Safety, Tolerability and Pharmacokinetics of MRG-106 in Patients With Mycosis Fungoides (MF), CLL, DLBCL or ATLL

Study Overview
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Brief Summary
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Objectives of this clinical trial are to evaluate the safety, tolerability, pharmacokinetics and potential efficacy of the investigational drug, cobomarsen (MRG-106), in patients diagnosed with certain lymphomas and leukemias, including cutaneous T-cell lymphoma (CTCL) [mycosis fungoides (MF) subtype], chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) [activated B-cell (ABC) subtype], and adult T-cell leukemia/lymphoma (ATLL). Cobomarsen is an inhibitor of a molecule called miR-155 that is found at high levels in these types of cancers and may be important in promoting the growth and survival of the cancer cells. Participants in the clinical trial will receive weekly doses of cobomarsen administered by injection under the skin or into a vein, or by injection directly into cancerous lesions in the skin (for CTCL only). Blood samples will be collected to measure how cobomarsen is processed by the body, and other measurements will be performed to study how normal and cancerous cells of the immune system respond when exposed to cobomarsen.

Detailed Description
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Study Design: Part A: Cohorts of 3-6 patients diagnosed with MF will receive up to five intratumoral injections of cobomarsen over a period of up to 15 days with follow-up for an additional 20 days, beginning with the maximum deliverable intratumoral dose. Doses may be decreased in subsequent cohorts to determine the minimum pharmacodynamically active dose. Parts B-F: Patients in these parts of the study will be diagnosed with MF (Parts B and C), CLL (Part D), DLBCL (Part E), or ATLL (Part F). All patients will receive subcutaneous or intravenous cobomarsen (or a combination of systemic and intratumoral administration for MF patients only) on Days 1, 3 and 5, and will continue dosing on a weekly schedule until the patient becomes intolerant, develops clinically significant side effects, progresses, or the trial is terminated. Doses administered will not exceed a dose level predicted to be safe based on all prior treatment experience with the drug. Patients in Part B may continue on a stable background therapy for their disease during their treatment with cobomarsen, while patients in Parts C-F will be treated with cobomarsen alone.

Official Title
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A Phase 1 Dose-ranging Study to Investigate the Safety, Tolerability, and Pharmacokinetics of MRG-106 Following Local Intratumoral, Subcutaneous, and Intravenous Administration in Subjects With Various Lymphomas and Leukemias

Conditions
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Cutaneous T-cell Lymphoma (CTCL), Mycosis Fungoides (MF), Chronic Lymphocytic Leukemia (CLL), Diffuse Large B-Cell Lymphoma (DLBCL), ABC Subtype, Adult T-Cell Leukemia/Lymphoma (ATLL)

Intervention / Treatment
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* Drug: Cobomarsen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parts A-C only: Patients must have biopsy proven MF, clinical stage I, II, or III (excluding visceral or nodal involvement), and must be refractory to or intolerant of established therapies for their condition Part D only: Patients diagnosed with CLL who are intolerant to, or have disease that is relapsed/refractory after, at least two prior therapies Part E only: Patients with biopsy-proven DLBCL who are intolerant to, or have disease that is relapsed/refractory after, at least two prior therapies, including any anti-CD20 monoclonal antibody and chemotherapy with curative intent Part F only: Patients with documented HTLV-1 infection and histologically or cytologically proven ATLL of any stage, and who are intolerant to, or have disease that is relapsed/refractory after, at least one prior therapy Females must not be pregnant or lactating. Women of child-bearing potential must use a highly effective method of contraception throughout their study participation and for at least 6 months following the last dose of study drug. Males must be surgically sterile, abstinent, or if engaged in sexual relations with a female of child-bearing potential, must be willing to use a highly effective method of contraception throughout their study participation and for at least 6 months after the last dose of study drug. Exclusion Criteria: Evidence of renal or liver dysfunction at screening Clinically significant anemia, neutropenia or thrombocytopenia at screening History of bleeding diathesis or coagulopathy Clinically significant cardiovascular disease, history of myocardial infarction within the last 6 months, or evidence of QTc interval prolongation at screening Serologically positive for HIV; serologically positive for Hepatitis B or Hepatitis C with evidence of liver dysfunction or documented liver cirrhosis Prior malignancies within the past 3 years (with allowance for adequately treated in situ carcinoma of the cervix uteri, and basal cell or localized squamous cell carcinoma of the skin treated with curative intent) Use of an investigational small molecule drug during the 30 days prior to screening or use of an investigational oligonucleotide or biologic drug during the prior 90 days

