Hodgkin Lymphoma, Lymphoid Malignancies, Lymphoma, Non-hodgkin Lymphoma
Conditions
Keywords
Lymphoid Malignancies, Lymphoma, Hodgkin Lymphoma, Non-hodgkin Lymphoma, Follicular Lymphoma, Diffuse Large B-Cell Lymphoma, Anaplastic Large Cell Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Burkitt Lymphoma, Waldenstrom Macroglobulinemia, Peripheral T-cell Lymphoma, Cutaneous T-cell Lymphoma
Brief summary
This is an open label, phase I/IIa, 3 x 3 dose escalation study with an initial phase I followed by a disease focused phase II. The primary objective of the phase I is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of oral 5-azacitidine and romidepsin in patients with lymphoma. The safety and toxicity of this combination will be evaluated throughout the entire study. If the combination of oral 5-azacitidine and romidepsin is found to be feasible and an MTD is established, the phase II part of the study will be initiated. Phase II will consist of a 2 stage design of the combination of oral 5-azacitidine and romidepsin for patients with relapsed or refractory T-cell lymphomas.
Detailed description
Subjects will receive oral 5-azacitidine and romidepsin, administered as follows: oral 5-azacitidine from Days 1-14 (Dose cohorts -1 to 5) or Days 1-21 (Dose cohort 6); and romidepsin administered intravenously on Days 8 (Dose cohorts 1-4) of a 28 day cycle, and Day 22 (Dose cohorts 5 and 6) of a 35 day cycle. Cohorts of 3 patients will be enrolled sequentially as outlined in the dose escalation scheme. Once the MTD is reached the Phase II part of the protocol will be initiated in patients with T-Cell Lymphoma.
Interventions
DRUGRomiDEPsin 10 MG/M2
Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (10 mg/m2)
DRUGOral 5-Azacitidine 100 MG
A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100 mg)
DRUGRomidepsin 14 MG/M2
Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (14 mg/m2)
DRUGOral 5-Azacitidine 200 MG
A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (200 mg)
DRUGOral 5-Azacitidine 300 MG
A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (300 mg)
Sponsors
Celgene
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Phase I: Histologically confirmed relapsed or refractory non-Hodgkin lymphoma or Hodgkin lymphoma (WHO criteria), with no accepted curative options. * Phase II: Relapsed or refractory T-cell lymphoma, including patients with central nervous system (CNS) involvement or lymphomatous meningitis are allowed on study. * Relapsed or refractory disease following frontline chemotherapy. No upper limit for the number of prior therapies. Patients may have relapsed after prior autologous or allogeneic stem cell transplant. * Evaluable Disease in the Phase I, and measurable disease for the Phase II. * Age \> or = 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status \< or = 2. * Patients must have adequate organ and marrow function. * Negative urine or serum pregnancy test for females of childbearing potential. * All females of childbearing potential must use an effective barrier method of contraception during the treatment period and for at least 1 month thereafter. Male subjects should use a barrier method of contraception during the treatment period and for at least 3 months thereafter. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Prior Therapy * Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. * Systemic steroids that have not been stabilized ( ≥ 5 days) to the equivalent of ≤10 mg/day prednisone prior to the start of the study drugs. * No other concurrent investigational agents are allowed. * History of allergic reactions to Oral 5-azacitidine or Romidepsin. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women. * Nursing women. * Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancy, the patient must be disease-free for ≥ 3 years. * Patients known to be Human Immunodeficiency Virus (HIV)-positive. * Patients with active hepatitis A, hepatitis B, or hepatitis C infection. * Concomitant use of CYP3A4 inhibitors. * Any known cardiac abnormalities.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose (MTD) of the Combination of Oral 5-azacitidine in Combination With Romidepsin | up to 1.5 years | The highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found. |
| Phase I: Maximum Tolerated Dose (MTD) of Romidepsin in Combination With Oral 5-azacytidine | up to 1.5 years | The highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found. |
| Percentage of Patients Who Experienced Significant Toxicities in Phase 1 | Up to 1.5 years | Patients receiving the combination of oral 5-azacitidine and romidepsin and experiencing grades 1-4 toxicities will be tallied based on events observed and assessed by a qualified investigator. This Outcome Measure is specifically for Phase 1 of the study. |
| Phase II: Overall Response Rate (ORR) (Complete + Partial Response) of the Combination of Oral 5-azacitidine and Romidepsin in Patients With Relapsed/Refractory T-Cell Lymphoma | Up to 3 years | The percentage of people in a study or treatment group who have a partial response or complete response to the treatment within a certain period of time. A partial response is a decrease in the size of a tumor or in the amount of cancer in the body, and a complete response is the disappearance of all signs of cancer in the body. In a clinical trial, measuring the ORR is one way to see how well a new treatment works. |
Countries
United States
Participant flow
Recruitment details
From November 2013 through January 2016, 33 patients were enrolled, and 7 withdrew from the study before receiving the study interventions. 26 patients received the study interventions in Phase 1. From April 2017 and March 2019, 25 patients were enrolled in Phase 2 and received the study interventions.
