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CompletedNCT02580552Updated Nov 23, 2020

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

A Phase 1 interventional study of Cobomarsen in Cutaneous T-cell Lymphoma (CTCL), Mycosis Fungoides (MF) and Chronic Lymphocytic Leukemia (CLL), sponsored by miRagen Therapeutics, Inc.. Completed at 19 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-11-23.

Sponsored by miRagen Therapeutics, Inc. · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
66
Allocation
Non-randomized
Ages
18 Years and older
Sex
All
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Study 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.

Read the 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.
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Conditions studied

  • 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
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Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
04

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
66 participants (actual)

Study arms

  • Experimental
    Part A, MF

    Intratumoral Injection of cobomarsen

    Drug: Cobomarsen

  • Experimental
    Part B, MF

    Subcutaneous, intravenous or a combination of systemic and intratumoral administration of cobomarsen with or without stable background therapy

    Drug: Cobomarsen

  • Experimental
    Part C, MF

    Subcutaneous or intravenous administration of cobomarsen as monotherapy

    Drug: Cobomarsen

  • Experimental
    Part D, CLL

    Subcutaneous or intravenous administration of cobomarsen as monotherapy

    Drug: Cobomarsen

  • Experimental
    Part E, DLBCL, activated B-cell (ABC) subtype

    Subcutaneous or intravenous administration of cobomarsen as monotherapy

    Drug: Cobomarsen

  • Experimental
    Part F, ATLL

    Subcutaneous or intravenous administration of cobomarsen as monotherapy

    Drug: Cobomarsen

Interventions

  • DrugCobomarsen

    Also known as: MRG-106

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What researchers measure

Primary outcomes

  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 outcomes

  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

    Changes in MF skin lesion severity before and after treatment based on the Composite Assessment of Index Lesion Severity (CAILS) score

    Time frame: Every 2 weeks from start of treatment until end of study participation

  5. 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

    Time frame: Every 2 weeks from start of treatment until end of study participation

  6. 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

    Time frame: Approximately 1 year

  7. 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

    Time frame: Approximately 1 year

  8. Minimal Residual Disease (MRD) - CLL only

    Proportion of subjects who achieve a CR with no evidence of MRD by flow cytometry

    Time frame: Approximately 1 year

  9. 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

    Time frame: Approximately 1 year

  10. 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

    Time frame: Approximately 1 year

  11. Duration of Response

    Number of days from initial date of confirmed PR or CR until loss of response or relapse

    Time frame: Up to approximately 2 years

  12. Time to Progression

    Number of days from first dose until objective disease progression

    Time frame: Up to approximately 2 years

  13. Progression Free Survival (PFS)

    Number of days from first dose until objective disease progression or death from any cause

    Time frame: Up to approximately 2 years

  14. Overall Survival (OS)

    Number of days from first dose until death from any cause

    Time frame: Up to approximately 2 years

Other outcomes

  1. miR-155-5p expression in cutaneous lesions of subjects with MF

    Exploratory assessment based on quantitative real time polymerase chain reaction (qRT-PCR) analysis of total RNA isolated from skin biopsies

    Time frame: At baseline and between Week 16 and end of study participation

  2. Proportion of neoplastic lymphoid cells in cutaneous lesions of subjects with MF

    Exploratory histological assessment before and after treatment with cobomarsen

    Time frame: At baseline and between Week 16 and end of study participation

  3. Proportions of immune cell subsets

    Exploratory assessment before and after treatment with cobomarsen by flow cytometry on whole blood

    Time frame: At baseline and monthly or bimonthly, up to end of study participation

  4. Dermatology-specific quality of life - MF only

    Changes in skin-related quality of life based on the Skindex-29 assessment tool

    Time frame: At baseline and monthly, up to approximately 2 years

  5. Pruritus - MF only

    Changes in intensity of skin itch based on the Pruritus Numerical Rating Scale

    Time frame: At baseline and monthly, up to approximately 2 years

06

Study locations

19 sites
  • City of Hope
    Duarte, California 91010, United States
  • UCSD Moores Cancer Center
    La Jolla, California 92093, United States
  • UCLA Department of Medicine
    Los Angeles, California 90095, United States
  • Chao Family Comprehensive Cancer Center at University of California, Irvine
    Orange, California 92868, United States
  • Stanford University Hospital and Clinics
    Stanford, California 94063, United States
  • University of Colorado, Anschutz Medical Campus
    Aurora, Colorado 80045, United States
  • Smilow Cancer Hospital at Yale-New Haven
    New Haven, Connecticut 06510, United States
  • University of Miami Sylvester Comprehensive Cancer Center
    Miami, Florida 33136, United States
  • Northwestern University; Department of Dermatology
    Chicago, Illinois 60611, United States
  • Beth Israel Deaconess Medical Center
    Boston, Massachusetts 02215, United States
  • University of Nebraska Medical Center
    Omaha, Nebraska 68198, United States
  • Montefiore Medical Center, Albert Einstein College of Medicine
    Bronx, New York 10467, United States
  • Memorial Sloan Kettering Cancer Center
    New York, New York 10065, United States
  • Weill Cornell Medicine
    New York, New York 10065, United States
  • The Ohio State University Comprehensive Cancer Center
    Columbus, Ohio 43210, United States
  • Thomas Jefferson University Hospital
    Philadelphia, Pennsylvania 19107, United States
  • The University of Texas MD Anderson Cancer Center
    Houston, Texas 77030, United States
  • Huntsman Cancer Institute
    Salt Lake City, Utah 84112, United States
  • Inova Melanoma and Skin Cancer Center / Inova Schar Cancer Institute
    Fairfax, Virginia 22003, United States
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References and documents

