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Phase I Study of Recombinant Human IL-15 (rhIL-15) and Mogamulizumab for People With Refractory or Relapsed Adult T-Cell Leukemia and Mycosis Fungoides/Sezary Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04185220
Recruitment Status : Not yet recruiting
First Posted : December 4, 2019
Last Update Posted : January 23, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Adult T-cell leukemia/lymphoma (ATLL) and mycosis fungoides/Sezary syndrome (MF/SS) are cancers that form in the T cells, a type of white blood cell that helps with the body s immune response. A combination of drugs might be able to better treat these cancers than existing therapies.

Objective:

To test if the drugs IL-15 and mogamulizumab are safe and effective to treat people with ATLL or MF/SS.

Eligibility:

People ages 18 and older with relapsed ATLL or MF/SS that has not responded to at least one standard treatment

Design:

Participants will be screened with:

Medical history

Physical exam

Blood (including HIV, hepatitis B and C), urine, lung, and heart tests

Bone marrow tests (if needed): A needle inserted in the participant s hip will take a small amount of marrow.

CT, PET and/or MRI scans

Tumor biopsy (if needed): A needle will take out a small piece of the participant s tumor.

Participants will get the study drugs by vein for up to six 28-day cycles. They will get IL-15 the first 5 days of each cycle. They will get mogamulizumab on days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of the other cycles. They will be hospitalized for 1 week in cycle 1. They may need to get a midline catheter. This is a soft tube put into a vein leading to the heart.

Participants will have repeats of the screening tests throughout the study.

After treatment, participants will have visits every 60 days for 6 months, every 90 days for 2 years, and then every 6 months for 2 years.


Condition or disease Intervention/treatment Phase
Adult T-Cell Lymphoma/Leukemia Sezary Syndrome Mycosis Fungoides Drug: rhIL-15 Biological: Mogamulizumab Phase 1

Detailed Description:

Background:

  • Advanced mycosis fungoides, its leukemic form Sezary syndrome (MF/SS), and adult T- cell leukemia/lymphoma (ATLL) are all aggressive mature T-cell malignancies which are considered incurable without an allogeneic stem cell transplant.
  • Mogamulizumab is a defucosylated monoclonal antibody directed towards CCR4, a chemokine receptor expressed by the majority of MS/SS and ATLL cells. It is approved by the United States Food and Drug Administration for treatment of relapsed MF/SS, and is recommended by the National Comprehensive Cancer Network for treatment of ATLL.
  • Defucosylation of mogamulizumab is thought to enhance its capacity for antibody- dependent cell cytotoxicity (ADCC), which is mediated by natural killer (NK) cells and macrophages.
  • The immunologic effects of recombinant human Interleukin-15 (rhIL-15), a stimulatory cytokine that promotes the differentiation and activation of NK cells, monocytes and long- term CD8+ memory T-cells, has been assessed in several phase I trials in cancer patients.
  • Concomitant administration of rhIL-15 with mogamulizumab may further enhance the ADCC capacity of the antibody and result in improved efficacy for patients with CCR4- expressing cancers.

Objectives:

-To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of continuous intravenous infusion (civ) rhIL-15 administration in combination with standard intravenous (IV) mogamulizumab treatment

Eligibility:

  • Age greater than or equal to 18 years of age
  • ECOG performance status of less than or equal to 1
  • Histologically or cytologically confirmed mycosis fungoides/S(SqrRoot)(Copyright)zary syndrome or adult T- cell leukemia/lymphoma relapsed after or refractory to at least one line of systemic treatment.
  • Adequate organ and marrow function

Design:

  • Open-label, single-center, non-randomized phase I study
  • Standard "3 + 3" design will be used to determine the MTD of dose-escalated rhIL-15 with fixed dose of mogamulizumab, with an expansion cohort at the MTD
  • Maximum 6 cycles (28-day cycles) of combination therapy
  • To explore all dose levels, including further evaluation in a dose expansion cohort, and to account for unevaluable patients the accrual ceiling will be set at 20 patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of Recombinant Human IL-15 (rhIL-15) and Mogamulizumab for Patients With Refractory or Relapsed Adult T-Cell Leukemia and Mycosis Fungoides/Sezary Syndrome
Estimated Study Start Date : January 28, 2020
Estimated Primary Completion Date : March 1, 2023
Estimated Study Completion Date : September 1, 2023


Arm Intervention/treatment
Experimental: 1- Experimental Treatment: Dose Escalation
IL-15 by CIV infusion at escalating doses of 2 and 4 mcg/kg/day on days 1-5 of each 28-day cycle (max 6 cycles) with mogamulizumab by IV infusion at a dose of 1 mg/kgdays 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of each subsequent cycle to determine MTD.
Drug: rhIL-15
IL-15 will be administered by continuous intravenous infusion in a dose-escalation 3 + 3 system with a starting dose of 2 mcg/kg/day and a second dose level of 4 mcg/kg/day on days 1-5 of each of six cycles.

Biological: Mogamulizumab
Mogamulizumab (IV over at least 1 hour) will be administered at a dose of 1 mg/kg on days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of each subsequent cycle. Treatment will continue for a maximum of 6 cycles.

Experimental: 2- Experimental Treatment: Dose Expansion
IL-15 by CIV infusion at the MTD on days 1- 5 of each 28-day cycle (max 6 cycles) with mogamulizumab by IV infusion at a dose of 1 mg/kgdays 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of each subsequent cycle.
Drug: rhIL-15
IL-15 will be administered by continuous intravenous infusion in a dose-escalation 3 + 3 system with a starting dose of 2 mcg/kg/day and a second dose level of 4 mcg/kg/day on days 1-5 of each of six cycles.