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, MF<br>Intratumoral Injection of cobomarsen | Drug: Cobomarsen<br> <br> * Other names: MRG-106;|
| Experimental: Part B, MF<br>Subcutaneous, intravenous or a combination of systemic and intratumoral administration of cobomarsen with or without stable background therapy | Drug: Cobomarsen<br> <br> * Other names: MRG-106;|
| Experimental: Part C, MF<br>Subcutaneous or intravenous administration of cobomarsen as monotherapy | Drug: Cobomarsen<br> <br> * Other names: MRG-106;|
| Experimental: Part D, CLL<br>Subcutaneous or intravenous administration of cobomarsen as monotherapy | Drug: Cobomarsen<br> <br> * Other names: MRG-106;|
| Experimental: Part E, DLBCL, activated B-cell (ABC) subtype<br>Subcutaneous or intravenous administration of cobomarsen as monotherapy | Drug: Cobomarsen<br> <br> * Other names: MRG-106;|
| Experimental: Part F, ATLL<br>Subcutaneous or intravenous administration of cobomarsen as monotherapy | Drug: Cobomarsen<br> <br> * Other names: MRG-106;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of cobomarsen based on vital signs, physical examination, clinical laboratory tests, ECG, and incidence and severity of adverse events |  | From start of treatment to end of study participation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration vs. time curve (AUC) of cobomarsen following single and repeat doses administered intratumorally, subcutaneously or intravenously |  | Up to 56 days | 
| Peak plasma concentration (Cmax) of cobomarsen following single and repeat doses administered intratumorally, subcutaneously or intravenously |  | Up to 56 days | 
| Trough plasma concentration (Ctrough) of cobomarsen following each 4-week cycle of dosing |  | Monthly from Week 5 up to end of study participation | 
| Skin disease severity (index lesions) - MF only | Changes in MF skin lesion severity before and after treatment based on the Composite Assessment of Index Lesion Severity (CAILS) score | Every 2 weeks from start of treatment until end of study participation | 
| Skin disease severity (whole body) - MF only | Changes in MF skin lesion severity before and after treatment based on the modified Severity Weighted Assessment Tool (mSWAT) score | Every 2 weeks from start of treatment until end of study participation | 
| Overall Response Rate in the skin - MF | Proportion of subjects who achieve a partial response (PR) or complete response (CR) in the skin, based on SWAT score | Approximately 1 year | 
| Overall Response Rate - CLL | Proportion of subjects who achieve a PR or CR as defined by IWCLL criteria (Hallek et al., 2008) based on CT scans, bone marrow biopsies, and flow cytometry | Approximately 1 year | 
| Minimal Residual Disease (MRD) - CLL only | Proportion of subjects who achieve a CR with no evidence of MRD by flow cytometry | Approximately 1 year | 
| Overall Response Rate - DLBCL | Proportion of subjects who achieve a PR or CR as defined by the Lugano classification (Cheson et al., 2014) based on positron emission tomography-computed tomography (PET-CT) scans and bone marrow biopsy to confirm CR | Approximately 1 year | 
| Overall Response Rate - ATLL | Proportion of subjects who achieve a PR or CR as defined by international consensus criteria (Tsukasaki et al., 2009) based on CT scans and flow cytometry, and bone marrow biopsy to confirm CR | Approximately 1 year | 
| Duration of Response | Number of days from initial date of confirmed PR or CR until loss of response or relapse | Up to approximately 2 years | 
| Time to Progression | Number of days from first dose until objective disease progression | Up to approximately 2 years | 
| Progression Free Survival (PFS) | Number of days from first dose until objective disease progression or death from any cause | Up to approximately 2 years | 
| Overall Survival (OS) | Number of days from first dose until death from any cause | Up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cutaneous T-cell Lymphoma, CTCL, Mycosis Fungoides, Chronic lymphocytic leukemia, CLL, Diffuse large B-cell lymphoma, DLBCL, Adult T-cell leukemia/lymphoma, ATLL