Lymphoma
Conditions
Keywords
Non-Hodgkin's Lymphoma, Lymphoma, Nausea, Cyclophosphamide, Cytoxan, Neosar, Doxorubicin, AD, Hydroxydaunomycin hydrochloride, Vincristine, Prednisone, Rituximab, Rituxan, Aprepitant, Emend, L754030, MK869, Drug Metabolism, CHOP, R-CHOP, NHL
Brief summary
The goal of this clinical research study is to learn the effect of combining aprepitant with CHOP or R-CHOP in patients with Non-Hodgkin's Lymphoma (NHL) that is either newly diagnosed or has come back. Researchers also want to see if aprepitant can help to prevent nausea and/or vomiting that may be caused by chemotherapy treatment with CHOP or R-CHOP, in these patients. CHOP consists of four drugs - Cyclophosphamide (also called Cytoxan/Neosar), Doxorubicin (or Adriamycin), Vincristine (Oncovin) and Prednisolone while R-CHOP includes Rituximab and CHOP.
Detailed description
The Study Drugs: Aprepitant is designed to block the natural substance in the brain that causes nausea and vomiting. This may help to prevent and/or control nausea and vomiting caused by cancer chemotherapy treatment. CHOP and R-CHOP are commonly used chemotherapy regimens for treating NHL. In the blood, aprepitant may increase or decrease the drug levels of cyclophosphamide, vincristine, and/or prednisone (which are part of the CHOP and R-CHOP regimens), but this is not known for certain. This study is designed to help researchers learn the effect of combining aprepitant with CHOP and R-CHOP. Study Groups: If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to 1 of 2 groups. There is an equal chance of being assigned to either group. Standard Chemotherapy Administration: Both CHOP and R-CHOP typically have 21-day cycles but can vary from every 14 to 28 days. You will receive CHOP or R-CHOP according to the schedule prescribed by your doctor. You will also receive standard medications for preventing nausea and vomiting. You will sign a separate consent form that will describe these treatments in detail, along with their risks. Aprepitant Administration: Aprepitant is taken by mouth, with or without food. Group 1 will take aprepitant on Days 1, 2, and 3 of Study Cycle 1 only. Group 2 will take aprepitant on Days 1, 2, and 3 of Study Cycle 2 only. Study Diary: Prior to each study cycle, you will be given a study diary to use throughout the study. Once a day, you will record any side effects you may have experienced. You should bring your study diary to every study visit so the study staff can review it. Study Visits: Prior to each study cycle, you will have a study visit with the following tests/procedures performed: * Your medical history will be recorded. * You will have a physical exam, including measurement of vital signs and weight. * You will have a performance status evaluation. * You will fill out the same questionnaire you did at screening, about any nausea and vomiting you may be experiencing. * You will be asked about any other medications you may be taking. Be sure to tell the study doctor about all medications (including vitamins, herbal products, and nutritional supplements), because some medications/substances will cause side effects when taken at the same time as aprepitant. * The study staff will review your study diary. Pharmacokinetic Testing: You will have additional blood samples drawn for pharmacokinetic (PK) testing of cyclophosphamide, vincristine, and prednisone levels. PK testing measures the amount of the drug in the body at different time points. These PK