Metastatic Melanoma
Conditions
Keywords
Melanoma, PD1, PD-1, refractory, metastatic, IMO-2125, illuminate 301, TLR9 agonist, advanced melanoma, CTLA4, CTLA-4, immunotherapy, skin cancer, ILLUMINATE-301
Brief summary
A Phase 3 comparison of ipilimumab with and without IMO-2125 in advanced melanoma
Detailed description
A Phase 3 global, multi-center, open-label comparison of ipilimumab with and without intratumoral IMO-2125 in subjects with advanced melanoma who had confirmed disease progression while on anti-PD-1
Interventions
DRUGIpilimumab
Arm A: 4 doses administered intravenously at a dose of 3 mg/kg over 90 minutes on Weeks 1, 4, 7, and 10.
DRUGTilsotolimod with Ipilimumab
IMO-2125 intratumoral injection administered as 9 doses on Weeks 1, 2, 3, 5, 8, 11, 16, 20, and 24. WITH (Arm B): Ipilimumab administered as 4 doses on Weeks 2, 5, 8, and 11. in combination with tilsotolimod
Sponsors
Bristol-Myers Squibb
Idera Pharmaceuticals, 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
1. Subjects must be willing and able to sign the informed consent and comply with the study protocol. 2. Subjects must be ≥18 years of age. 3. Subjects must have histologically confirmed metastatic melanoma with measurable (by RECIST v1.1), stage III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease that is accessible for injection. 4. Patients must have confirmed progression during or after treatment with a PD-1 inhibitor (cannot be part of a bi-specific antibody) e.g. nivolumab or pembrolizumab. Confirmed progression is defined as: * Radiological progression (confirmed at least 4 weeks after the initial scan showing PD); or * (For progression based solely on worsening of non-target or new, non-measurable disease) confirmation by an additional scan at least 4 weeks after the initial scan unless it is accompanied by correlative symptoms. In addition, all the following must hold: 1. No intervening anti-cancer therapy between the last course of PD-1 inhibitor treatment and the first dose of study treatment is allowed except for local measures (e.g., surgical excision or biopsy, focal radiation therapy). 2. The interval between last PD-1 inhibitor and start of study treatment should be at least 21 days with no residual anti-PD-1-related immune toxicities in excess of Grade 1 severity. 3. If BRAF mutation status is unknown, before randomization the subject must have BRAF testing performed using an approved assay method. 4. Patients with BRAF-positive tumor(s) are eligible for the study if they received prior treatment with a BRAF inhibitor (alone of in combination with a MEK inhibitor) or declined targeted therapy. 5. Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. 6. Patients must meet the following laboratory criteria: 1. Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (1500/mm3) 2. Platelet count ≥ 75 x 10\^9/L (75,000/mm3) 3. Hemoglobin ≥ 8.0 g/dL (4.96 mmol/L) 4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/minute 5. Aspartate aminotransferase (AST) ≤ 2.5 x ULN; alanine aminotransferase (ALT) ≤ 2.5 x ULN; AST/ALT \< 5 x ULN if liver involvement 6. Serum bilirubin ≤ 1.5 x ULN, except in subjects with Gilbert's Syndrome who must have a total bilirubin \< 3 mg/dL 7. Women of childbearing potential (WOCBP) and men must agree to use effective contraceptive methods from Screening throughout the study treatment period and until at least 90 days after the last dose of either ipilimumab or IMO-2125, whichever is later. 8. WOCBP must have a negative pregnancy test (serum or urine).