Pre-assignment details
The participants in Phase 1 (n=26) are a different population than the participants in Phase 2 (n=25).
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Phase 1 is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of oral 5-azacitidine and romidepsin in patients with lymphoma. Patients will be administered the study drugs in a 3 + 3 dose-escalation study. | 33 |
| Phase 2 Patients will be treated with oral 5-azacytidine and Romidepsin at the MTD. The treatment will be administered as follows: oral 5-azacytidine 300 mg (flat dose) on Days 1-14 and Romidepsin 14 mg/m2 (flat dose) on Days 8, 15, and 22 on a 35-day cycle. | 25 |
| Total | 58 |
Baseline characteristics
| Characteristic | Phase 1 | Total | Phase 2 |
|---|---|---|---|
| Age, Continuous | 57 years | NA years | 63 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 13 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 42 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 6 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) White | 25 Participants | 47 Participants | 22 Participants |
| Sex/Gender, Customized Female | 12 Participants | 22 Participants | 10 Participants |
| Sex/Gender, Customized Male | 19 Participants | 34 Participants | 15 Participants |
| Sex/Gender, Customized Unknown | 2 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 26 | 0 / 25 |
| other Total, other adverse events | 26 / 26 | 25 / 25 |
| serious Total, serious adverse events | 11 / 26 | 12 / 25 |
Outcome results
Primary
Percentage of Patients Who Experienced Significant Toxicities in Phase 1
Patients receiving the combination of oral 5-azacitidine and romidepsin and experiencing grades 1-4 toxicities will be tallied based on events observed and assessed by a qualified investigator. This Outcome Measure is specifically for Phase 1 of the study.
Time frame: Up to 1.5 years
Population: This Outcome Measure is specific for Phase 1 of the study. This Outcome Measure was NOT applied to Phase 2, therefore data was only collected and reported for Phase 1. Results were not collected per dose level and thus cannot be reported per dose level.~26 participants received the study interventions in Phase 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Percentage of Patients Who Experienced Significant Toxicities in Phase 1 | 10 percentage of participants |
Primary
Phase II: Overall Response Rate (ORR) (Complete + Partial Response) of the Combination of Oral 5-azacitidine and Romidepsin in Patients With Relapsed/Refractory T-Cell Lymphoma
The percentage of people in a study or treatment group who have a partial response or complete response to the treatment within a certain period of time. A partial response is a decrease in the size of a tumor or in the amount of cancer in the body, and a complete response is the disappearance of all signs of cancer in the body. In a clinical trial, measuring the ORR is one way to see how well a new treatment works.
Time frame: Up to 3 years
Population: This Outcome Measure is specific for Phase 2 of the study, therefore data was only collected and reported for Phase 2. Results were not collected per dose level and thus cannot be reported per dose level.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Phase II: Overall Response Rate (ORR) (Complete + Partial Response) of the Combination of Oral 5-azacitidine and Romidepsin in Patients With Relapsed/Refractory T-Cell Lymphoma | 30 percentage of participants |
Primary
Phase I: Maximum Tolerated Dose (MTD) of Romidepsin in Combination With Oral 5-azacytidine
The highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.
Time frame: up to 1.5 years
Population: This Outcome Measure is specific for Phase 1 of the study. This Outcome Measure was NOT applied to Phase 2, therefore data was only collected and reported for Phase 1.~26 participants received the study interventions in Phase 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Phase I: Maximum Tolerated Dose (MTD) of Romidepsin in Combination With Oral 5-azacytidine | 14 mg/m2 |
Primary
Phase I: Maximum Tolerated Dose (MTD) of the Combination of Oral 5-azacitidine in Combination With Romidepsin
The highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.
Time frame: up to 1.5 years
Population: This Outcome Measure is specific for Phase 1 of the study. This Outcome Measure was NOT applied to Phase 2, therefore data was only collected and reported for Phase 1.~26 participants received the study interventions in Phase 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Phase I: Maximum Tolerated Dose (MTD) of the Combination of Oral 5-azacitidine in Combination With Romidepsin | 300 mg |