blood draws will be about 2 tablespoons each. On Days 1 and 2 of Study Cycles 1 and 2, blood will be drawn for PK testing at the following times: before taking prednisone, 30 minutes after the start of the cyclophosphamide infusion, and at 60 minutes, 75 minutes, 90 minutes, and 2, 4, 6, 8, and 24 hours after the start of the cyclophosphamide infusion. Other Blood Tests: At least twice a week during Study Cycles 1 and 2, blood (about 1 teaspoon) will be drawn for routine tests. Aprepitant may increase the blood sugar during the first few days the drug is taken. Because of this, on Day 1 of Study Cycle 1, you will be given a glucometer (a machine to check your blood sugar). You will use the glucometer at home during the study (or in the hospital if you are admitted there for chemotherapy). You will be given instructions on how to use it, and what to be looking for. On Days 1-6 of Study Cycle 1, you will give yourself a fingerstick blood sugar test once a day (before breakfast). You will take a fingerstick blood sugar test before you receive each dose of aprepitant. Length of Study: You may receive up to 2 cycles of chemotherapy, including 1 cycle of aprepitant. If intolerable side effects occur or the disease gets worse, you will be taken off study early. End-of-Study Visit: At 30 days after your last dose of aprepitant, you will return for an end-of-study visit. At this visit, you will have the same tests/procedures performed that you did at the other study visits. You will return the glucometer to the study staff. This is an investigational study. The CHOP and R-CHOP regimens are commercially available and FDA approved for use in NHL. Aprepitant is commercially available and FDA approved (when used in combination with other nausea medication, such as ondansetron) for the prevention of nausea and vomiting that may be caused by chemotherapy. However, this study is considered experimental because researchers want to find out how aprepitant may affect the drug levels of cyclophosphamide, vincristine, and prednisone in the blood. (Cyclophosphamide, vincristine, and prednisone are part of the CHOP and R-CHOP regimens.) The use of aprepitant is authorized for this experimental purpose. Up to 18 patients will take part in this study. All will be enrolled at M. D. Anderson.
Interventions
DRUGPrednisone
100 mg PO for 5 Days
DRUGRituximab
375 mg/m\^2 By Vein On Day 1.
DRUGOndansetron
8 mg daily for 2 days
DRUGAprepitant
125 mg By Mouth (PO) On Day 1, followed by 80 mg PO Daily On Days 2-3.
DRUGCyclophosphamide
750 mg/m\^2 By Vein On Day 1
DRUGDoxorubicin
25 mg/m\^2 By Vein Over 48 Hours On Days 1-2
DRUGVincristine
2 mg By Vein On Day 1
Sponsors
Merck Sharp & Dohme LLC
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Newly diagnosed or relapsed lymphoid malignancy. 2. Patients receiving either:(1) Bolus or 48-hr infusion CHOP (cyclophosphamide 750 mg/m\^2 IV Day 1, doxorubicin 25 mg/m\^2/day IV given as bolus infusion or over 48 hours continuous infusion Days 1-2, vincristine 2 mg IV Day 1, prednisone PO 100 mg \* 5 days) OR (2) Bolus or 48-hr infusion R-CHOP (Rituximab 375mg/m\^2 on Day 1+ CHOP as above). (For patients receiving R-CHOP, CHOP may be administered starting on Day 2 at the discretion of the treating physician 3. Age \>/= to 18 years 4. Adequate organ function defined as serum total bilirubin \</= 1.2 mg/dL, serum aspartate aminotransferase or serum glutamate oxaloacetate transaminase (SGOT) \</= 60 IU/L, creatinine \< 1.5 mg/dL.