Exclusion criteria
1. Ocular melanoma. 2. Prior therapy with a toll-like receptor (TLR) agonist, excluding topical agents. 3. Prior ipilimumab treatment with the exception of adjuvant treatment completed ≥6 months prior to enrollment 4. Systemic treatment with interferon (IFN)-α within the previous 6 months. 5. Known hypersensitivity to any oligodeoxynucleotide. 6. Active autoimmune disease requiring disease-modifying therapy at the time of Screening. 7. Subjects requiring systemic steroid therapy receiving \>10 mg/day of prednisone (or equivalent) for the 2 weeks preceding start of study. 8. Subjects with another primary malignancy that has not been in remission for at least 3 years, with the exception of non-melanoma skin cancer, curatively treated localized prostate cancer with non-detectable prostate-specific antigen, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou (Pap) smear, and thyroid cancer (except anaplastic). 9. Active systemic infections requiring antibiotics 10. Active hepatitis A, B, or C infection. 11. Known diagnosis of human immunodeficiency virus (HIV) infection. 12. Women who are pregnant or breastfeeding. 13. Prior severe reaction to treatment with a human antibody that cannot be managed with standard supportive measures. 14. Presence of known central nervous system, meningeal, or epidural metastatic disease. However, subjects with known brain metastases are allowed if the brain metastases are stable for ≥4 weeks before the first dose of study treatment. Stable is defined as neurological symptoms not present or resolved to baseline, no radiologic evidence of progression, and steroid requirement of prednisone ≤10 mg/day or equivalent 15. Impaired cardiac function or clinically significant cardiac disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Response is measured from the date of randomization, until disease progression, death, or start of new anti-cancer therapy (up to 36 months). | The ORR for evaluable participants was calculated using the participant's best overall response (BOR). Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target lesions as assessed by MRI, CT or X-ray: Complete Response (CR) - disappearance of all target lesions; Partial Response (PR) - \>=30% decrease from baseline of the sum of diameters of all target lesions; Stable Disease (SD) - does not qualify for CR, PR or Progression; Progressive Disease (PD) - 20% increase in the sum of diameters of target lesions. The calculation is derived from measuring the diameter (mm) of the target lesion at baseline and comparing target lesion diameter (mm) at intervals during treatment and/or post-treatment. Based on the percent of tumor decrease or increase, the appropriate category is assigned. |
| Summary of Overall Survival | OS is measured from the date of randomization to the date of death from any cause (up to 36 months). | Efficacy measured by overall survival (OS) was defined as the number of participants alive compared to the number of participants that died by treatment group. |
Countries
Australia, Canada, Czechia, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
The global Phase 3 study was conducted at academic cancer centers across 11 countries. Participating countries included United States, Australia, Canada, Czech Republic, France, Germany, Italy, Netherlands, Spain, Sweden, and United Kingdom.
Pre-assignment details
The study was an open-label comparison of ipilimumab with and without intratumoral IMO-2125 (tilsotolimod) in participants with advanced melanoma who had disease progression while on or after PD-1 directed therapy. Study participants were randomized 1:1 to ipilimumab alone (Arm A) or ipilimumab with tilsotolimod given intratumorally (Arm B). Randomization was stratified on the duration of prior anti-PD-1 therapy, metastasis stage, and BRAF mutation status.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Ipilimumab ipilimumab 3 mg/kg intravenous
Ipilimumab: Arm A: 4 doses administered intravenously at a dose of 3 mg/kg over 90 minutes on Weeks 1, 4, 7, and 10. | 243 |
| Arm B: IMO-2125 Plus Ipilimumab IMO-2125 by intratumoral injection plus ipilimumab 3 mg/kg intravenous
Tilsotolimod with Ipilimumab: IMO-2125 intratumoral injection administered as 9 doses on Weeks 1, 2, 3, 5, 8, 11, 16, 20, and 24. WITH (Arm B): Ipilimumab administered as 4 doses on Weeks 2, 5, 8, and 11. in combination with tilsotolimod | 238 |
| Total | 481 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 60 | 64 |
| Overall Study | Death | 9 | 19 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Miscellaneous | 0 | 16 |
| Overall Study | Never Received any Study Treatment | 7 | 4 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Progressive Disease | 48 | 81 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Arm A: Ipilimumab | Total | Arm B: IMO-2125 Plus Ipilimumab |
