Maintenance Rituximab With mTor Inhibition After High-dose Consolidative Therapy in Lymphoma

Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
Overall Status
Completed
CT.gov ID
NCT01665768
Collaborator
Novartis Pharmaceuticals (Industry)
56
Enrollment
1
Location
1
Arm
95
Actual Duration (Months)
0.6
Patients Per Site Per Month

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.

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

Study Type:
Interventional
Actual Enrollment :
56 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Trial of Maintenance Rituximab With mTor Inhibition After High-dose Consolidative Therapy in CD20+, B-cell Lymphomas, Gray Zone Lymphoma, and Hodgkin's Lymphoma
Actual Study Start Date :
Sep 1, 2012
Actual Primary Completion Date :
Oct 1, 2017
Actual Study Completion Date :
Aug 1, 2020

Arms and Interventions

ArmIntervention/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:
  • RAD001
  • Biological: Rituximab
    375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)
    Other Names:
  • Rituxan
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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.

    2. 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.

    3. 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

    Ages Eligible for Study:
    18 Years to 100 Years
    Sexes Eligible for Study:
    All
    Accepts 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.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreMarylandUnited States21231

    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.
    Responsible Party:
    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    ClinicalTrials.gov Identifier:
    NCT01665768
    Other Study ID Numbers:
    • J1228
    • NA_00067315
    First Posted:
    Aug 15, 2012
    Last Update Posted:
    Oct 26, 2021
    Last Verified:
    Oct 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail7 participants were screen failures.
    Arm/Group TitleEverolimus and Rituximab
    Arm/Group DescriptionEverolimus 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
    STARTED49
    COMPLETED26
    NOT COMPLETED23

    Baseline Characteristics

    Arm/Group TitleEverolimus and Rituximab
    Arm/Group DescriptionEverolimus 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 Participants49
    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

    1. Primary Outcome
    TitleSafety as Assessed by Avoidance of Grade 3-4 Adverse Events
    DescriptionNumber of participants who did not experience at least one grade 3-4 adverse event by CTCAE 4.0.
    Time FrameUp to 3 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleEverolimus and Rituximab
    Arm/Group DescriptionEverolimus 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 Participants49
    Count of Participants [Participants]
    1
    2%
    2. Secondary Outcome
    TitleEvent Free Survival (EFS)
    DescriptionPercentage 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 Frame2.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleEverolimus and Rituximab
    Arm/Group DescriptionEverolimus 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 Participants49
    Number (95% Confidence Interval) [percentage of participants]
    58
    118.4%
    3. Secondary Outcome
    TitlePercentage Change in the Frequency of Circulating Cancer Cells
    DescriptionPercentage change in circulating cancer cells between baseline and each timepoint noted below.
    Time FrameBaseline, 1 year, 2 years and 3 years

    Outcome Measure Data

    Analysis Population Description
    Data was not collected.
    Arm/Group TitleEverolimus and Rituximab
    Arm/Group DescriptionEverolimus 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 Participants0
    4. Secondary Outcome
    TitlePercentage Change in Cancer Cells When mTOR Kinase Inhibition is Applied
    DescriptionPercentage change in cancer cells when mTOR inhibition is applied in the laboratory. Samples from participants will be evaluated at each timepoint noted below.
    Time Frame1 year, 2 years, and 3 years

    Outcome Measure Data

    Analysis Population Description
    Data was not collected.
    Arm/Group TitleEverolimus and Rituximab
    Arm/Group DescriptionEverolimus 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 Participants0

    Adverse Events

    Time FrameUp 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 TitleEverolimus and Rituximab
    Arm/Group DescriptionEverolimus 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
    Total0/49 (0%)
    Serious Adverse Events
    Everolimus and Rituximab
    Affected / at Risk (%)# Events
    Total13/49 (26.5%)
    Eye disorders
    Retinal tear1/49 (2%) 1
    Gastrointestinal disorders
    Diarrhea1/49 (2%) 1
    Infections and infestations
    Cellulitis4/49 (8.2%) 4
    MRSA1/49 (2%) 1
    Febrile neutropenia2/49 (4.1%) 2
    Pneumonia2/49 (4.1%) 2
    Sepsis3/49 (6.1%) 3
    Zoster1/49 (2%) 1
    Investigations
    Hyperglycemia1/49 (2%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma1/49 (2%) 1
    Renal and urinary disorders
    Acute kidney injury2/49 (4.1%) 2
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure1/49 (2%) 1
    Skin and subcutaneous tissue disorders
    Skin lesions1/49 (2%) 1
    Other (Not Including Serious) Adverse Events
    Everolimus and Rituximab
    Affected / at Risk (%)# Events
    Total47/49 (95.9%)
    Gastrointestinal disorders
    Diarrhea3/49 (6.1%) 3
    General disorders
    Fatigue3/49 (6.1%) 3
    Insomnia3/49 (6.1%) 3
    Pain - throat3/49 (6.1%) 4
    Investigations
    ALT increased4/49 (8.2%) 6
    Anemia5/49 (10.2%) 12
    Hyperglycemia10/49 (20.4%) 25
    Hypertriglyceridemia10/49 (20.4%) 17
    Leukopenia31/49 (63.3%) 73
    Lymphopenia6/49 (12.2%) 15
    Neutropenia29/49 (59.2%) 75
    Thrombocytopenia8/49 (16.3%) 18
    Nervous system disorders
    Neuropathy4/49 (8.2%) 5
    Respiratory, thoracic and mediastinal disorders
    Dyspnea3/49 (6.1%) 3
    Skin and subcutaneous tissue disorders
    Mucositis4/49 (8.2%) 4
    Rash3/49 (6.1%) 3

    Limitations/Caveats

    [Not Specified]

    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/TitleDouglas Gladstone, MD
    OrganizationJohns Hopkins University
    Phone4109558781
    Emaildgladst1@jhmi.edu
    Responsible Party:
    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    ClinicalTrials.gov Identifier:
    NCT01665768
    Other Study ID Numbers:
    • J1228
    • NA_00067315
    First Posted:
    Aug 15, 2012
    Last Update Posted:
    Oct 26, 2021
    Last Verified:
    Oct 1, 2021