Cutaneous T-Cell Lymphoma/Mycosis Fungoides
Conditions
Keywords
SOLAR, Cutaneous T-cell Lymphoma, CTCL, Mycosis Fungoides, Lymphoma, Lymphoma, T-cell, Lymphoma, T-cell, cutaneous, Lymphoma, Non-Hodgkin, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Neoplasms, MicroRNAs, Vorinostat, Histone Deacetylase Inhibitors
Brief summary
The main objective of this clinical trial is to study the efficacy and safety of cobomarsen (also known as MRG-106) for the treatment of cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF) subtype. Cobomarsen is designed to inhibit the activity of a molecule called miR-155 that may be important to the growth and survival of MF cancer cells. The study will compare the effects of cobomarsen to vorinostat, a drug that has been approved for the treatment of CTCL in the United States and several other countries. Participants in the clinical trial will be randomly assigned to receive either weekly doses of cobomarsen by injection into a vein or daily oral doses of vorinostat. Participants will continue on their assigned treatment as long as there is no evidence of progression of their cancer. The effects of treatment will be measured based on changes in skin lesion severity, as well as the length of time that the subject's disease remains stable or improved, without evidence of disease progression. The safety and tolerability of cobomarsen will be assessed based on the frequency and severity of observed side effects. Participants assigned to receive vorinostat who experience progression of their disease during their participation in this study may have the option to be treated with cobomarsen in an open-label, crossover arm of the same study if they meet the entry criteria for that part of the study.
Detailed description
Study Design: Subjects will be randomly assigned in a 1:1 ratio to receive either cobomarsen or vorinostat. Approximately 126 subjects (63 per arm) are expected to be enrolled. Cobomarsen will be administered in the clinic by 2-hr intravenous infusion on Days 1, 3, 5 and 8, and weekly thereafter. Vorinostat will be dispensed to study subjects and taken as a daily oral dose according to the manufacturer's labeled dosing instructions. Treatment will continue until the subject becomes intolerant, develops clinically significant side effects, progresses, or the trial is terminated. An interim analysis will be conducted after approximately 40 subjects have been followed for a minimum of approximately 6 months. Enrollment will be suspended until the completion of the interim analysis.
Interventions
DRUGCobomarsen
At least weekly doses of cobomarsen (282 mg) throughout study treatment period
DRUGVorinostat
Daily doses of vorinostat throughout study treatment period
Sponsors
miRagen Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Biopsy-proven CTCL, MF subtype * Clinical stage IB, II, or III, with staging based on screening assessments * Minimum mSWAT score of 10 at screening * Receipt of at least one prior therapy for CTCL Key
Exclusion criteria
* Previous enrollment in a cobomarsen study * Prior therapy with vorinostat or other HDAC inhibitors, or contraindication to an HDAC inhibitor * Sézary syndrome or mycosis fungoides with B2 involvement, defined as documented history of B2 and/or B2 staging at screening * Evidence of large cell transformation * Lymph node involvement at screening, unless radiologically or histologically confirmed to be nonmalignant * Visceral involvement related to MF at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving an Objective Skin Response of at Least 4 Months Duration (ORR4) | Date of first dose through the earlier of last study visit or interim analysis data cut-off date of 12-Oct-2020, up to 16 months | ORR4 is the percentage of subjects with a complete response (CR) or partial response (PR) in the skin for 4 consecutive months confirmed by repeat assessments no less than 28 days (± 3 days) later. The modified Severity Weighted Assessment Tool (mSWAT) is used to measure skin disease severity based on the percentage of body surface area (BSA) with patches, plaques, or tumors. Total scores are calculated by multiplying the BSA percentage for each category of lesion (patch, plaque, or tumor) by a weighting factor and adding the three sub-scores. Lower scores indicate a lower degree of skin disease severity. CR corresponds to 100% clearance of skin lesions present at baseline (mSWAT score of 0). PR corresponds to 50-99% clearance of skin disease present at baseline (at least 50% reduction in mSWAT score), without new tumors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximal Effect in mSWAT | Monthly from first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Time to greatest improvement in mSWAT score |
| Percentage of Subjects Achieving ≥ 50% Improvement in mSWAT at 4 Months | 4 months after first dose | Percentage of subjects achieving ≥ 50% improvement from baseline in mSWAT at 4 months after first dose |
| Time to ≥ 50% Improvement in mSWAT | Monthly from first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Time from date of randomization until ≥ 50% improvement in mSWAT score |
| Duration of Response in Skin | Monthly from first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Duration of response in skin (no progression after achieving ≥ 50% improvement in mSWAT) |
| Pruritus Medication Utilization | Date of first dose through end of treatment or interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Change from baseline in number of pruritus medications taken per subject |