|---|---|---|---|
| Age, Continuous | 64.3 years STANDARD_DEVIATION 13.73 | 64.3 years STANDARD_DEVIATION 13.49 | 64.3 years STANDARD_DEVIATION 13.28 |
| Baseline Elevated LDH (lactate dehydrogenase) No | 112 Participants | 218 Participants | 106 Participants |
| Baseline Elevated LDH (lactate dehydrogenase) Unknown | 7 Participants | 13 Participants | 6 Participants |
| Baseline Elevated LDH (lactate dehydrogenase) Yes | 124 Participants | 250 Participants | 126 Participants |
| Baseline Melanoma Characteristics Primary Histology - Cutaneous | 210 Participants | 413 Participants | 203 Participants |
| Baseline Melanoma Characteristics Primary Histology - Missing | 1 Participants | 1 Participants | 0 Participants |
| Baseline Melanoma Characteristics Primary Histology - Mucosal | 14 Participants | 26 Participants | 12 Participants |
| Baseline Melanoma Characteristics Primary Histology - Other | 18 Participants | 41 Participants | 23 Participants |
| Baseline Melanoma Staging IIIA | 0 Participants | 1 Participants | 1 Participants |
| Baseline Melanoma Staging IIIB | 0 Participants | 2 Participants | 2 Participants |
| Baseline Melanoma Staging IIIC | 20 Participants | 55 Participants | 35 Participants |
| Baseline Melanoma Staging IVM1A | 36 Participants | 60 Participants | 24 Participants |
| Baseline Melanoma Staging IVM1B | 46 Participants | 70 Participants | 24 Participants |
| Baseline Melanoma Staging IVM1C | 137 Participants | 284 Participants | 147 Participants |
| Baseline Melanoma Staging Other | 4 Participants | 9 Participants | 5 Participants |
| Best Response from Last Prior Systemic Anti-cancer Treatment Complete Response | 6 Participants | 9 Participants | 3 Participants |
| Best Response from Last Prior Systemic Anti-cancer Treatment Partial Response | 26 Participants | 49 Participants | 23 Participants |
| Best Response from Last Prior Systemic Anti-cancer Treatment Progressive Disease | 135 Participants | 260 Participants | 125 Participants |
| Best Response from Last Prior Systemic Anti-cancer Treatment Stable Disease | 49 Participants | 98 Participants | 49 Participants |
| Best Response from Last Prior Systemic Anti-cancer Treatment Unknown | 27 Participants | 65 Participants | 38 Participants |
| BRAF Mutation Status and Prior Targeted Therapy BRAF Mutation Positive with no Prior Targeted Therapy | 20 Participants | 38 Participants | 18 Participants |
| BRAF Mutation Status and Prior Targeted Therapy BRAF Mutation Positive with Prior Targeted Therapy | 35 Participants | 69 Participants | 34 Participants |
| BRAF Mutation Status and Prior Targeted Therapy BRAF Wild Type | 188 Participants | 374 Participants | 186 Participants |
| Duration of Prior Anti-PD-1 Therapy Greater than or Equal to 12 Weeks | 207 Participants | 411 Participants | 204 Participants |
| Duration of Prior Anti-PD-1 Therapy Less than 12 Weeks | 36 Participants | 70 Participants | 34 Participants |
| ECOG Performance Status 0 | 146 Participants | 296 Participants | 150 Participants |
| ECOG Performance Status 1 | 96 Participants | 183 Participants | 87 Participants |
| ECOG Performance Status 2 | 1 Participants | 2 Participants | 1 Participants |
| ECOG Performance Status 3 | 0 Participants | 0 Participants | 0 Participants |
| ECOG Performance Status 4 | 0 Participants | 0 Participants | 0 Participants |
| ECOG Performance Status 5 | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 11 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 211 Participants | 398 Participants | 187 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 27 Participants | 72 Participants | 45 Participants |
| Prior Systemic Anti-cancer Treatment BRAK Inhibitor | 36 Prior Treatments | 71 Prior Treatments | 35 Prior Treatments |
| Prior Systemic Anti-cancer Treatment Chemotherapy | 8 Prior Treatments | 19 Prior Treatments | 11 Prior Treatments |
| Prior Systemic Anti-cancer Treatment CTLA-4 Inhibitor | 5 Prior Treatments | 11 Prior Treatments | 6 Prior Treatments |
| Prior Systemic Anti-cancer Treatment Cytokine | 14 Prior Treatments | 24 Prior Treatments | 10 Prior Treatments |
| Prior Systemic Anti-cancer Treatment MEK Inhibitor | 36 Prior Treatments | 69 Prior Treatments | 33 Prior Treatments |
| Prior Systemic Anti-cancer Treatment Oncolytic Virus | 6 Prior Treatments | 11 Prior Treatments | 5 Prior Treatments |
| Prior Systemic Anti-cancer Treatment Other | 27 Prior Treatments | 65 Prior Treatments | 38 Prior Treatments |
| Prior Systemic Anti-cancer Treatment Other Immunotherapy | 14 Prior Treatments | 32 Prior Treatments | 18 Prior Treatments |
| Prior Systemic Anti-cancer Treatment Other Targeted Therapy | 6 Prior Treatments | 11 Prior Treatments | 5 Prior Treatments |
| Prior Systemic Anti-cancer Treatment PD-1 Inhibitor | 242 Prior Treatments | 479 Prior Treatments | 237 Prior Treatments |
