Clinical trial NCT02580552: Safety, Tolerability and Pharmacokinetics of MRG-106 in Patients With Mycosis Fungoides (MF), CLL, DLBCL or ATLL
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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)
Keywords: Cutaneous T-cell Lymphoma
CTCL
Mycosis Fungoides
Chronic lymphocytic leukemia
CLL
Diffuse large B-cell lymphoma
DLBCL
Adult T-cell leukemia/lymphoma
ATLL
Lead sponsor: miRagen Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2015-10-20
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety and tolerability of cobomarsen based on vital signs, physical examination, clinical laboratory tests, ECG, and incidence and severity of adverse events
timeFrame: From start of treatment to end of study participation
Secondary outcomes:
measure: Area under the plasma concentration vs. time curve (AUC) of cobomarsen following single and repeat doses administered intratumorally, subcutaneously or intravenously
timeFrame: Up to 56 days
measure: Peak plasma concentration (Cmax) of cobomarsen following single and repeat doses administered intratumorally, subcutaneously or intravenously
timeFrame: Up to 56 days
measure: Trough plasma concentration (Ctrough) of cobomarsen following each 4-week cycle of dosing
timeFrame: Monthly from Week 5 up to end of study participation
measure: Skin disease severity (index lesions) - MF only
timeFrame: Every 2 weeks from start of treatment until end of study participation
measure: Skin disease severity (whole body) - MF only
timeFrame: Every 2 weeks from start of treatment until end of study participation
measure: Overall Response Rate in the skin - MF
timeFrame: Approximately 1 year
measure: Overall Response Rate - CLL
timeFrame: Approximately 1 year
measure: Minimal Residual Disease (MRD) - CLL only
timeFrame: Approximately 1 year
measure: Overall Response Rate - DLBCL
timeFrame: Approximately 1 year
measure: Overall Response Rate - ATLL
timeFrame: Approximately 1 year
measure: Duration of Response
timeFrame: Up to approximately 2 years
measure: Time to Progression
timeFrame: Up to approximately 2 years
measure: Progression Free Survival (PFS)
timeFrame: Up to approximately 2 years
measure: Overall Survival (OS)
timeFrame: Up to approximately 2 years
Other outcomes:
measure: miR-155-5p expression in cutaneous lesions of subjects with MF
timeFrame: At baseline and between Week 16 and end of study participation
measure: Proportion of neoplastic lymphoid cells in cutaneous lesions of subjects with MF
timeFrame: At baseline and between Week 16 and end of study participation
measure: Proportions of immune cell subsets
timeFrame: At baseline and monthly or bimonthly, up to end of study participation
measure: Dermatology-specific quality of life - MF only
timeFrame: At baseline and monthly, up to approximately 2 years
measure: Pruritus - MF only
timeFrame: At baseline and monthly, up to approximately 2 years
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: UCSD Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Department of Medicine
state: California
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center at University of California, Irvine
state: California
city: Stanford
country: United States
facility: Stanford University Hospital and Clinics
state: California
city: Aurora
country: United States
facility: University of Colorado, Anschutz Medical Campus
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale-New Haven
state: Connecticut
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University; Department of Dermatology
state: Illinois
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Bronx
country: United States
facility: Montefiore Medical Center, Albert Einstein College of Medicine
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Fairfax
country: United States
facility: Inova Melanoma and Skin Cancer Center / Inova Schar Cancer Institute
state: Virginia
Study officials:
affiliation: miRagen Therapeutics, Inc.
name: Diana M. Escolar, MD, FAAN
role: STUDY_DIRECTOR
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