| Progression-free Survival (PFS) | Date of first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Time from date of randomization until the date of earliest documented progression or death from any cause. The duration of PFS was censored at the date of the last mSWAT assessment if the subject was alive and had no documented progression. Disease progression in the skin is defined as ≥ 25% increase in mSWAT score from baseline or, in participants with complete or partial response, increase in mSWAT score of greater than the sum of the nadir plus 50% baseline score. |
| Complete Response Rate | Date of first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Percentage of subjects with a complete response in the skin based on mSWAT |
| Time to Progression | Date of first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Time from date of randomization until the earliest date of confirmed progression |
| Objective Response Rate in the Skin of at Least 28-days Duration (ORR1) | Monthly from first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Percentage of participants achieving ≥ 50% improvement in mSWAT of at least 28-days duration |
| Percentage of Subjects Achieving ≥ 50% Improvement in mSWAT at 28 Days | 28 days after first dose | Percentage of subjects achieving ≥ 50% improvement from baseline in mSWAT at 28 days after first dose |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration vs. Time Curve (AUC) of Cobomarsen - Week 5 | 1, 1.92 and 6 hours post-dose after the Week 5 dose | Area under the curve (AUClast) for cobomarsen plasma concentration versus time curve after the fourth (Week 5) dose |
| Number of Participants With Anti-drug Antibody Generation | Date of first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months | Number of participants who develop antibodies to cobomarsen during treatment |
| Peak Plasma Concentration (Cmax) of Cobomarsen - Week 5 | 1, 1.92 and 6 hours post-dose after the Week 5 dose | Peak plasma concentration (Cmax) of cobomarsen after fourth dose (Week 5) |
| Peak Plasma Concentration (Cmax) of Cobomarsen - First Dose | 1, 1.92, 6, 24 and 48 hours post-dose after the first dose | Peak plasma concentration (Cmax) of cobomarsen after first dose |
Countries
Australia, Belgium, Canada, France, Italy, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cobomarsen Cobomarsen: At least weekly doses of cobomarsen (282 mg) throughout study treatment period | 19 |
| Vorinostat Vorinostat: Daily doses of vorinostat throughout study treatment period | 18 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Cobomarsen Crossover Period | Physician Decision | 0 | 0 | 2 |
| Cobomarsen Crossover Period | Sponsor Decision to terminate trial | 0 | 0 | 5 |
| Randomized Period | Adverse Event | 1 | 5 | 0 |
| Randomized Period | Participant decision | 3 | 1 | 0 |
| Randomized Period | Physician Decision | 1 | 1 | 0 |
| Randomized Period | Study terminated by sponsor | 6 | 3 | 0 |
| Randomized Period | Withdrawal by Subject | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | Cobomarsen | Vorinostat | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 4 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 14 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 14 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 4 Participants |
| Lactate dehydrogenase (LDH) is greater than upper limit normal (ULN) at diagnosis | 4 Participants | 2 Participants | 6 Participants |
| LDH is not greater than ULN at diagnosis | 15 Participants | 14 Participants | 29 Participants |
| LDH not reported at diagnosis | 0 Participants | 2 Participants | 2 Participants |
| No skin tumor at screening | 13 Participants | 14 Participants | 27 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) White | 17 Participants | 13 Participants | 30 Participants |
| Region of Enrollment Belgium | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Canada | 1 participants | 0 participants | 1 participants |
| Region of Enrollment France | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Italy | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Spain | 2 participants | 1 participants | 3 participants |
| Region of Enrollment United Kingdom | 4 participants | 2 participants | 6 participants |
| Region of Enrollment United States | 9 participants | 8 participants | 17 participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Male | 10 Participants | 11 Participants | 21 Participants |
| Skin tumor at screening | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 18 | 0 / 7 |
| other Total, other adverse events | 18 / 19 | 18 / 18 | 5 / 7 |
| serious Total, serious adverse events | 2 / 19 | 1 / 18 | 0 / 7 |
Outcome results
Primary
Percentage of Subjects Achieving an Objective Skin Response of at Least 4 Months Duration (ORR4)
ORR4 is the percentage of subjects with a complete response (CR) or partial response (PR) in the skin for 4 consecutive months confirmed by repeat assessments no less than 28 days (± 3 days) later. The modified Severity Weighted Assessment Tool (mSWAT) is used to measure skin disease severity based on the percentage of body surface area (BSA) with patches, plaques, or tumors. Total scores are calculated by multiplying the BSA percentage for each category of lesion (patch, plaque, or tumor) by a weighting factor and adding the three sub-scores. Lower scores indicate a lower degree of skin disease severity. CR corresponds to 100% clearance of skin lesions present at baseline (mSWAT score of 0). PR corresponds to 50-99% clearance of skin disease present at baseline (at least 50% reduction in mSWAT score), without new tumors.
