CD20+, B-cell Lymphomas, Gray Zone Lymphoma, Hodgkin's Disease, Mantle Cell Lymphoma, Non-Mantle Cell Low Grade B Cell Lymphomas (SLL/CLL), Transformed Lymphoma/DLBCL/PMBCL
Conditions
Brief summary
This research is being done to determine if combining an investigational drug called Everolimus with Rituximab can reduce the risk of your cancer from returning after high dose chemotherapy.
Detailed description
Everolimus is a pill that interferes with lymphoma cell growth by blocking a cellular pathway important in causing cancer cells to grow, called mTor. Rituximab is an intravenous medication that specifically attacks a protein commonly found on lymphoma cells called CD20. Rituximab is already widely used to treat multiple forms of lymphoma. Moreover, continuing rituximab after the completion of chemotherapy is already commonly used to help patients stay in remission longer. Everolimus has been shown in many types of relapsed lymphoma to decrease the size of lymph nodes by itself. Everolimus is approved by the Food and Drug Administration (FDA) for the treatment of advanced kidney cancer and subependymal giant cell astocytoma. It is not approved for use in lymphoma. The use of everolimus in this research study is investigational. The word investigational means that everolimus is not approved for marketing by the Food and Drug Administration (FDA). The FDA is allowing the use of everolimus in this study. The combination of everolimus and rituximab for 1 year after high dose therapy is also new. We believe the combination of these medications right after your chemotherapy will be more effective in attacking your remaining cancer before they have time to re-grow. The usual treatment of lymphoma after high-dose chemotherapy is observation. After your body has fully recovered from the effects of the chemotherapy, you will receive everolimus daily for one year and IV rituximab four times during that year.
Interventions
DRUGEverolimus
The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL.
BIOLOGICALRituximab
375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)
Sponsors
Novartis Pharmaceuticals
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Age \>18 years of age * ECOG performance status ≤ 2 * INR ≤ 2 * Adequate renal and hepatic function defined as a serum creatinine \<2.0mg/dL, total bilirubin \<5mg/dL, and AST and ALT ˂ 2.5 ULN. * Platelet count \>75 x 109/L * Hemoglobin \>10mg/dL * ANC \>3.0x109/L * Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L and fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication. * A willingness to use an accepted and effective method of birth control for sexually active women of childbearing potential during the study and for 8 weeks after the end of study drug treatment. * Ability to sign informed consent
Exclusion criteria
Patient who have previously received an mTor inhibitor * Patients who are pre-terminal or moribund * Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of Everolimus (including chemotherapy, radiation therapy, antibody based therapy, etc.) * Uncontrolled diabetes mellitus as defined by HbA1c\>8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary * Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled cortosteroids are allowed * Patients who have received live attenuated vaccines within 1 week of start of Everolimus and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines; * Patients who have a history of another primary solild malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for ≥3 years; * Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study; * Patients with active bacterial or fungal infections requiring oral or intravenous antimicrobials are not eligible until resolution of the infection * Female patients who are pregnant or breast feeding, or of reproductive potential whoe are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug. * Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment * Patients with known intolerance to rituximab * Known history of HIV or Hepatitis C * Active Hepatitis B as defined by seropositivity for hepatitis B surface antigen. Subjects with positive hepatitis B core antibody titers and normal liver transaminases are allowed provided that prophylaxis is administered per institutional guidelines. Please see Addendum 8 for the action to be taken for patients with positive baseline hepatitis B results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety as Assessed by Avoidance of Grade 3-4 Adverse Events | Up to 3 years | Number of participants who did not experience at least one grade 3-4 adverse event by CTCAE 4.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Cancer Cells When mTOR Kinase Inhibition is Applied | 1 year, 2 years, and 3 years | Percentage change in cancer cells when mTOR inhibition is applied in the laboratory. Samples from participants will be evaluated at each timepoint noted below. |
| Event Free Survival (EFS) | 2.5 years | Percentage of participants alive without disease progression. As defined by Cheson criteria, disease progression is a new lesion or \>= 50% increase in the size of previously identified sites of disease. EFS was estimated using Kaplan-Meier survival analysis. |
| Percentage Change in the Frequency of Circulating Cancer Cells | Baseline, 1 year, 2 years and 3 years | Percentage change in circulating cancer cells between baseline and each timepoint noted below. |
Countries
United States
Participant flow
Pre-assignment details
7 participants were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus and Rituximab Everolimus daily for one year and IV rituximab four times during that year.
Everolimus: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. Previously the study allowed for starting doses of 5mg and 10mg; the starting dose was reduced in subsequent amendments due to a high incidence of dose reductions. 2.5mg was the most frequent daily dose for all patients, and the entire population was analyzed as one arm.
Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions) | 49 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Lack of Efficacy | 19 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Everolimus and Rituximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants |
| Age, Continuous | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Number of Prior Therapies Four Prior Therapies | 1 Participants |
| Number of Prior Therapies Three Prior Therapies | 18 Participants |
| Number of Prior Therapies Two Prior Therapies | 30 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 43 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 49 |
| other Total, other adverse events | 47 / 49 |
| serious Total, serious adverse events | 13 / 49 |
Outcome results
Primary
Safety as Assessed by Avoidance of Grade 3-4 Adverse Events
Number of participants who did not experience at least one grade 3-4 adverse event by CTCAE 4.0.
Time frame: Up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Everolimus and Rituximab | Safety as Assessed by Avoidance of Grade 3-4 Adverse Events | 1 Participants |
Secondary
Event Free Survival (EFS)
Percentage of participants alive without disease progression. As defined by Cheson criteria, disease progression is a new lesion or \>= 50% increase in the size of previously identified sites of disease. EFS was estimated using Kaplan-Meier survival analysis.
Time frame: 2.5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus and Rituximab | Event Free Survival (EFS) | 58 percentage of participants |
Secondary
Percentage Change in Cancer Cells When mTOR Kinase Inhibition is Applied
Percentage change in cancer cells when mTOR inhibition is applied in the laboratory. Samples from participants will be evaluated at each timepoint noted below.
Time frame: 1 year, 2 years, and 3 years
Population: Data was not collected.
Secondary
Percentage Change in the Frequency of Circulating Cancer Cells
Percentage change in circulating cancer cells between baseline and each timepoint noted below.
Time frame: Baseline, 1 year, 2 years and 3 years
Population: Data was not collected.