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

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ClinicalTrials.gov Identifier: NCT02580552
Recruitment Status : Completed
First Posted : October 20, 2015
Last Update Posted : November 23, 2020
Sponsor:
Information provided by (Responsible Party):
miRagen Therapeutics, Inc.

Study Description
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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.

Condition or disease Intervention/treatment Phase
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) Drug: Cobomarsen Phase 1

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 9, 2016
Actual Primary Completion Date : October 6, 2020
Actual Study Completion Date : October 6, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Part A, MF
Intratumoral Injection of cobomarsen
 Drug: Cobomarsen
Other Name: MRG-106
Experimental: Part B, MF
Subcutaneous, intravenous or a combination of systemic and intratumoral administration of cobomarsen with or without stable background therapy
 Drug: Cobomarsen
Other Name: MRG-106
Experimental: Part C, MF
Subcutaneous or intravenous administration of cobomarsen as monotherapy
 Drug: Cobomarsen
Other Name: MRG-106
Experimental: Part D, CLL
Subcutaneous or intravenous administration of cobomarsen as monotherapy
 Drug: Cobomarsen
Other Name: MRG-106
Experimental: Part E, DLBCL, activated B-cell (ABC) subtype
Subcutaneous or intravenous administration of cobomarsen as monotherapy
 Drug: Cobomarsen
Other Name: MRG-106
Experimental: Part F, ATLL
Subcutaneous or intravenous administration of cobomarsen as monotherapy
 Drug: Cobomarsen
Other Name: MRG-106


Outcome Measures
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Primary Outcome Measures :
  1. Safety and tolerability of cobomarsen based on vital signs, physical examination, clinical laboratory tests, ECG, and incidence and severity of adverse events [ Time Frame: From start of treatment to end of study participation ]

Secondary Outcome Measures :
  1. Area under the plasma concentration vs. time curve (AUC) of cobomarsen following single and repeat doses administered intratumorally, subcutaneously or intravenously [ Time Frame: Up to 56 days ]
  2. Peak plasma concentration (Cmax) of cobomarsen following single and repeat doses administered intratumorally, subcutaneously or intravenously [ Time Frame: Up to 56 days ]
  3. Trough plasma concentration (Ctrough) of cobomarsen following each 4-week cycle of dosing [ Time Frame: Monthly from Week 5 up to end of study participation ]
  4. Skin disease severity (index lesions) - MF only [ Time Frame: 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

  5. Skin disease severity (whole body) - MF only [ Time Frame: 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

  6. Overall Response Rate in the skin - MF [ Time Frame: Approximately 1 year ]
    Proportion of subjects who achieve a partial response (PR) or complete response (CR) in the skin, based on SWAT score

  7. Overall Response Rate - CLL [ Time Frame: 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

  8. Minimal Residual Disease (MRD) - CLL only [ Time Frame: Approximately 1 year ]
    Proportion of subjects who achieve a CR with no evidence of MRD by flow cytometry

  9. Overall Response Rate - DLBCL [ Time Frame: 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

  10. Overall Response Rate - ATLL [ Time Frame: 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

  11. Duration of Response [ Time Frame: Up to approximately 2 years ]
    Number of days from initial date of confirmed PR or CR until loss of response or relapse

  12. Time to Progression [ Time Frame: Up to approximately 2 years ]
    Number of days from first dose until objective disease progression

  13. Progression Free Survival (PFS) [ Time Frame: Up to approximately 2 years ]
    Number of days from first dose until objective disease progression or death from any cause

  14. Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
    Number of days from first dose until death from any cause


Other Outcome Measures:
  1. miR-155-5p expression in cutaneous lesions of subjects with MF [ Time Frame: At baseline and between Week 16 and end of study participation ]
    Exploratory assessment based on quantitative real time polymerase chain reaction (qRT-PCR) analysis of total RNA isolated from skin biopsies

  2. Proportion of neoplastic lymphoid cells in cutaneous lesions of subjects with MF [ Time Frame: At baseline and between Week 16 and end of study participation ]
    Exploratory histological assessment before and after treatment with cobomarsen

  3. Proportions of immune cell subsets [ Time Frame: At baseline and monthly or bimonthly, up to end of study participation ]
    Exploratory assessment before and after treatment with cobomarsen by flow cytometry on whole blood

  4. Dermatology-specific quality of life - MF only [ Time Frame: At baseline and monthly, up to approximately 2 years ]
    Changes in skin-related quality of life based on the Skindex-29 assessment tool

  5. Pruritus - MF only [ Time Frame: At baseline and monthly, up to approximately 2 years ]
    Changes in intensity of skin itch based on the Pruritus Numerical Rating Scale


Eligibility Criteria
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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:

  • 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
Contacts and Locations
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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): NCT02580552


Locations
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Sponsors and Collaborators
miRagen Therapeutics, Inc.
Investigators
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Study Director: Diana M. Escolar, MD, FAAN miRagen Therapeutics, Inc.
More Information
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Publications:
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, Wood GS, Willemze R, Demierre MF, Pimpinelli N, Bernengo MG, Ortiz-Romero PL, Bagot M, Estrach T, Guitart J, Knobler R, Sanches JA, Iwatsuki K, Sugaya M, Dummer R, Pittelkow M, Hoppe R, Parker S, Geskin L, Pinter-Brown L, Girardi M, Burg G, Ranki A, Vermeer M, Horwitz S, Heald P, Rosen S, Cerroni L, Dreno B, Vonderheid EC; International Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011 Jun 20;29(18):2598-607. doi: 10.1200/JCO.2010.32.0630. Epub 2011 May 16.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.

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Responsible Party: miRagen Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02580552    
Other Study ID Numbers: MRG106-11-101
First Posted: October 20, 2015    Key Record Dates
Last Update Posted: November 23, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by miRagen Therapeutics, Inc.:
Cutaneous T-cell Lymphoma
CTCL
Mycosis Fungoides
Chronic lymphocytic leukemia
CLL
 Diffuse large B-cell lymphoma
DLBCL
Adult T-cell leukemia/lymphoma
ATLL
Additional relevant MeSH terms:
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Mycoses
Lymphoma
Leukemia
Lymphoma, B-Cell
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, T-Cell
Lymphoma, T-Cell, Peripheral
Lymphoma, Large B-Cell, Diffuse
Mycosis Fungoides
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma, T-Cell, Cutaneous
Neoplasms by Histologic Type
 Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hematologic Diseases
Lymphoma, Non-Hodgkin
Leukemia, B-Cell
Chronic Disease
Disease Attributes
Pathologic Processes
Bacterial Infections and Mycoses
Infections