Time frame: Date of first dose through the earlier of last study visit or interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: Intent to treat population (includes all randomized subjects who received at least one dose of study treatment (cobomarsen or vorinostat) and had at least one post-baseline assessment. Assignment of subjects to treatment group is based on the planned treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cobomarsen (Randomized) | Percentage of Subjects Achieving an Objective Skin Response of at Least 4 Months Duration (ORR4) | 15.8 Percentage of participants |
| Vorinostat (Randomized) | Percentage of Subjects Achieving an Objective Skin Response of at Least 4 Months Duration (ORR4) | 16.7 Percentage of participants |
Comparison: Comparison of the treatment groups is based on a Cochran-Mantel-Haenzel test controlling for the number of tumors at screening (at least one tumor at screening versus no tumors at screening) and number of prognostic factors (0-1 versus 2 prognostic factors). Prognostic factors include age at diagnosis \> 60 years and lactate dehydrogenase level \> upper limit of normal at diagnosis. Number of subjects achieving ORR4 and exact binomial (Clopper-Pearson) confidence intervals are presented.p-value: 0.9539Cochran-Mantel-Haenszel
Secondary
Complete Response Rate
Percentage of subjects with a complete response in the skin based on mSWAT
Time frame: Date of first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: Intent to treat population (includes all randomized subjects who received at least one dose of study treatment (cobomarsen or vorinostat) and had at least one post-baseline assessment. Assignment of subjects to treatment group is based on the planned treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cobomarsen (Randomized) | Complete Response Rate | 0 Percentage of participants |
| Vorinostat (Randomized) | Complete Response Rate | 5.6 Percentage of participants |
Secondary
Duration of Response in Skin
Duration of response in skin (no progression after achieving ≥ 50% improvement in mSWAT)
Time frame: Monthly from first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: Subjects who achieved an objective response in skin (≥ 50% improvement in mSWAT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cobomarsen (Randomized) | Duration of Response in Skin | NA Months |
| Vorinostat (Randomized) | Duration of Response in Skin | 7.85 Months |
Secondary
Objective Response Rate in the Skin of at Least 28-days Duration (ORR1)
Percentage of participants achieving ≥ 50% improvement in mSWAT of at least 28-days duration
Time frame: Monthly from first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: Intent to treat population (includes all randomized subjects who received at least one dose of study treatment (cobomarsen or vorinostat) and had at least one post-baseline assessment. Assignment of subjects to treatment group is based on the planned treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cobomarsen (Randomized) | Objective Response Rate in the Skin of at Least 28-days Duration (ORR1) | 31.6 percentage of participants |
| Vorinostat (Randomized) | Objective Response Rate in the Skin of at Least 28-days Duration (ORR1) | 33.3 percentage of participants |
Secondary
Percentage of Subjects Achieving ≥ 50% Improvement in mSWAT at 28 Days
Percentage of subjects achieving ≥ 50% improvement from baseline in mSWAT at 28 days after first dose
Time frame: 28 days after first dose
Population: Intent to treat population (includes all randomized subjects who received at least one dose of study treatment (cobomarsen or vorinostat) and had at least one post-baseline assessment. Assignment of subjects to treatment group is based on the planned treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cobomarsen (Randomized) | Percentage of Subjects Achieving ≥ 50% Improvement in mSWAT at 28 Days | 5.3 percentage of participants |
| Vorinostat (Randomized) | Percentage of Subjects Achieving ≥ 50% Improvement in mSWAT at 28 Days | 11.1 percentage of participants |
Secondary
Percentage of Subjects Achieving ≥ 50% Improvement in mSWAT at 4 Months
Percentage of subjects achieving ≥ 50% improvement from baseline in mSWAT at 4 months after first dose
Time frame: 4 months after first dose
Population: Intent to treat population (includes all randomized subjects who received at least one dose of study treatment (cobomarsen or vorinostat) and had at least one post-baseline assessment. Assignment of subjects to treatment group is based on the planned treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cobomarsen (Randomized) | Percentage of Subjects Achieving ≥ 50% Improvement in mSWAT at 4 Months | 21.1 percentage of participants |
| Vorinostat (Randomized) | Percentage of Subjects Achieving ≥ 50% Improvement in mSWAT at 4 Months | 22.2 percentage of participants |
Secondary
Progression-free Survival (PFS)
Time from date of randomization until the date of earliest documented progression or death from any cause. The duration of PFS was censored at the date of the last mSWAT assessment if the subject was alive and had no documented progression. Disease progression in the skin is defined as ≥ 25% increase in mSWAT score from baseline or, in participants with complete or partial response, increase in mSWAT score of greater than the sum of the nadir plus 50% baseline score.
Time frame: Date of first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: Intent to treat population (includes all randomized subjects who received at least one dose of study treatment \[cobomarsen or vorinostat\] and had at least one post-baseline assessment). Assignment of subjects to treatment group is based on the planned treatment assignment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cobomarsen (Randomized) | Progression-free Survival (PFS) | NA months |
| Vorinostat (Randomized) | Progression-free Survival (PFS) | 6.01 months |
Comparison: Hazard ratio (cobomarsen/vorinostat) and p-value comparing the treatment groups is based on a Cox proportional hazards model. A hazard ratio \< 1 favors cobomarsen over vorinostat.p-value: 0.011Regression, Cox
Secondary
Pruritus Medication Utilization
Change from baseline in number of pruritus medications taken per subject
Time frame: Date of first dose through end of treatment or interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: All subjects with any predose or postdose pruritus medications, including subjects with no predose medications and at least one postdose medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cobomarsen (Randomized) | Pruritus Medication Utilization | -1 Number of pruritus medications | Standard Deviation 2.39 |
| Vorinostat (Randomized) | Pruritus Medication Utilization | -0.9 Number of pruritus medications | Standard Deviation 1.35 |
Secondary
Time to ≥ 50% Improvement in mSWAT
Time from date of randomization until ≥ 50% improvement in mSWAT score
Time frame: Monthly from first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: Subjects who achieved an objective response in skin (≥ 50% improvement in mSWAT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cobomarsen (Randomized) | Time to ≥ 50% Improvement in mSWAT | 3.7 Months | Standard Deviation 2.7 |
| Vorinostat (Randomized) | Time to ≥ 50% Improvement in mSWAT | 2.7 Months | Standard Deviation 1.8 |
Secondary
Time to Maximal Effect in mSWAT
Time to greatest improvement in mSWAT score
Time frame: Monthly from first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: Participants with improvement in mSWAT score
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cobomarsen (Randomized) | Time to Maximal Effect in mSWAT | 4.5 Months | Standard Deviation 3.7 |
| Vorinostat (Randomized) | Time to Maximal Effect in mSWAT | 3.0 Months | Standard Deviation 2.7 |
Secondary
Time to Progression
Time from date of randomization until the earliest date of confirmed progression
Time frame: Date of first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: Intent to treat population (includes all randomized subjects who received at least one dose of study treatment (cobomarsen or vorinostat) and had at least one post-baseline assessment. Assignment of subjects to treatment group is based on the planned treatment assignment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cobomarsen (Randomized) | Time to Progression | NA Months |
| Vorinostat (Randomized) | Time to Progression | 6.01 Months |
Other Pre-specified
Area Under the Plasma Concentration vs. Time Curve (AUC) of Cobomarsen - Week 5
Area under the curve (AUClast) for cobomarsen plasma concentration versus time curve after the fourth (Week 5) dose
Time frame: 1, 1.92 and 6 hours post-dose after the Week 5 dose
Population: Population analyzed included those randomized to cobomarsen treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cobomarsen (Randomized) | Area Under the Plasma Concentration vs. Time Curve (AUC) of Cobomarsen - Week 5 | 25.5 µg*hr/mL | Standard Deviation 6.27 |
Other Pre-specified
Number of Participants With Anti-drug Antibody Generation
Number of participants who develop antibodies to cobomarsen during treatment
Time frame: Date of first dose through interim analysis data cut-off date of 12-Oct-2020, up to 16 months
Population: The study was prematurely terminated for business reasons. No data were collected to evaluate this endpoint.
Other Pre-specified
Peak Plasma Concentration (Cmax) of Cobomarsen - First Dose
Peak plasma concentration (Cmax) of cobomarsen after first dose
Time frame: 1, 1.92, 6, 24 and 48 hours post-dose after the first dose
Population: Population analyzed included those randomized to cobomarsen treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cobomarsen (Randomized) | Peak Plasma Concentration (Cmax) of Cobomarsen - First Dose | 10.5 µg/mL | Standard Deviation 7.17 |
Other Pre-specified
Peak Plasma Concentration (Cmax) of Cobomarsen - Week 5
Peak plasma concentration (Cmax) of cobomarsen after fourth dose (Week 5)
Time frame: 1, 1.92 and 6 hours post-dose after the Week 5 dose
Population: Population analyzed included those randomized to cobomarsen treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cobomarsen (Randomized) | Peak Plasma Concentration (Cmax) of Cobomarsen - Week 5 | 9.34 µg/mL | Standard Deviation 3.24 |