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

Chronic Lymphocytic Leukemia (CLL) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02580552
• Other study ID #: MRG106-11-101
• Status: Completed
• Phase: Phase 1
• Start date: February 9, 2016
• Est. completion date: October 6, 2020

Study information

• Verified date: November 2020
• Source: miRagen Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 66
• Est. completion date: October 6, 2020
• Est. primary completion date: October 6, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adult T-Cell Leukemia/Lymphoma (ATLL)
• Chronic Lymphocytic Leukemia (CLL)
• Cutaneous T-cell Lymphoma (CTCL)
• Diffuse Large B-Cell Lymphoma (DLBCL), ABC Subtype
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, T-Cell
• Leukemia-Lymphoma, Adult T-Cell
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Cutaneous
• Mycoses
• Mycosis Fungoides
• Mycosis Fungoides (MF)

Intervention

Drug:
• Cobomarsen

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
miRagen Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (12)

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 Español de Médula Ósea; 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. — View Citation

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. — View Citation

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. Epub 2005 Feb 28. — View Citation

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. — View Citation

Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner 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. — View Citation

Kopp KL, Ralfkiaer U, Gjerdrum LM, Helvad R, Pedersen IH, Litman T, Jønson L, Hagedorn PH, Krejsgaard T, Gniadecki R, Bonefeld CM, Skov L, Geisler C, Wasik MA, Ralfkiaer E, Ødum 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. — View Citation

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. — View Citation

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. — View Citation

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 Sézary 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	Peak plasma concentration (Cmax) of cobomarsen following single and repeat doses administered intratumorally, subcutaneously or intravenously		Up to 56 days
Secondary	Trough plasma concentration (Ctrough) of cobomarsen following each 4-week cycle of dosing		Monthly from Week 5 up to end of study participation
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Minimal Residual Disease (MRD) - CLL only	Proportion of subjects who achieve a CR with no evidence of MRD by flow cytometry	Approximately 1 year
Secondary	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
Secondary	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
Secondary	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
Secondary	Time to Progression	Number of days from first dose until objective disease progression	Up to approximately 2 years
Secondary	Progression Free Survival (PFS)	Number of days from first dose until objective disease progression or death from any cause	Up to approximately 2 years
Secondary	Overall Survival (OS)	Number of days from first dose until death from any cause	Up to approximately 2 years