Trials / Withdrawn

WithdrawnNCT04639843

Doxorubicin, CC-(486) (5-azacitidine), Romidepsin, and Duvelisib (hARD) for T-cell Lymphoma

A Phase 1 Study of Doxorubicin, CC-486 (5-azacitidine), Romidepsin, and Duvelisib (hARD) for T-cell Lymphoma

Status: Withdrawn
Phase: Phase 1
Study type: Interventional
Enrollment: 0 (actual)

Sponsor: National Cancer Institute (NCI) · NIH
Sex: All
Age: 18 Years
Healthy volunteers: Not accepted

Summary

Background: T-cell lymphomas (TCLs) are rare cancers. Many types of TCLs do not develop in the lymph nodes but in places like the skin, spleen, and bone marrow. Researchers want to see if a mix of 4 drugs can help people with TCL. Objective: To test if the combination of romidepsin, CC-486 (5-azacitidine), duvelisib, and doxorubicin can be used safely in people with TCL. Eligibility: Adults 18 and older with TCL that is newly diagnosed or that returned after or did not respond to standard treatments. Design: Participants will be screened on a separate protocol. They may have a tumor biopsy. Participants will have medical histories, medicine reviews, and physical exams. Their ability to do daily activities will be assessed. They will have blood and urine tests. Participants will take duvelisib and CC-486 (5-azacitidine) by mouth. They will get romidepsin and doxorubicin by intravenous infusion. They will take the drugs for up to eight 21-day cycles. They will keep a medicine diary. Participants will have a bone marrow aspiration and/or biopsy. Bone marrow will be taken through a needle inserted in the hip. Participants will have tumor imaging scans. Some may have a brain MRI and lumbar puncture. Some may have skin assessments. Participants will give blood, saliva, and tumor samples for research. Participants will have a safety visit 30 days after treatment ends. Then they will have follow-up visits every 60 days for 6 months, then every 90 days for 2 years, and then every 6 months for 2 years. Then they will have yearly visits until their disease gets worse or they start a new treatment....

Detailed description

Background: T-cell lymphomas (TCLs) are a heterogeneous group of lymphoid malignancies defined by clonal proliferation of post-thymic T lymphocytes. Patients with newly diagnosed TCLs are most commonly treated with a CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen, with less than 30% having durable complete responses (CRs). Of the chemotherapy agents used, doxorubicin is the one which was consistently associated with prolonged progression-free survival (PFS) and overall survival (OS) in retrospective studies. Treatment options for the 70% of patients with TCL who relapse are limited and of minimal efficacy; novel treatment strategies are urgently needed. Many TCL have mutations in epigenetic modifier genes, and histone deacetylase inhibitors such as romidepsin are approved for treatment of peripheral T-cell lymphoma (PTCL); however, the overall response rate (ORR) with single-agent treatment is only 20-30%, and improvement in OS was not shown. Romidepsin and the hypomethylating agent CC-486 (5-azacitidine) acted synergistically in vitro, and showed high clinical activity, with an ORR of up to 79% in some types of TCL. Many TCLs rely on the PI3K pathway, whether through activation of CD28 through fusions or gain-of-function mutations or by interruptions of the CD28-inhibiting PD-1/PD-L1 immune checkpoint. Duvelisib is an inhibitor of the PI3K gamma and delta isoforms; in phase I trials it has shown both single-agent activity and synergy with romidepsin for patients with TCL. As combinations of both CC-486 (5-azacitidine)/romidepsin and duvelisib/romidepsin have demonstrated both adequate safety and clinical efficacy, safety and efficacy of the triplet combination should be explored. Objectives: To determine the safety and toxicity profile, maximum tolerated dose (MTD), and the recommended phase II dose (RP2D) of the four-drug combination of CC-486 (5-azacitidine), romidepsin and duvelisib, and doxorubicin, in patients with TCL. Eligibility: Patients with histologically or cytologically confirmed newly diagnosed or relapsed/refractory T-cell lymphoma (TCL) defined as follows: Cohort 2: Untreated patients with any peripheral TCL, not including anaplastic large cell lymphoma (ALCL), but including acute and lymphoma subtypes of adult T-cell leukemia/lymphoma (ATLL). Cohorts 1 and 3: Any relapsed/refractory peripheral T-cell lymphoma including ATLL and ALCL who have disease after receiving at least one line of systemic therapy, which must include brentuximab vedotin if the disease is ALCL. Age \>= 18 years of age ECOG performance status of \<= 2 Adequate organ and marrow function Design: Open-label, single-center, non-randomized Phase 1 study "3 + 3" design will be used to determine the RP2D of dose-escalated duvelisib with fixed dose romidepsin CC-486 (5-azacitidine) and doxorubicin with two expansion cohorts at the RP2D Maximum 8 cycles (21-day cycles) of combination therapy To explore all dose levels, including further evaluation in two dose expansion cohorts, the accrual ceiling will be set at 60 patients

Conditions

Interventions

Type	Name	Description
DRUG	CC-486 (5-azacitidine)	CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 8 cycles.
DRUG	Duvelisib	Duvelisib by oral intake at escalating doses of 25, 50 and 75 mg/BID on days -14 to 14 of the 1st cycle then days 1-14 of Cycles 2-8 of each 21- day cycle (max 8 cycles).
DRUG	Romidepsin	Romidepsin (12mg/m2) will be administered on days 1 and 8 of each cycle through a peripheral or central intravenous catheter for 8 cycles.
DRUG	Doxorubicin	Doxorubicin at 25 mg/ m2 by IV infusion on Day 1 of cycles 3-8.

Timeline

Start date: 2022-11-03
Primary completion: 2022-11-03
Completion: 2022-11-03
First posted: 2020-11-23
Last updated: 2022-11-04

Locations

1 site across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT04639843. Inclusion in this directory is not an endorsement.