Biological: Mogamulizumab
Mogamulizumab (IV over at least 1 hour) will be administered at a dose of 1 mg/kg on days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of each subsequent cycle. Treatment will continue for a maximum of 6 cycles.




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: 28 days ]
    Frequency (number and percentage) of treatment emergent adverse events


Secondary Outcome Measures :
  1. Event free survival [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval.

  2. Progression-free survival [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval.

  3. Overall response rate [ Time Frame: 6 cycles ]
    The response rate will be determined and reported along with a 95% confidence interval.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Patients must have one of the following histologically or cytologically proven relapsed and/or refractory to at least one line of systemic treatment, T-cell malignancies confirmed by the Laboratory of Pathology, NCI: mycosis fungoides/Sezary syndrome, or adult T-cell leukemia (chronic, acute, or lymphoma subtype by Shimoyama criteria)
  2. Patients with CD30+ MF/SS must have relapsed after or become intolerant to treatment with brentuximab vedotin
  3. A formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) must be available for performance of correlative studies. NOTE: Patients must be willing to have a tumor biopsy if prior tissue or adequate archival tissue is not available (i.e., post- enrollment and prior to treatment).
  4. Disease must be measurable with at least one measurable lesion by RECIL 2017 or mSWAT criteria, or have an abnormal clonal T-cell population detectable by peripheral blood flow cytometry
  5. Age >18 years

    NOTE: Because no dosing or adverse event data are currently available on the use of rhIL-15 in combination with mogamulizumab in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

  6. ECOG performance status less than or equal to 1 (Karnofsky greater than or equal to 80%
  7. Patients must have normal organ and marrow function as defined below:

    • Absolute neutrophil count: greater than or equal to 1,000/mcL
    • Platelets: > 100,000/mcL
    • Total bilirubin: less than or equal to 1.5 X institutional upper limit of normal (ULN)
    • AST(SGOT)/ALT(SGPT): less than or equal to 2.5 X institutional ULN
    • Serum creatinine: less than or equal to 1.5 X institutional ULN, OR Creatinine clearance: greater than or equal to 50 mL/min/1.73 m2 for patients with creatinine levels >1.5 institutional ULN
  8. Negative serum or urine pregnancy test at screening for women of childbearing potential (WOCBP)

    NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.

  9. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of rhIL-15 and mogamulizumab administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  10. Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA:

  1. Patients with other T-cell leukemias/lymphomas not specified in the inclusion criteria
  2. Anti-cancer treatment within 2 weeks of the first dose of rhIL-15 and mogamulizumab (4 weeks for anti-cancer monoclonal antibody or investigational agents, 100 days for allogeneic stem cell transplant)
  3. Systemic treatment for acute or chronic graft versus host disease (GVHD) within 12 weeks of the first dose of rhIL-15 and mogamulizumab
  4. Cohort 1 (Dose Escalation) only: history of grade 3/4 GVHD, or active grade 1/2 GVHD regardless of treatment
  5. Persisting toxicity related to prior therapy of grade > 1, with the exception of the following: alopecia, sensory neuropathy grade less than or equal to 2, or other grade less than or equal to 2 not constituting a safety risk based on investigator's judgment
  6. Patients who are receiving any other investigational agents
  7. Current use of immunosuppressive medication, EXCEPT for the following:

    • Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
    • Systemic corticosteroids at physiologic doses less than or equal to 10 mg/day of prednisone or equivalent; or,
    • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  8. Patients with previous malignant disease other than the target malignancy within the last 3 years with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ
  9. Cohort 1 (Dose Escalation) only: Active or history of any autoimmune disease thought to be unrelated to their malignancy; for Cohort 2 (Dose Expansion), patients with history of autoimmune disease who are not on active immunosuppressive therapy
  10. Patients with asthma requiring chronic inhaled or oral corticosteroids, or history of asthma requiring mechanical ventilation. Patients with a history of mild asthma that are on or can be switched to non-corticosteroid bronchodilator regimens are eligible
  11. Patients with active bacterial infections, documented HIV infection or positive HIV 1/2 antibodies at screening, PCR evidence for active or chronic hepatitis B or hepatitis C, or positive screening HBV/HCV serology without documentation of successful curative treatment
  12. Presence of uncontrolled intercurrent illnesses including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, cognitive impairment, active substance abuse, or psychiatric illness/social situations that in the view of the Investigator would preclude safe treatment and limit compliance with study requirements
  13. Inability or refusal to practice effective contraception during therapy or the presence of pregnancy or active breastfeeding. Because there is no significant preclinical information regarding the risks to a fetus or a newborn infant, all pregnant or breastfeeding woman will be excluded from participation in this trial
  14. History of allergic reactions attributed to compounds of similar chemical or biologic composition to rhIL-15 or mogamulizumab, unless felt to be in the best interests of the patient in the opinion of the investigator
  15. Patients who received a live vaccine within 30 days of planned start of study therapy. Vaccination with a live vaccine while on trial is prohibited. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist ) are live attenuated vaccines, and are not allowed

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04185220


Contacts
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Contact: Maureen E Edgerly, R.N. (240) 760-6013 NCIMO_Referrals@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Milos Miljkovic, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04185220    
Other Study ID Numbers: 200011
20-C-0011
First Posted: December 4, 2019    Key Record Dates
Last Update Posted: January 23, 2020
Last Verified: January 14, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Antibody-Dependent Cell Cytotoxicity (ADCC)
CCR4
Monoclonal Antibodies
Additional relevant MeSH terms:
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Mycoses
Leukemia
Mycosis Fungoides
Sezary Syndrome
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Lymphoma, T-Cell
Lymphoma, Non-Hodgkin
Lymphoma
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, T-Cell, Cutaneous
Leukemia, Lymphoid
Mogamulizumab
Antibodies
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents