Safety, Tolerability and Pharmacokinetics of MRG-106 in Patients With Mycosis Fungoides (MF), CLL, DLBCL or ATLL
- Conditions
- Cutaneous T-cell Lymphoma (CTCL)Diffuse Large B-Cell Lymphoma (DLBCL), ABC SubtypeAdult T-Cell Leukemia/Lymphoma (ATLL)Mycosis Fungoides (MF)Chronic Lymphocytic Leukemia (CLL)
- Interventions
- Registration Number
- NCT02580552
- Lead Sponsor
- miRagen Therapeutics, Inc.
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 66
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part C, MF Cobomarsen Subcutaneous or intravenous administration of cobomarsen as monotherapy Part A, MF Cobomarsen Intratumoral Injection of cobomarsen Part B, MF Cobomarsen Subcutaneous, intravenous or a combination of systemic and intratumoral administration of cobomarsen with or without stable background therapy Part D, CLL Cobomarsen Subcutaneous or intravenous administration of cobomarsen as monotherapy Part E, DLBCL, activated B-cell (ABC) subtype Cobomarsen Subcutaneous or intravenous administration of cobomarsen as monotherapy Part F, ATLL Cobomarsen Subcutaneous or intravenous administration of cobomarsen as monotherapy
- Primary Outcome Measures
Name Time Method 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
Name Time Method Overall Response Rate - CLL Approximately 1 year 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
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 Overall Response Rate in the skin - MF Approximately 1 year Proportion of subjects who achieve a partial response (PR) or complete response (CR) in the skin, based on SWAT score
Minimal Residual Disease (MRD) - CLL only Approximately 1 year Proportion of subjects who achieve a CR with no evidence of MRD by flow cytometry
Overall Response Rate - ATLL Approximately 1 year 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
Duration of Response Up to approximately 2 years Number of days from initial date of confirmed PR or CR until loss of response or relapse
Progression Free Survival (PFS) Up to approximately 2 years Number of days from first dose until objective disease progression or death from any cause
Overall Survival (OS) Up to approximately 2 years Number of days from first dose until death from any cause
Time to Progression Up to approximately 2 years Number of days from first dose until objective disease progression
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 Every 2 weeks from start of treatment until end of study participation Changes in MF skin lesion severity before and after treatment based on the Composite Assessment of Index Lesion Severity (CAILS) score
Skin disease severity (whole body) - MF only Every 2 weeks from start of treatment until end of study participation Changes in MF skin lesion severity before and after treatment based on the modified Severity Weighted Assessment Tool (mSWAT) score
Overall Response Rate - DLBCL Approximately 1 year 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
Trial Locations
- Locations (19)
UCLA Department of Medicine
🇺🇸Los Angeles, California, United States
University of Miami Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
The Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
Inova Melanoma and Skin Cancer Center / Inova Schar Cancer Institute
🇺🇸Fairfax, Virginia, United States
UCSD Moores Cancer Center
🇺🇸La Jolla, California, United States
Montefiore Medical Center, Albert Einstein College of Medicine
🇺🇸Bronx, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Northwestern University; Department of Dermatology
🇺🇸Chicago, Illinois, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Chao Family Comprehensive Cancer Center at University of California, Irvine
🇺🇸Orange, California, United States
Weill Cornell Medicine
🇺🇸New York, New York, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
City of Hope
🇺🇸Duarte, California, United States
Stanford University Hospital and Clinics
🇺🇸Stanford, California, United States
University of Colorado, Anschutz Medical Campus
🇺🇸Aurora, Colorado, United States
Smilow Cancer Hospital at Yale-New Haven
🇺🇸New Haven, Connecticut, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States