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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia (CLL); Cutaneous T-cell Lymphoma (CTCL); Mycosis Fungoides (MF); Diffuse Large B-Cell Lymphoma (DLBCL), ABC Subtype; Adult T-Cell Leukemia/Lymphoma (ATLL)
• Intervention / Treatment: Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A, MF; Intratumoral Injection of cobomarsen	Drug: Cobomarsen; Other Names: 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 Names: MRG-106
Experimental: Part C, MF; Subcutaneous or intravenous administration of cobomarsen as monotherapy	Drug: Cobomarsen; Other Names: MRG-106
Experimental: Part D, CLL; Subcutaneous or intravenous administration of cobomarsen as monotherapy	Drug: Cobomarsen; Other Names: MRG-106
Experimental: Part E, DLBCL, activated B-cell (ABC) subtype; Subcutaneous or intravenous administration of cobomarsen as monotherapy	Drug: Cobomarsen; Other Names: MRG-106
Experimental: Part F, ATLL; Subcutaneous or intravenous administration of cobomarsen as monotherapy	Drug: Cobomarsen; Other Names: MRG-106

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	At baseline and between Week 16 and end of study participation
Proportion of neoplastic lymphoid cells in cutaneous lesions of subjects with MF	Exploratory histological assessment before and after treatment with cobomarsen	At baseline and between Week 16 and end of study participation
Proportions of immune cell subsets	Exploratory assessment before and after treatment with cobomarsen by flow cytometry on whole blood	At baseline and monthly or bimonthly, up to end of study participation
Dermatology-specific quality of life - MF only	Changes in skin-related quality of life based on the Skindex-29 assessment tool	At baseline and monthly, up to approximately 2 years
Pruritus - MF only	Changes in intensity of skin itch based on the Pruritus Numerical Rating Scale	At baseline and monthly, up to approximately 2 years

Collaborators and Investigators

• Sponsor: miRagen Therapeutics, Inc.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2016
• Primary Completion (Actual): October 6, 2020
• Study Completion (Actual): October 6, 2020

Study Registration Dates

• First Submitted: October 15, 2015
• First Submitted That Met QC Criteria: October 16, 2015
• First Posted (Estimate): October 20, 2015

Study Record Updates

• Last Update Posted (Actual): November 23, 2020
• Last Update Submitted That Met QC Criteria: November 19, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: DLBCL; CLL; Diffuse large B-cell lymphoma; CTCL; Mycosis Fungoides; Chronic lymphocytic leukemia; ATLL; Cutaneous T-cell Lymphoma; Adult T-cell leukemia/lymphoma
• Additional Relevant MeSH Terms: Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Bacterial Infections and Mycoses; Leukemia, B-Cell; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Leukemia; Mycoses; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphoma, T-Cell, Cutaneous; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell; Mycosis Fungoides
• Other Study ID Numbers: MRG106-11-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No