Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies
- Conditions
- Cutaneous T-Cell LymphomaMature T-cell MalignanciesPeripheral T-Cell LymphomaRelapsed/ Refractory T-cell Malignancies
- Interventions
- Registration Number
- NCT04447027
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Mature T-cell malignancies (TCMs) are a rare group of cancers that usually do not have effective treatments or cures. Because of this, participants with TCMs often relapse and have a poor overall prognosis. This trial is testing if combining several drugs against TCMs can be a more effective.
Primary Objective:
To test if the combination of romidepsin, CC-486 (5-azacitidine), dexamethasone, and lenalidomide (RAdR) can be given safely to participants with relapsed or treatment refractory TCM.
Other (Secondary) Objective:
Measure the activity of this combination treatment.
Eligibility:
People age 18 and older who have a failed or relapsed after standard treatments for mature TCMs.
Design:
Participants will be screened for eligibility by performing the following tests or procedures:
Physical exam
Medical history
Medicine review
Blood and urine tests
Symptom review
Bone marrow examination
Total Body imaging scans or x-rays
Tumor biopsy
Participants will have blood tests during treatment to make sure their blood cell counts are okay.
Romidepsin is infused through an IV placed in one of the veins usually in the arm. Lenalidomide, dexamethasone, and CC-486 (5-azacitidine) are pills or capsules taken by mouth.
Participants are asked to keep a diary of when they take their pills to make sure they are taking these medicines properly.
Participants will have tumor imaging scans after every 2nd cycle (or 6 weeks) to check if the treatment is working. If the doctors are concerned the cancer has spread to the brain and/or spine, they will have scans of the area(s) and a sampling of the fluid around the brain/spine which is obtained through a small needle inserted into the lower part of the back for a short time to collect the fluid. This procedure is called a spinal tap or lumbar puncture.
Participants who have tumor in their skin will have repeat exams of their skin and sometimes photographs taken of these areas to see if the treatment is working.
Participants will also be asked to give blood, saliva, and sometimes have optional biopsies of their tumor where these tests are done for research purposes.
After they have completed the protocol treatment (6 cycles), they will be asked to return to clinic 30 days after treatment has ended, then every other month (or 60 days) for the first 6 months, then every 3 months (90 days) for 2 years, and then every 6 months for years 2 to 4 after completing treatment. After 4.5 years, they will be seen once a year.
- Detailed Description
Background:
* Mature T-cell malignancies (TCM) are rare and heterogeneous group of leukemias and lymphomas accounting for 5 to 10% of all lymphomas in the US
* Patients with systemic TCM are most commonly treated with a CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimens, that produce long-term progression-free survival in about 30% of these cases
* Patients with relapsed/refractory (R/R) TCM have very poor prognosis with median overall survival of less than 1 year. Treatment options for R/R TCM are very few and of limited efficacy, thus novel treatment strategies are urgently needed.
* Mutations in epigenetic regulators are common in aggressive TCMs and standard treatment with histone deacetylase inhibitors (HDACi) such as romidepsin show modest clinical activity with single agent the overall response (ORR) around 25%
* Combination of romidepsin and 5-azacitidine (hypomethylating agents) was synergistic in preclinical models, and has demonstrated high clinical activity with an ORR of 79%
* Many TCMs rely on The Ikaros-dependent NF-kB/IRF4 signaling pathway to maintain proliferation, which is why lenalidomide, which induces degradation of Ikaros and downregulates IRF4, has single agent activity in R/R TCM with ORR of 26% to 42%, depending on the subtype.
* Lenalidomide synergizes with romidepsin and enhances tumor cell death in TCM cell lines, predicting that the addition of lenalidomide to the established romidepsin/ CC-486 (5-azacitidine) combination will further improve efficacy.
Objectives:
-To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of the four drug combination of CC-486 (5-azacitidine), romidepsin, lenalidomide and dexamethasone in patients with TCM
Eligibility:
* Refractory/relapsed TCM (excluding in Cutaneous T-Cell Lymphoma) defined as follows:
* Patients with systemic disease
* Have received at least one line of prior therapy
* Must have received brentuximab vedotin if the disease is anaplastic large cell lymphoma or CD30-positive cutaneous T-cell lymphoma
* Age \>= 18 years of age
* ECOG performance status of \<= 2 (or \<= 3 if decrease is due to the disease)
* Histologically or cytologically confirmed relapsed and/or refractory mature TCM
* Adequate organ and marrow function
Design:
* Open-label, single-center, uncontrolled Phase 1 study
* 3 + 3 design will be used to determine the MTD of dose-escalated lenalidomide with fixed dose of romidepsin and CC-486 (5-azacitidine)
* An expansion cohort of 9 patients will be evaluated at the MTD
* Maximum 6 cycles (28-day cycle) of combination therapy
* To explore all dose levels, including further evaluation in a dose expansion cohort, the accrual ceiling will be set at 30 patients
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 20
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1- Experimental Treatment: Dose Escalation CC-486 (5-azacitidine) Lenalidomide by oral intake at escalating doses of 5, 10, 15, or 20 mg/day on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine MTD 1- Experimental Treatment: Dose Escalation Dexamethasone Lenalidomide by oral intake at escalating doses of 5, 10, 15, or 20 mg/day on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine MTD 2 - Experimental Treatment: Dose Expansion CC-486 (5-azacitidine) Lenalidomide by oral intake at MTD on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle 1- Experimental Treatment: Dose Escalation Lenalidomide Lenalidomide by oral intake at escalating doses of 5, 10, 15, or 20 mg/day on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine MTD 1- Experimental Treatment: Dose Escalation Romidepsin Lenalidomide by oral intake at escalating doses of 5, 10, 15, or 20 mg/day on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine MTD 2 - Experimental Treatment: Dose Expansion Romidepsin Lenalidomide by oral intake at MTD on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle 2 - Experimental Treatment: Dose Expansion Lenalidomide Lenalidomide by oral intake at MTD on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle 2 - Experimental Treatment: Dose Expansion Dexamethasone Lenalidomide by oral intake at MTD on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle
- Primary Outcome Measures
Name Time Method Maximum tolerated dose (MTD) 21 days Frequency (number and percentage) of treatment emergent adverse events
safety and tolerability 6 cycles rate and severity of AEs will be summarized by grade and type of toxicity
- Secondary Outcome Measures
Name Time Method Progression-free survival every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually The response rate will be determined and reported along with a 95% confidence interval
Complete Response Rate 6 cycles The response rate will be determined and reported along with a 95% confidence interval
Duration of response (DOR) every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually The response rate will be determined and reported along with a 95% confidence interval
Overall Repsonse Rate 6 cycles The response rate will be determined and reported along with a 95% confidence interval
Overall Survival (OS) every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually The response rate will be determined and reported along with a 95% confidence interval
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States