Exclusion criteria
1. Evidence of neoplastic central nervous system disease 2. Patients who are unable to take oral medication (e.g. due to tumor obstruction) 3. History of Diabetes Mellitus (Diabetes as defined by established diagnosis of diabetes currently receiving medications for the diabetes management and/or a fasting blood glucose of \>/= 126 mg/dL.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Area Under Curve (AUC) of Analyte, Cyclophosphamide (CP), in Aprepitant Treatment and Control Group | Time points over 24 hours of cyclophosphamide infusion for both cycles (21 day cycle) | Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of Cyclophosphamide (CP) during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. micrograms (ug)/milliliters (mL) times hour (hr). |
| Geometric Mean Area Under Curve (AUC) of Analyte, 2-dechloro-cyclophosphamide(2-deCI-CP), in Aprepitant Treatment and Control Group | Time points over 24 hours of cyclophosphamide infusion for both cycles (21 day cycle) | Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of 2-deCI-CP, during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. micrograms (ug)/milliliters (mL) times hour (hr). |
| Geometric Mean Area Under Curve (AUC) of Analyte, 4-hydroxy-cyclophosphamide (4-OH-CP), in Aprepitant Treatment and Control Group | Time points over 24 hours of cyclophosphamide infusion for both cycles (21 day cycle) | Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of 4-hydroxy-cyclophosphamide (4-OH-CP), during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. micrograms (ug)/milliliters (mL) times hour (hr). |
| Geometric Mean Area Under Curve (AUC) of Analyte, Vincristine (VC), in Aprepitant Treatment and Control Group | Time points over 24 hours of cyclophosphamide infusion for both cycles (21 day cycle) | Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of VC, during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. nanograms (ng)/milliliters (mL) times hour (hr). |
| Geometric Mean Area Under Curve (AUC) of Analyte,Prednisone (PR), in Aprepitant Treatment and Control Group | Time points over 8 hours of cyclophosphamide infusion for both cycles (21 day cycle) | Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of PR, during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. nanograms (ng)/milliliters (mL) times hour (hr). |
| Geometric Mean Area Under Curve (AUC) of Analyte, Prednisolone (PL), in Aprepitant Treatment and Control Group | Time points over 8 hours of cyclophosphamide infusion for both cycles (21 day cycle) | Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of PL, during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. nanograms (ng)/milliliters (mL) times hour (hr). |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: March 14, 2008 to May 3, 2010. All recruitment done at The University of Texas MD Anderson Cancer Center.
Pre-assignment details
Of the 23 participants who enrolled, three (3) withdrew prior to group assignment and were excluded from the trial.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Participants randomized to Aprepitant or control (Standard of Care) in Cycle 1 crossover for different treatment in Cycle 2. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Cycle 1 (First 21 Days) | Withdrawal by Subject | 1 | 0 |
| Cycle 2 (Second 21 Days) | Not Evaluable | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age Continuous | 58 years |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 20 | 2 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Geometric Mean Area Under Curve (AUC) of Analyte, 2-dechloro-cyclophosphamide(2-deCI-CP), in Aprepitant Treatment and Control Group
Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of 2-deCI-CP, during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. micrograms (ug)/milliliters (mL) times hour (hr).
Time frame: Time points over 24 hours of cyclophosphamide infusion for both cycles (21 day cycle)
Population: There were 18 participants eligible for PK analysis, one was excluded from the final analysis due to data issues.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aprepitant | Geometric Mean Area Under Curve (AUC) of Analyte, 2-dechloro-cyclophosphamide(2-deCI-CP), in Aprepitant Treatment and Control Group | 4.5 ug/mL*hr |
| Control Group | Geometric Mean Area Under Curve (AUC) of Analyte, 2-dechloro-cyclophosphamide(2-deCI-CP), in Aprepitant Treatment and Control Group | 6.0 ug/mL*hr |
95% CI: [0.65, 0.86]equivalence analysis
Primary
Geometric Mean Area Under Curve (AUC) of Analyte, 4-hydroxy-cyclophosphamide (4-OH-CP), in Aprepitant Treatment and Control Group
Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of 4-hydroxy-cyclophosphamide (4-OH-CP), during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. micrograms (ug)/milliliters (mL) times hour (hr).
Time frame: Time points over 24 hours of cyclophosphamide infusion for both cycles (21 day cycle)
Population: There were 18 participants eligible for PK analysis, one was excluded from the final analysis due to data issues.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aprepitant | Geometric Mean Area Under Curve (AUC) of Analyte, 4-hydroxy-cyclophosphamide (4-OH-CP), in Aprepitant Treatment and Control Group | 3.9 ug/mL*hr |
| Control Group | Geometric Mean Area Under Curve (AUC) of Analyte, 4-hydroxy-cyclophosphamide (4-OH-CP), in Aprepitant Treatment and Control Group | 4.0 ug/mL*hr |
90% CI: [0.83, 1.13]equivalence analysis
Primary
Geometric Mean Area Under Curve (AUC) of Analyte, Cyclophosphamide (CP), in Aprepitant Treatment and Control Group
Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of Cyclophosphamide (CP) during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. micrograms (ug)/milliliters (mL) times hour (hr).
