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

Sponsor

miRagen Therapeutics, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02580552

Collaborator

(none)

Enrollment

Locations

Arms

55.9

Actual Duration (Months)

3.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

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 :

Feb 9, 2016

Actual Primary Completion Date :

Oct 6, 2020

Actual Study Completion Date :

Oct 6, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

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 [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
Skin disease severity (whole body) - MF only [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
Overall Response Rate in the skin - MF [Approximately 1 year]
Proportion of subjects who achieve a partial response (PR) or complete response (CR) in the skin, based on SWAT score
Overall Response Rate - CLL [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
Minimal Residual Disease (MRD) - CLL only [Approximately 1 year]
Proportion of subjects who achieve a CR with no evidence of MRD by flow cytometry
Overall Response Rate - DLBCL [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
Overall Response Rate - ATLL [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
Duration of Response [Up to approximately 2 years]
Number of days from initial date of confirmed PR or CR until loss of response or relapse
Time to Progression [Up to approximately 2 years]
Number of days from first dose until objective disease progression
Progression Free Survival (PFS) [Up to approximately 2 years]
Number of days from first dose until objective disease progression or death from any cause
Overall Survival (OS) [Up to approximately 2 years]
Number of days from first dose until death from any cause

Other Outcome Measures

miR-155-5p expression in cutaneous lesions of subjects with MF [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
Proportion of neoplastic lymphoid cells in cutaneous lesions of subjects with MF [At baseline and between Week 16 and end of study participation]
Exploratory histological assessment before and after treatment with cobomarsen
Proportions of immune cell subsets [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
Dermatology-specific quality of life - MF only [At baseline and monthly, up to approximately 2 years]
Changes in skin-related quality of life based on the Skindex-29 assessment tool
Pruritus - MF only [At baseline and monthly, up to approximately 2 years]
Changes in intensity of skin itch based on the Pruritus Numerical Rating Scale

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

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