A Phase 1 Study of Doxorubicin, CC-486 (5-azacitidine), Romidepsin, and Duvelisib (hARD) for T-cell Lymphoma
Trial Snapshot
- Phase
- Phase 1
- Status
- Withdrawn
- Locations
- 1
- Primary Endpoint
- Safety and tolerability
Study Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
1- Experimental Treatment: Dose Escalation
Duvelisib (PO BID) at escalating doses of 25, 50 and 75 mg/BID on days -14 to 14 of C1 and days 1-14 of all other cycles of each 21- day cycle (max 8 cycles) with CC-486 (5-azacitidine) (PO) at 300mg/day on days 1-10, romidepsin at 12mg/m2 (IV) on Days 1 and 8 of each cycle and doxorubicin (IV) at 25 mg/ m2 on Day 1 of cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy), to determine RP2D of duvelisib and doxorubicin
Intervention: CC-486 (5-azacitidine) (Drug)
1- Experimental Treatment: Dose Escalation
Duvelisib (PO BID) at escalating doses of 25, 50 and 75 mg/BID on days -14 to 14 of C1 and days 1-14 of all other cycles of each 21- day cycle (max 8 cycles) with CC-486 (5-azacitidine) (PO) at 300mg/day on days 1-10, romidepsin at 12mg/m2 (IV) on Days 1 and 8 of each cycle and doxorubicin (IV) at 25 mg/ m2 on Day 1 of cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy), to determine RP2D of duvelisib and doxorubicin
Intervention: Duvelisib (Drug)
1- Experimental Treatment: Dose Escalation
Duvelisib (PO BID) at escalating doses of 25, 50 and 75 mg/BID on days -14 to 14 of C1 and days 1-14 of all other cycles of each 21- day cycle (max 8 cycles) with CC-486 (5-azacitidine) (PO) at 300mg/day on days 1-10, romidepsin at 12mg/m2 (IV) on Days 1 and 8 of each cycle and doxorubicin (IV) at 25 mg/ m2 on Day 1 of cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy), to determine RP2D of duvelisib and doxorubicin
Intervention: Romidepsin (Drug)
1- Experimental Treatment: Dose Escalation
Duvelisib (PO BID) at escalating doses of 25, 50 and 75 mg/BID on days -14 to 14 of C1 and days 1-14 of all other cycles of each 21- day cycle (max 8 cycles) with CC-486 (5-azacitidine) (PO) at 300mg/day on days 1-10, romidepsin at 12mg/m2 (IV) on Days 1 and 8 of each cycle and doxorubicin (IV) at 25 mg/ m2 on Day 1 of cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy), to determine RP2D of duvelisib and doxorubicin
Intervention: Doxorubicin (Drug)
2 - Experimental Treatment: Dose Expansion
Duvelisib (PO BID) at RP2D on days -14 to 14 of C1 and days 1-14 of all other 21-day cycle (max 8 cycles) with CC-486 (5-azacitidine) at 300mg/day (PO) on days 1-10, romidepsin at 12mg/m2 (IV) on days 1 and 8 of each cycle, and doxorubicin at 25 mg/m2 on day 1 of Cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy
Intervention: CC-486 (5-azacitidine) (Drug)
2 - Experimental Treatment: Dose Expansion
Duvelisib (PO BID) at RP2D on days -14 to 14 of C1 and days 1-14 of all other 21-day cycle (max 8 cycles) with CC-486 (5-azacitidine) at 300mg/day (PO) on days 1-10, romidepsin at 12mg/m2 (IV) on days 1 and 8 of each cycle, and doxorubicin at 25 mg/m2 on day 1 of Cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy
Intervention: Duvelisib (Drug)
2 - Experimental Treatment: Dose Expansion
Duvelisib (PO BID) at RP2D on days -14 to 14 of C1 and days 1-14 of all other 21-day cycle (max 8 cycles) with CC-486 (5-azacitidine) at 300mg/day (PO) on days 1-10, romidepsin at 12mg/m2 (IV) on days 1 and 8 of each cycle, and doxorubicin at 25 mg/m2 on day 1 of Cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy
Intervention: Romidepsin (Drug)
2 - Experimental Treatment: Dose Expansion
Duvelisib (PO BID) at RP2D on days -14 to 14 of C1 and days 1-14 of all other 21-day cycle (max 8 cycles) with CC-486 (5-azacitidine) at 300mg/day (PO) on days 1-10, romidepsin at 12mg/m2 (IV) on days 1 and 8 of each cycle, and doxorubicin at 25 mg/m2 on day 1 of Cycles 3-8 (Cycles 3-6 for patients with prior anthracycline-based therapy
Intervention: Doxorubicin (Drug)
Outcomes
Primary Outcomes
Safety and tolerability
Time Frame: 8 cycles
Rate and severity of AEs will be summarized by grade and type of toxicity
Maximum tolerated dose (MTD)
Time Frame: 21 days
Frequency (number and percentage) of treatment emergent adverse events
Secondary Outcomes
- Overall Survival (OS)(every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually)
- Overall Repsonse Rate(8 cycles)
- Complete Response Rate(8 cycles)
- Duration of response (DOR)(every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually)
- Event Free Survival (EFS)(every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually)
- Progression-free survival(every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually)