Maintenance Rituximab With mTor Inhibition After High-dose Consolidative Therapy in Lymphoma
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Everolimus and Rituximab Everolimus daily for one year and IV rituximab four times during that year. |
Drug: 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.
Other Names:
Biological: Rituximab
375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
- 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.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | 21231 |
Sponsors and Collaborators
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Novartis Pharmaceuticals
Investigators
- Principal Investigator: Douglas Gladstone, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Documents (Full-Text)
More Information
Publications
None provided.- J1228
- NA_00067315
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | 7 participants were screen failures. |
| Arm/Group Title | Everolimus and Rituximab |
|---|---|
| Arm/Group Description | 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) |
| Period Title: Overall Study | |
| STARTED | 49 |
| COMPLETED | 26 |
| NOT COMPLETED | 23 |
Baseline Characteristics
| Arm/Group Title | Everolimus and Rituximab |
|---|---|
| Arm/Group Description | 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) |
| Overall Participants | 49 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
37
75.5%
|
| >=65 years |
12
24.5%
|
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
59
|
| Sex: Female, Male (Count of Participants) | |
| Female |
7
14.3%
|
| Male |
42
85.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
1
2%
|
| Not Hispanic or Latino |
46
93.9%
|
| Unknown or Not Reported |
2
4.1%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
3
6.1%
|
| White |
43
87.8%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
3
6.1%
|
| Number of Prior Therapies (Count of Participants) | |
| Two Prior Therapies |
30
61.2%
|
| Three Prior Therapies |
18
36.7%
|
| Four Prior Therapies |
1
2%
|
Outcome Measures
| Title | Safety as Assessed by Avoidance of Grade 3-4 Adverse Events |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Everolimus and Rituximab |
|---|---|
| Arm/Group Description | 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) |
| Measure Participants | 49 |
| Count of Participants [Participants] |
1
2%
|
| Title | Event Free Survival (EFS) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Everolimus and Rituximab |
|---|---|
| Arm/Group Description | 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) |
| Measure Participants | 49 |
| Number (95% Confidence Interval) [percentage of participants] |
58
118.4%
|
| Title | Percentage Change in the Frequency of Circulating Cancer Cells |
|---|---|
| Description | Percentage change in circulating cancer cells between baseline and each timepoint noted below. |
| Time Frame | Baseline, 1 year, 2 years and 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data was not collected. |
| Arm/Group Title | Everolimus and Rituximab |
|---|---|
| Arm/Group Description | 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) |
| Measure Participants | 0 |
| Title | Percentage Change in Cancer Cells When mTOR Kinase Inhibition is Applied |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data was not collected. |
| Arm/Group Title | Everolimus and Rituximab |
|---|---|
| Arm/Group Description | 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) |
| Measure Participants | 0 |
Adverse Events
| Time Frame | Up to 3 years | |
|---|---|---|
| Adverse Event Reporting Description | Adverse events were assessed every 2 weeks for the first 2 months, monthly for the remainder of the first year, every 90 days for the second year, and every 6 months for the third year. Per protocol, all adverse events were collected for the first 13 participants. Only grade 3-4 and all serious adverse events were collected for the remaining participants. | |
| Arm/Group Title | Everolimus and Rituximab | |
| Arm/Group Description | 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) | |
All Cause Mortality |
||
| Everolimus and Rituximab | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/49 (0%) | |
Serious Adverse Events |
||
| Everolimus and Rituximab | ||
| Affected / at Risk (%) | # Events | |
| Total | 13/49 (26.5%) | |
| Eye disorders | ||
| Retinal tear | 1/49 (2%) | 1 |
| Gastrointestinal disorders | ||
| Diarrhea | 1/49 (2%) | 1 |
| Infections and infestations | ||
| Cellulitis | 4/49 (8.2%) | 4 |
| MRSA | 1/49 (2%) | 1 |
| Febrile neutropenia | 2/49 (4.1%) | 2 |
| Pneumonia | 2/49 (4.1%) | 2 |
| Sepsis | 3/49 (6.1%) | 3 |
| Zoster | 1/49 (2%) | 1 |
| Investigations | ||
| Hyperglycemia | 1/49 (2%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Basal cell carcinoma | 1/49 (2%) | 1 |
| Renal and urinary disorders | ||
| Acute kidney injury | 2/49 (4.1%) | 2 |
| Respiratory, thoracic and mediastinal disorders | ||
| Respiratory failure | 1/49 (2%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Skin lesions | 1/49 (2%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Everolimus and Rituximab | ||
| Affected / at Risk (%) | # Events | |
| Total | 47/49 (95.9%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 3/49 (6.1%) | 3 |
| General disorders | ||
| Fatigue | 3/49 (6.1%) | 3 |
| Insomnia | 3/49 (6.1%) | 3 |
| Pain - throat | 3/49 (6.1%) | 4 |
| Investigations | ||
| ALT increased | 4/49 (8.2%) | 6 |
| Anemia | 5/49 (10.2%) | 12 |
| Hyperglycemia | 10/49 (20.4%) | 25 |
| Hypertriglyceridemia | 10/49 (20.4%) | 17 |
| Leukopenia | 31/49 (63.3%) | 73 |
| Lymphopenia | 6/49 (12.2%) | 15 |
| Neutropenia | 29/49 (59.2%) | 75 |
| Thrombocytopenia | 8/49 (16.3%) | 18 |
| Nervous system disorders | ||
| Neuropathy | 4/49 (8.2%) | 5 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 3/49 (6.1%) | 3 |
| Skin and subcutaneous tissue disorders | ||
| Mucositis | 4/49 (8.2%) | 4 |
| Rash | 3/49 (6.1%) | 3 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Douglas Gladstone, MD |
|---|---|
| Organization | Johns Hopkins University |
| Phone | 4109558781 |
| dgladst1@jhmi.edu |
- J1228
- NA_00067315