Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies

Phase 1

Active, not recruiting

Conditions: Cutaneous T-Cell Lymphoma
Mature T-cell Malignancies
Peripheral T-Cell Lymphoma
Relapsed/ Refractory T-cell Malignancies

Interventions: Drug: Romidepsin
Drug: Lenalidomide
Drug: CC-486 (5-azacitidine)
Drug: Dexamethasone
Diagnostic Test: EKG
Procedure: Bone Marrow Aspiration/Biopsy
Diagnostic Test: MRI
Procedure: Lumbar Puncture
Diagnostic Test: TTE

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 intravenous (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 nuclear factor κB (NF-κB)/interferon regulatory factor 4 (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 overall response rate (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 cluster of differentiation 30 (CD30)-positive cutaneous T-cell lymphoma

* Age \>= 18 years of age

* Eastern Cooperative Oncology Group 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 maximum tolerated dose (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: 26

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).
2 - Experimental Treatment: Dose Expansion	Lenalidomide	Lenalidomide by oral intake at maximum tolerated dose (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/m\^2 by intravenous (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	CC-486 (5-azacitidine)	Lenalidomide by oral intake at maximum tolerated dose (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/m\^2 by intravenous (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 maximum tolerated dose (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/m\^2 by intravenous (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	EKG	Lenalidomide by oral intake at maximum tolerated dose (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/m\^2 by intravenous (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	Bone Marrow Aspiration/Biopsy	Lenalidomide by oral intake at maximum tolerated dose (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/m\^2 by intravenous (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	MRI	Lenalidomide by oral intake at maximum tolerated dose (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/m\^2 by intravenous (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	Lumbar Puncture	Lenalidomide by oral intake at maximum tolerated dose (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/m\^2 by intravenous (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	TTE	Lenalidomide by oral intake at maximum tolerated dose (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/m\^2 by intravenous (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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).
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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).
1- Experimental Treatment: Dose Escalation	EKG	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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).
1- Experimental Treatment: Dose Escalation	Bone Marrow Aspiration/Biopsy	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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).
1- Experimental Treatment: Dose Escalation	MRI	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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).
1- Experimental Treatment: Dose Escalation	Lumbar Puncture	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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).
1- Experimental Treatment: Dose Escalation	TTE	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/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).
2 - Experimental Treatment: Dose Expansion	Romidepsin	Lenalidomide by oral intake at maximum tolerated dose (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/m\^2 by intravenous (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
Arm 1, Cohort 1, Dose Level 3, and Arm 1, Cohort 1, Dose Level 4 Treatment Emergent Serious Grades 3, 4, and/or 5 Adverse Events Possibly Related to Drug Grouped by Relationship to the Study Drug and/or Combination	6 cycles (each cycle is 28 days)	Treatment emergent grades 3, 4, and/or 5 adverse events possibly related grouped by relationship to the study drug (e.g., lenalidomide, romidepsin, CC-486 (5-azacitidine) in any combinations) assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event.
Arm 2, Cohort 2, Dose Level 2 and 4; and Arm 3, Cohort 2, Dose Level 4 Treatment Emergent Serious Grades 3, 4, and/or 5 Adverse Events Possibly Related to Drug Grouped by Relationship to the Study Drug and/or Combination	6 cycles (each cycle is 28 days)	Treatment emergent grades 3, 4, and/or 5 adverse events possibly related grouped by relationship to the study drug (e.g., lenalidomide, romidepsin, CC-486 (5-azacitidine) in any combinations) assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event.
Maximum Tolerated Dose (MTD)	21 days	The MTD is the dose level at which no more than 1 of up to 6 participants experience dose-limiting toxicity (DLT) during the DLT evaluation window(s), or the dose below that at which at least 2 (of ≤6) participants have DLT. A DLT is defined as any treatment-emergent and related severe (grade ≥3) toxicity related to lenalidomide, romidepsin and/or CC-486 (5-azacitidine) and occurring during the maximum tolerated dose (MTD) observation time, defined as day -7 until end of cycle 1 (normally day 22).
Rate and Severity of Serious and/or Non-serious Adverse Events (AE's) by Grade and Type of Toxicity	6 cycles (each cycle is 28 days)	Rate and severity of AEs will be summarized by grade and type of toxicity. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Number of Treatment Emergent Grades 3, 4 and/or 5 Adverse Events Possibly Related to Drug Grouped by Severity	6 cycles (each cycle is 28 days)	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Arm 1, Cohort 1, Dose Level -1, 1, and 2 Treatment Emergent Serious Grades 3, 4, and/or 5 Adverse Events Possibly Related to Drug Grouped by Relationship to the Study Drug and/or Combination	6 cycles (each cycle is 28 days)	Treatment emergent grades 3, 4, and/or 5 adverse events possibly related grouped by relationship to the study drug (e.g., lenalidomide, romidepsin, CC-486 (5-azacitidine) in any combinations) assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (Complete Response + Partial Response)	6 cycles (each cycle is 28 days)	The response rate will be estimated using the Kaplan-Meier curve and reported along with a 95% confidence interval. Response was measured by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria. Complete response (CR) is disappearance of all target lesions and all nodes with long axis \<10mm. Partial response (PR) is a ≥30% decrease in the sum of longest diameters of target lesions but not a CR.
Progression-free Survival (PFS) in Months Reported Along With a 95% Confidence Interval	up to a median of 13.1 months	PFS will be estimated using the Kaplan-Meier curve and reported along with a 95% confidence interval. PFS is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first measured by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria. Progressive disease is \>20% increase in the sum of longest diameters of target lesions. Disease relapse is defined as new areas of disease or \>50% increase in growth of target lesion.
Complete Response Rate (CRR)	6 cycles (each cycle is 28 days)	CRR will be estimated using the Kaplan-Meier curve and reported along with a 95% confidence interval. Response was measured by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria. Complete response (CR) is disappearance of all target lesions and all nodes with long axis \<10mm.
Duration of Response (DOR) in Months Reported Along With a 95% Confidence Interval	up to a median of 11.7 months	DOR will be determined and reported along with a 95% confidence interval. DOR is measured from the time measurement criteria are met for complete response (CR) or partial response (PR (whichever is recorded first) until the first date that recurrent or progressive disease is objectively documented. Response was measured by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria. Complete response (CR) is disappearance of all target lesions and all nodes with long axis \<10mm. Partial response (PR) is a ≥30% decrease in the sum of longest diameters of target lesions but not a CR. Progressive disease is \>20% increase in the sum of longest diameters of target lesions.
Overall Survival (OS)	up to a median of 8.7 months	OS will be estimated using the Kaplan-Meier curve and reported along with a 95% confidence interval. OS is defined as the time from the date of study enrollment until time of death from any cause.

Trial Locations

Locations (1): National Institutes of Health Clinical Center
🇺🇸
Bethesda, Maryland, United States
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States