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

Angioimmunoblastic T-cell Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04803201
• Other study ID #: A051902
• Secondary ID: NCI-2021-01380U1
• Status: Recruiting
• Phase: Phase 2
• Start date: July 30, 2021
• Est. completion date: January 1, 2026

Study information

• Verified date: May 2024
• Source: Alliance for Clinical Trials in Oncology
• Contact: Neha Mehta-Shah, MD, MSCI
• Phone: 314-747-7510
• Email: mehta-n[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 170
• Est. completion date: January 1, 2026
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Angioimmunoblastic T-cell Lymphoma
• Enteropathy-Associated T-Cell Lymphoma
• Follicular T-Cell Lymphoma
• Lymphoma
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Peripheral
• 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

Drug:
• Cyclophosphamide
Given IV
• Doxorubicin
Given IV
• Vincristine
Given IV
• Prednisone
Given PO
• Etoposide
Given IV or PO
• Duvelisib
Given PO
• Oral azacitidine
Given PO

Locations

Country	Name	City	State
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Grady Health System	Atlanta	Georgia
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Nebraska Medicine-Bellevue	Bellevue	Nebraska
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Saint Luke's Hospital	Chesterfield	Missouri
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Dayton Physician LLC - Englewood	Dayton	Ohio
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Greater Dayton Cancer Center	Kettering	Ohio
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Medicine-Village Pointe	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Dartmouth Cancer Center - North	Saint Johnsbury	Vermont
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	FHCC South Lake Union	Seattle	Washington
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Memorial Hospital East	Shiloh	Illinois
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Carle Cancer Center	Urbana	Illinois
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Wilmot Cancer Institute at Webster	Webster	New York
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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