Alemtuzumab or Tocilizumab in Combination With Etoposide and Dexamethasone for the Treatment of Adult Patients With Hemophagocytic Lymphohistiocytosis

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02385110
Collaborator
(none)
22
Enrollment
1
Location
2
Arms
84.2
Anticipated Duration (Months)
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to compare the effect of adding either alemtuzumab or tocilizumab to the drug combination of etoposide and dexamethasone in controlling HLH. The safety of the drug combinations will also be studied.

This is an investigational study. Alemtuzumab, etoposide, tocilizumab, and dexamethasone are not FDA approved for the treatment of HLH. Etoposide is FDA approved and commercially available for the treatment of testicular cancer and lung cancer. Alemtuzumab is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia. Dexamethasone is a steroid used to reduce inflammation. Tocilizumab is FDA approved and commercially available for the treatment of arthritis. The combination of alemtuzumab, etoposide, tocilizumab, and dexamethasone to treat HLH is investigational. The study doctor can explain how the drugs are designed to work.

Up to 40 participants will be enrolled in this study. All will take part at MD Anderson.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

Study Treatment:

If you are found to be eligible to take part in this study, your doctor will assign you to either Group 1 or Group 2.

You will receive the study treatment in 2 parts. The first part of the study will last about 8 weeks (Weeks 1-8) and will be called the "induction phase". The second part of the study will start after the induction phase and will last about 16 weeks (Weeks 9-16). This part will be called the "maintenance phase". However, the parts of the study may be longer or shorter depending on if/how the disease responds to the treatment, how the biomarkers react to treatment, and what the doctor thinks is in your best interest.

  • If you are in Group 1, you will receive alemtuzumab by vein over 2 hours or through an injection under the skin every day on Days 1-4 of the induction phase and about 1 time every 4 weeks during the maintenance phase.

  • If you are in Group 2, you will receive tocilizumab by vein over 60 minutes on Day 1 or Day 2 of the Induction phase. Tocilizumab will not be given in the Maintenance Phase.

Participants in both Groups 1 and 2 will receive etoposide by vein about 1 time each week during the induction phase. You will not receive it in the maintenance phase unless the disease stops responding to the study drugs. At that point, you may begin to receive etoposide again. The study doctor will tell you more about this.

The length of time it takes to infuse the study drugs will be different from patient to patient and will depend on rate of injection. Your doctor will discuss this with you.

Participants in both Groups 1 and 2 will receive dexamethasone by vein on Days 1-7 of the induction phase. After this, you will take pills of dexamethasone every day during the induction phase. In the maintenance phase, you will take these pills 3 times each week with at least a day between each dose (for example, Monday, Wednesday, and Friday).

Your dose of the study drugs may be raised, lowered, and/or delayed if the doctor thinks it is in your best interest.

If the disease involves the central nervous system during the Induction phase, you may receive methotrexate. Methotrexate is given 1 time a week for 5 weeks.

Study Visits:
You will have physical exams on the following days:
  • Day 1,

  • Every week for the first 4 weeks,

  • Every 2 weeks during the next 4 weeks,

  • Every 4 weeks during the next 16 weeks, and

  • Every 8 weeks after that.

Blood (about 3 tablespoons) will be drawn for routine tests on the following days. During the first 4 weeks, these tests must be performed at MD Anderson. After that, these can be performed at a local clinic:

  • Day 1,

  • Two (2) times each week for the first 4 weeks,

  • Every week for the next 4 weeks,

  • Every 2 weeks for the next 16 weeks, and

  • Every 4 weeks after that.

You will have a bone marrow aspiration/biopsy 4 weeks after starting the study treatment and then every 4-12 weeks after that.

At any time that the doctor thinks it is needed, you may have additional blood draws or bone marrow aspirations/biopsies to check the status of the disease. If you receive treatment for longer than 24 weeks, the timing of these procedures may be changed if the study doctor thinks it is in your best interest.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Study Visit:

If you are taken off or if you leave the study before you have received treatment for 24 weeks, the following tests and procedures will be performed within 30 days (+/- 7 days) of the last dose of the study drug:

  • Blood (about 2-3 tablespoons) will be drawn for routine tests.

  • If the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease.

If you cannot make it to MD Anderson for this visit, these procedures may be done with a local doctor and the records can be forwarded to the study doctor.

Follow-Up:

If you respond to the study drugs, you will be followed every 3-6 months for up to 5 years after completion of treatment. You will be called and asked about how you are doing. Each call will last about 5-10 minutes.

