prednisone<br>* Given PO<br>Drug: Etoposide<br>* Given IV or PO<br>Drug: Duvelisib<br>* Given PO<br>|
| Experimental: Arm B (CC-486, CHO[E]P)<br>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. | Drug: Cyclophosphamide<br>* Given IV<br>Drug: Doxorubicin<br>* Given IV<br>Drug: Vincristine<br>* Given IV<br>Drug: Prednisone<br>* Given PO<br>Drug: Etoposide<br>* Given IV or PO<br>Drug: Oral azacitidine<br>* Given PO<br>|
| Active Comparator: Arm C (CHO[E]P)<br>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. | Drug: Cyclophosphamide<br>* Given IV<br>Drug: Doxorubicin<br>* Given IV<br>Drug: Vincristine<br>* Given IV<br>Drug: Prednisone<br>* Given PO<br>Drug: Etoposide<br>* Given IV or PO<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission (CR) rate | Defined as the number of patients with complete remission (CR) divided by the total number of patients randomized. Will be measured by fludeoxyglucose F-18 (FDG) positron emission tomography (PET)/computed tomography (CT) at the completion of treatment (at end of treatment) and will be compared between each experimental arm and control arm. Final analyses will use z-scores obtained from a stratified Cochran-Mantel-Haenszel test to compare the CR rates between each experimental arm and control arm. For each treatment arm, CR rates will be estimated with their 95% confidence intervals. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Adverse events will be collected and graded according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. For CTCAE data, the maximum grade for each type of adverse will be recorded for each patient, and described using frequency tables. All-cause adverse events will be summarized as well as treatment-related adverse events. | Up to 5 years | 
| Overall response rate (ORR) | Overall response includes complete and partial remissions by FDG PET/CT at the completion of treatment (at end of treatment). ORR will be estimated for each treatment arm and calculated as the number of patients with response divided by the total number of patients randomized. For each treatment arm, ORRs will be estimated with their 95% confidence intervals. ORR at the interim assessment will be summarized in the same manner, and how response changes between the interim and final assessment will be described. | Up to 6 months | 
| Duration of response | The Kaplan-Meier method will be used to estimate duration of response for each treatment arm, with 2-year estimates and medians along with their 95% confidence intervals. | From first date of complete or partial remission until the earlier of disease progression, death from any cause, or non-protocol lymphoma-directed therapy to treat residual or progressive disease, assessed up to 5 years | 
| Progression-free Survival (PFS) | The Kaplan-Meier method will be used to estimate PFS for each treatment arm, with 2-year PFS estimates and PFS medians along with their 95% confidence intervals. | From randomization date until the earlier of disease progression, death from any cause, or non-protocol lymphoma-directed therapy to treat residual or progressive disease, assessed up to 5 years | 
| Event-free Survival (EFS) | The Kaplan-Meier method will be used to estimate event-free survival (EFS) for each treatment arm, with 2-year EFS estimates and EFS medians along with their 95% confidence intervals. | From randomization date until earlier of non-protocol lymphoma-directed therapy for any reason (excluding planned consolidative transplant), disease progression, or death from any cause, assessed up to 5 years | 
| Overall Survival (OS) | The Kaplan-Meier method will be used to estimate overall survival (OS) for each treatment arm, with 2-year OS estimates and OS medians along with their 95% confidence intervals. | From randomization date until death from any cause, censoring patients alive at the date of last contact, assessed up to 5 years | 
| Correlation of follicular helper T-cell phenotype with response, PFS, EFS and OS | CR rates and ORRs will be estimated with 95% confidence intervals for patients with and without the follicular helper T-cell phenotype, as well for patients with the peripheral T-cell lymphomas (PTCL) genotype. | Up to 5 years | 
| Patient reported outcomes (PROs) | Patient reported outcomes (PROs) will be captured using the NCI PRO-CTCAE. Scores (0-4) and maximum score for each PRO-CTCAE item, with and without taking into account whether it is worse than the patient's own baseline score, will be recorded for each patient. PRO-CTCAE data will, at minimum, be analyzed similarly to CTCAE data. | Up to 6 months |