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

Study Overview
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Brief Summary
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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 interleukin-15 (IL-15) and mogamulizumab are safe and effective to treat people with Adult T-Cell Leukemia and Mycosis Fungoides/Sezary Syndrome (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 human immunodeficiency virus (HIV), hepatitis B and C), urine, lung, and heart tests Bone marrow tests (if needed): A needle inserted in the participants hip will take a small amount of marrow. Computed tomography (CT), positron emission tomography (PET) and/or magnetic resonance imaging (MRI) scans Tumor biopsy (if needed): A needle will take out a small piece of the participants 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.

Detailed Description
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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 C-C Motif Chemokine Receptor 4 (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 natural killer (NK) cells, monocytes and long- term cluster of differentiation 8 (CD) 8+ 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 Eastern Cooperative Oncology Group (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 maximum tolerated dose (MTD) of dose-escalated recombinant human Interleukin-15 (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.

Official Title
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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

Conditions
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Adult T-Cell Lymphoma/Leukemia, Sezary Syndrome, Mycosis Fungoides

Intervention / Treatment
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* Drug: Recombinant human Interleukin-15 (rhIL-15)
* Biological: Mogamulizumab


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: 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, National Cancer Institute (NCI): mycosis fungoides/Sezary syndrome, or adult T-cell leukemia (chronic, acute, or lymphoma subtype by Shimoyama criteria) Patients with luster of differentiation 30 (CD30)+ Mycosis Fungoides/Sezary Syndrome (MF/SS) must have relapsed after or become intolerant to treatment with brentuximab vedotin 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). Disease must be measurable with at least one measurable lesion by Response Evaluation Criteria in Lymphoma (RECIL 2017) or modified severity-weighted assessment tool (mSWAT) criteria, or have an abnormal clonal T-cell population detectable by peripheral blood flow cytometry 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 Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 80% 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) Aspartate aminotransferase (AST)Serum glutamic oxaloacetic transaminase (SGOT)/Alanine aminotransferase (ALT)Serum glutamic pyruvic transaminase (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 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. 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. Ability of subject to understand and the willingness to sign a written informed consent document EXCLUSION CRITERIA: Patients with other T-cell leukemias/lymphomas not specified in the inclusion criteria 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, 6 weeks for donor lymphocyte infusion,100 days for allogeneic stem cell transplant) Systemic treatment for acute or chronic graft versus host disease (GVHD) within 12 weeks of the first dose of rhIL-15 and mogamulizumab Cohort 1 (Dose Escalation) only: history of grade 3/4 GVHD, or active grade 1/2 GVHD regardless of treatment 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 Patients who are receiving any other investigational agents 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., computed tomography (CT) scan premedication) 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 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 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 Patients with active bacterial infections, documented human immunodeficiency virus (HIV) infection or positive HIV 1/2 antibodies at screening, polymerase chain reaction (PCR) evidence for active or chronic hepatitis B or hepatitis C, or positive screening hepatitis B virus (HBV)/hepatitis C virus (HCV) serology without documentation of successful curative treatment 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 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 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1- Experimental Treatment: Dose Escalation<br>Interleukin-15 (IL-15) by continuous intravenous (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 intravenous (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: Recombinant human Interleukin-15 (rhIL-15)<br>* Interleukin 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.<br>* Other names: Human interleukin 15;Biological: Mogamulizumab<br>* Mogamulizumab (intravenous (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.<br>* Other names: Poteligeo;|
| Experimental: 2- Experimental Treatment: Dose Expansion<br>Interleukin-15 (IL-15) by continuous intravenous (CIV) infusion at the maximum tolerated dose (MTD) on days 1- 5 of each 28-day cycle (max 6 cycles) with mogamulizumab by intravenous (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: Recombinant human Interleukin-15 (rhIL-15)<br>* Interleukin 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.<br>* Other names: Human interleukin 15;Biological: Mogamulizumab<br>* Mogamulizumab (intravenous (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.<br>* Other names: Poteligeo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Recombinant Human Interleukin 15 (IL-15) (rhIL-15) | The MTD is the dose level at which no more than 1 of up to 6 patients experience DLT during the DLT evaluation window(s), or the dose below that at which at least 2 (of ≤6) patients have DLT. A dose-limiting toxicity (DLT) is defined as: any grade 3, 4, or 5 toxicity if not incontrovertibly due to disease progression or an extraneous cause, and deemed possibly, probably or definitely related to IL-15 or mogamulizumab. | 28 days | 
| Number of Grade 1-4 Treatment Related Adverse Events | Adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event. | Date treatment consent signed to date off study, approximately 5 months and 25 days for dose level 1, and 4 months and 14 days for dose level 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival | Event-free survival (EFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, alternative therapy for lymphoma given (such as radiation), or death, whichever occurs first. | Up to one year | 
| Progression-free Survival | Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first. Progressive Disease (PD) is new or increased lesions. | Up to one year | 
| Number of Participants Overall Response | Overall response was assessed by the Response Criteria for Adult T-cell Leukemia-Lymphoma. The response rate was determined and reported along with a 95% confidence interval. Complete Response (CR) is disappearance of all disease. Unconfirmed Complete Response (CRu) is stable residual mass in bulky lesion. Partial Response (PR) is regression of disease. Relapsed Disease (RD)/Progressive Disease (PD) is new or increased lesions. And Stable Disease (SD) is failure to attain CR/PR and no PD. | 6 cycles (one cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibody-Dependent Cell Cytotoxicity (ADCC), CCR4, Monoclonal Antibody