Study Design

Study Type:
Interventional
Actual Enrollment :
22 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Alemtuzumab or Tocilizumab in Combination With Etoposide and Dexamethasone for the Treatment of Adult Patients With Hemophagocytic Lymphohistiocytosis
Actual Study Start Date :
Sep 23, 2015
Anticipated Primary Completion Date :
Sep 30, 2022
Anticipated Study Completion Date :
Sep 30, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: Group 1: Alemtuzumab + Etoposide + Dexamethasone

Induction Phase: Participants receive Alemtuzumab daily on Days 1 - 4 with weekly Etoposide, and Dexamethasone by vein on Days 1-7 during the 8-week induction phase. Participants with central nervous system involvement receive intrathecal methotrexate 12 mg once a week for 5 weeks during the Induction Phase. Dexamethasone by vein on Days 1-7 of the induction phase. Maintenance Phase: The maintenance phase will last 16 weeks and starts after the Induction Phase. Participants receive Alemtuzumab once every 4 weeks and Dexamethasone three times per week during the maintenance phase. Participants who have evidence of budding relapse during the maintenance phase may revert back to receiving Etoposide. If participant responds to study drugs, they will receive a phone call by study staff every 3 - 6 months for up to 5 years after completion of treatment. Each call will last about 5-10 minutes.

Drug: Alemtuzumab
Group 1 and 2 Induction Phase: Alemtuzumab total dose of 1.0 mg/kg subcutaneously or by vein over 4 days (days 1-4) during the 8 week induction phase. Day 1 0.1 mg/kg, Day 2 0.3 mg/kg, Day 3 0.3 mg/kg, Day 4 0.3 mg/kg. Group 1 Maintenance Phase: 0.2 mg/kg once every 4 weeks for 6 weeks.
Other Names:
  • CAMPATH-1H
  • Campath
  • Drug: Etoposide
    Induction Phase: 150 mg/m2 given by vein once a week for 8 weeks. Maintenance Phase: Participants who have evidence of refractory disease or budding relapse during the maintenance phase may revert back to receiving Etoposide.
    Other Names:
  • VePesid
  • Drug: Dexamethasone
    Induction Phase: 10 mg/m2 for 1 week followed by Dexamethasone 5 mg/m2 for 2 weeks followed by Dexamethasone 2.5 mg/m2 for 2 weeks followed by Dexamethasone 1.25 mg/m2 for 2 weeks. Maintenance Phase: 1.25 mg/m2 by mouth three times a week for 16 weeks.
    Other Names:
  • Decadron
  • Drug: Methotrexate
    Participants with central nervous system involvement receive intrathecal methotrexate 12 mg once a week for 5 weeks during the Induction Phase.

    Behavioral: Phone Call
    If participant responds to study drugs, they will receive a phone call by study staff every 3 - 6 months for up to 5 years after completion of treatment. Each call will last about 5-10 minutes.

    Experimental: Group 2: Etoposide + Dexamethasone + Tocilizumab

    Induction Phase: Participants receive Tocilizumab by vein over 60 minutes on Day 1 or Day 2 of the Induction phase. Participants receive Alemtuzumab daily on Days 1 - 4 with weekly Etoposide and Dexamethasone by vein on Days 1-7 during the 8-week induction phase. Participants with central nervous system involvement receive intrathecal methotrexate 12 mg once a week for 5 weeks during the Induction Phase. Maintenance Phase: The maintenance phase will last 16 weeks and starts after the Induction Phase. Tocilizumab not given in the Maintenance Phase. Dexamethasone three times per week during the maintenance phase. If participant responds to study drugs, they will receive a phone call by study staff every 3 - 6 months for up to 5 years after completion of treatment. Each call will last about 5-10 minutes