Publications

  • van Kester MS, Ballabio E, Benner MF, Chen XH, Saunders NJ, van der Fits L, van Doorn R, Vermeer MH, Willemze R, Tensen CP, Lawrie CH. miRNA expression profiling of mycosis fungoides. Mol Oncol. 2011 Jun;5(3):273-80. doi: 10.1016/j.molonc.2011.02.003. Epub 2011 Feb 24. PubMed 21406335 ↗
  • Moyal L, Barzilai A, Gorovitz B, Hirshberg A, Amariglio N, Jacob-Hirsch J, Maron L, Feinmesser M, Hodak E. miR-155 is involved in tumor progression of mycosis fungoides. Exp Dermatol. 2013 Jun;22(6):431-3. doi: 10.1111/exd.12161. PubMed 23711069 ↗
  • Maj J, Jankowska-Konsur A, Sadakierska-Chudy A, Noga L, Reich A. Altered microRNA expression in mycosis fungoides. Br J Dermatol. 2012 Feb;166(2):331-6. doi: 10.1111/j.1365-2133.2011.10669.x. Epub 2012 Jan 9. PubMed 21966986 ↗
  • Kopp KL, Ralfkiaer U, Gjerdrum LM, Helvad R, Pedersen IH, Litman T, Jonson L, Hagedorn PH, Krejsgaard T, Gniadecki R, Bonefeld CM, Skov L, Geisler C, Wasik MA, Ralfkiaer E, Odum N, Woetmann A. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell Cycle. 2013 Jun 15;12(12):1939-47. doi: 10.4161/cc.24987. Epub 2013 May 15. PubMed 23676217 ↗
  • Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, Lund E, Dahlberg JE. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3627-32. doi: 10.1073/pnas.0500613102. Epub 2005 Feb 28. PubMed 15738415 ↗
  • Cui B, Chen L, Zhang S, Mraz M, Fecteau JF, Yu J, Ghia EM, Zhang L, Bao L, Rassenti LZ, Messer K, Calin GA, Croce CM, Kipps TJ. MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood. 2014 Jul 24;124(4):546-54. doi: 10.1182/blood-2014-03-559690. Epub 2014 Jun 9. PubMed 24914134 ↗
  • Guinn D, Ruppert AS, Maddocks K, Jaglowski S, Gordon A, Lin TS, Larson R, Marcucci G, Hertlein E, Woyach J, Johnson AJ, Byrd JC. miR-155 expression is associated with chemoimmunotherapy outcome and is modulated by Bruton's tyrosine kinase inhibition with Ibrutinib. Leukemia. 2015 May;29(5):1210-3. doi: 10.1038/leu.2014.344. Epub 2014 Dec 9. No abstract available. PubMed 25486872 ↗
  • Tomita M. Important Roles of Cellular MicroRNA miR-155 in Leukemogenesis by Human T-Cell Leukemia Virus Type 1 Infection. ISRN Microbiol. 2012 Sep 18;2012:978607. doi: 10.5402/2012/978607. Print 2012. PubMed 23762762 ↗
  • 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. PubMed 21576639 ↗
  • Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. doi: 10.1182/blood-2007-06-093906. Epub 2008 Jan 23. Erratum In: Blood. 2008 Dec 15;112(13):5259. PubMed 18216293 ↗
  • 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. PubMed 25113753 ↗
  • Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W Jr, O'Mahony D, Janik JE, Bittencourt AL, Taylor GP, Yamaguchi K, Utsunomiya A, Tobinai K, Watanabe T. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J Clin Oncol. 2009 Jan 20;27(3):453-9. doi: 10.1200/JCO.2008.18.2428. Epub 2008 Dec 8. PubMed 19064971 ↗

Individual participant data

Plan to share: No

08

Registry details

Key details

Study ID
NCT02580552
Lead sponsor
miRagen Therapeutics, Inc.
Responsible party
Sponsor
First posted
Oct 20, 2015
Start date
Feb 9, 2016
Primary completion
Oct 6, 2020
Completion
Oct 6, 2020
Last update
Nov 23, 2020

Study contacts

Diana M. Escolar, MD, FAAN
study director · miRagen Therapeutics, Inc.

Oversight

Data monitoring committee
No
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