Time frame: Time points over 24 hours of cyclophosphamide infusion for both cycles (21 day cycle)
Population: There were 18 participants eligible for PK analysis, one was excluded from the final analysis due to data issues.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aprepitant | Geometric Mean Area Under Curve (AUC) of Analyte, Cyclophosphamide (CP), in Aprepitant Treatment and Control Group | 300 ug/mL*hr |
| Control Group | Geometric Mean Area Under Curve (AUC) of Analyte, Cyclophosphamide (CP), in Aprepitant Treatment and Control Group | 250 ug/mL*hr |
90% CI: [1.08, 1.33]90% CI
Primary
Geometric Mean Area Under Curve (AUC) of Analyte, Prednisolone (PL), in Aprepitant Treatment and Control Group
Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of PL, during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. nanograms (ng)/milliliters (mL) times hour (hr).
Time frame: Time points over 8 hours of cyclophosphamide infusion for both cycles (21 day cycle)
Population: Per protocol, 18 participants were eligible for PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aprepitant | Geometric Mean Area Under Curve (AUC) of Analyte, Prednisolone (PL), in Aprepitant Treatment and Control Group | 4416 ng/mL*hr |
| Control Group | Geometric Mean Area Under Curve (AUC) of Analyte, Prednisolone (PL), in Aprepitant Treatment and Control Group | 3817 ng/mL*hr |
90% CI: [1.01, 1.32]equivalence analysis
Primary
Geometric Mean Area Under Curve (AUC) of Analyte,Prednisone (PR), in Aprepitant Treatment and Control Group
Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of PR, during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. nanograms (ng)/milliliters (mL) times hour (hr).
Time frame: Time points over 8 hours of cyclophosphamide infusion for both cycles (21 day cycle)
Population: Per protocol, 18 participants were eligible for PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aprepitant | Geometric Mean Area Under Curve (AUC) of Analyte,Prednisone (PR), in Aprepitant Treatment and Control Group | 287 ng/mL*hr |
| Control Group | Geometric Mean Area Under Curve (AUC) of Analyte,Prednisone (PR), in Aprepitant Treatment and Control Group | 265 ng/mL*hr |
90% CI: [1.02, 1.15]equivalence analysis
Primary
Geometric Mean Area Under Curve (AUC) of Analyte, Vincristine (VC), in Aprepitant Treatment and Control Group
Pharmacokinetic (PK) blood sampling to determine the geometric mean AUC of VC, during & post chemotherapy infusion, baseline, at 30, 60, 75, 90 minutes, and 2 , 4, 6, 8, and 24 hours from start of cyclophosphamide infusion. The absence of PK drug interactions was determined if the 90% Confidence Intervals (CI) of the geometric mean AUC ratio between 2 groups is within 0.80 to 1.25. Measurements reported as concentrate times the time, i.e. nanograms (ng)/milliliters (mL) times hour (hr).
Time frame: Time points over 24 hours of cyclophosphamide infusion for both cycles (21 day cycle)
Population: There were 18 patients eligible for PK analysis, two participants were excluded from the analysis due to data issues.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aprepitant | Geometric Mean Area Under Curve (AUC) of Analyte, Vincristine (VC), in Aprepitant Treatment and Control Group | 41 ng/mL*hr |
| Control Group | Geometric Mean Area Under Curve (AUC) of Analyte, Vincristine (VC), in Aprepitant Treatment and Control Group | 39 ng/mL*hr |
90% CI: [0.82, 1.33]equivalence analysis