    Drug: Alemtuzumab
    Group 1 and 2 Induction Phase: Alemtuzumab total dose of 1.0 mg/kg subcutaneously or by vein over 4 days (days 1-4) during the 8 week induction phase. Day 1 0.1 mg/kg, Day 2 0.3 mg/kg, Day 3 0.3 mg/kg, Day 4 0.3 mg/kg. Group 1 Maintenance Phase: 0.2 mg/kg once every 4 weeks for 6 weeks.
    Other Names:
  • CAMPATH-1H
  • Campath
  • Drug: Etoposide
    Induction Phase: 150 mg/m2 given by vein once a week for 8 weeks. Maintenance Phase: Participants who have evidence of refractory disease or budding relapse during the maintenance phase may revert back to receiving Etoposide.
    Other Names:
  • VePesid
  • Drug: Dexamethasone
    Induction Phase: 10 mg/m2 for 1 week followed by Dexamethasone 5 mg/m2 for 2 weeks followed by Dexamethasone 2.5 mg/m2 for 2 weeks followed by Dexamethasone 1.25 mg/m2 for 2 weeks. Maintenance Phase: 1.25 mg/m2 by mouth three times a week for 16 weeks.
    Other Names:
  • Decadron
  • Drug: Methotrexate
    Participants with central nervous system involvement receive intrathecal methotrexate 12 mg once a week for 5 weeks during the Induction Phase.

    Behavioral: Phone Call
    If participant responds to study drugs, they will receive a phone call by study staff every 3 - 6 months for up to 5 years after completion of treatment. Each call will last about 5-10 minutes.

    Drug: Tocilizumab
    Induction Phase: Tocilizumab at 4 to 8 mg/kg by vein. Day 1 0.1 mg/kg,Day 2 0.3 mg/kg, Day 3 0.3 mg/kg, Day 4 0.3 mg/kg.

    Outcome Measures

    Primary Outcome Measures

    1. Overall Response Rate (ORR) of Alemtuzumab or Tocilizumab in Combination With Etoposide and Dexamethasone for the Treatment of Adult Patients With Hemophagocytic Lymphohistiocytosis [8 weeks]

      Overall response rate (ORR), defined as complete response (CR) and/or partial response (PR) and/or parameter improvements (PI).

    2. Toxicity of Alemtuzumab or Tocilizumab in Combination With Etoposide and Dexamethasone for the Treatment of Adult Patients With Hemophagocytic Lymphohistiocytosis [8 weeks]

      Toxicity monitored simultaneously using the Bayesian approach of Thall, Simon, Estey (1995, 1996) and the extension by Thall and Sung (1998).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Sign an IRB-approved informed consent document.

    2. Patients must be >/= 18 years of age.

    3. • A documentation of diagnosis of hemophagocytic lymphocytosis, either newly diagnosed or relapsed/refractory by the treating physician and the PI in the patients chart. It must be noted that no diagnostic criteria have been established for diagnosis of HLH in adult patients as this was a hitherto poorly identified and considered to be a very rare disease in adults. We have seen an increasing number of cases of HLH at our institution over the last 2 years partly due to referrals and partly due to better understanding of the disease through discussions with our collaborators Dr Kenneth McClain and Dr Carl Allen at TCH (experts in pediatric HLH). Adult HLH seems to occur more frequently post malignancy and has a more fulminant course than pediatric HLH.

    4. Continued from No. 3: The diagnostic criteria that have been traditionally used for children (HLH 1991 and HLH 2004) may not adequately diagnose HLH in adults. This is the first adult HLH protocol in the country. In the absence of standard diagnostic guidelines if the patient's symptoms are highly suspicious for HLH and after an adequate work-up to rule out alternate potential alternate etiologies is performed we will treat the patient for HLH as missing the diagnosis is associated with high mortality. These patients will be discussed with the PI (Dr Daver) prior to enrollment in all such cases.

    5. Organ function as defined below (unless due to the HLH process): Serum creatinine </= 3.0 mg/dL, Total bilirubin </= 5.0 mg/dL. If organ dysfunction is thought to be related to the HLH process this must be clearly documented in the chart and the patients may be enrolled on study irrespective of creatinine and bilirubin levels.

    6. Women of childbearing potential must practice contraception. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study. Adequate forms of contraception are double barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, prior to study entry and for at least 3 months after the last dose of study drug.

    7. Negative urine pregnancy test and/or serum pregnancy test within 7 days of initiation of therapy.

    8. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, prior to study entry and for at least 3 months after the last dose of study drug.

    Exclusion Criteria:
    1. Pregnant and breast feeding women

    2. Any serious/and or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures

    3. Patients unwilling or unable to comply with the protocol.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of Texas MD Anderson Cancer CenterHoustonTexasUnited States77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center

    Investigators

    • Principal Investigator: Naval Daver, MD, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT02385110
    Other Study ID Numbers:
    • 2014-0989
    • NCI-2015-00526
    First Posted:
    Mar 11, 2015
    Last Update Posted:
    Feb 4, 2022
    Last Verified:
    Feb 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by M.D. Anderson Cancer Center
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Feb 4, 2022