| Prior Systemic Anti-cancer Treatment Setting Adjuvant | 58 Prior Treatment Settings | 134 Prior Treatment Settings | 76 Prior Treatment Settings |
| Prior Systemic Anti-cancer Treatment Setting Neoadjuvant | 6 Prior Treatment Settings | 8 Prior Treatment Settings | 2 Prior Treatment Settings |
| Prior Systemic Anti-cancer Treatment Setting Other | 1 Prior Treatment Settings | 5 Prior Treatment Settings | 4 Prior Treatment Settings |
| Prior Systemic Anti-cancer Treatment Setting Unresectable/Metastatic Disease | 214 Prior Treatment Settings | 414 Prior Treatment Settings | 200 Prior Treatment Settings |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 7 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 27 Participants | 71 Participants | 44 Participants |
| Race (NIH/OMB) White | 207 Participants | 394 Participants | 187 Participants |
| Region of Enrollment Australia | 10 Participants | 14 Participants | 4 Participants |
| Region of Enrollment Canada | 9 Participants | 20 Participants | 11 Participants |
| Region of Enrollment Czechia | 11 Participants | 30 Participants | 19 Participants |
| Region of Enrollment France | 71 Participants | 168 Participants | 97 Participants |
| Region of Enrollment Germany | 24 Participants | 38 Participants | 14 Participants |
| Region of Enrollment Italy | 53 Participants | 93 Participants | 40 Participants |
| Region of Enrollment Netherlands | 9 Participants | 11 Participants | 2 Participants |
| Region of Enrollment Spain | 29 Participants | 51 Participants | 22 Participants |
| Region of Enrollment Sweden | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United Kingdom | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 23 Participants | 46 Participants | 23 Participants |
| Sex: Female, Male Female | 116 Participants | 221 Participants | 105 Participants |
| Sex: Female, Male Male | 127 Participants | 260 Participants | 133 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 166 / 243 | 165 / 238 |
| other Total, other adverse events | 218 / 243 | 226 / 238 |
| serious Total, serious adverse events | 108 / 243 | 119 / 238 |
Outcome results
Primary
Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1
The ORR for evaluable participants was calculated using the participant's best overall response (BOR). Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target lesions as assessed by MRI, CT or X-ray: Complete Response (CR) - disappearance of all target lesions; Partial Response (PR) - \>=30% decrease from baseline of the sum of diameters of all target lesions; Stable Disease (SD) - does not qualify for CR, PR or Progression; Progressive Disease (PD) - 20% increase in the sum of diameters of target lesions. The calculation is derived from measuring the diameter (mm) of the target lesion at baseline and comparing target lesion diameter (mm) at intervals during treatment and/or post-treatment. Based on the percent of tumor decrease or increase, the appropriate category is assigned.
Time frame: Response is measured from the date of randomization, until disease progression, death, or start of new anti-cancer therapy (up to 36 months).
Population: All percentages were based on the number of participants in the Intent-to-Treat (ITT) analysis set within each group. Participants with no disease assessment in the study were included in the Not Evaluable category under Best Overall Response.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Partial Response | 20 Participants |
| Arm A: Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Progressive Disease | 110 Participants |
| Arm A: Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Stable Disease | 45 Participants |
| Arm A: Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Not Evaluable | 67 Participants |
| Arm A: Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Complete Response | 1 Participants |
| Arm B: IMO-2125 Plus Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Not Evaluable | 67 Participants |
| Arm B: IMO-2125 Plus Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Complete Response | 1 Participants |
| Arm B: IMO-2125 Plus Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Partial Response | 20 Participants |
| Arm B: IMO-2125 Plus Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Stable Disease | 61 Participants |
| Arm B: IMO-2125 Plus Ipilimumab | Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | Progressive Disease | 89 Participants |
Comparison: The ORR was defined as a percentage of subjects meeting criteria of CR and PR to calculate the p-value.p-value: 0.9394Cochran-Mantel-Haenszel
Primary
Summary of Overall Survival
Efficacy measured by overall survival (OS) was defined as the number of participants alive compared to the number of participants that died by treatment group.
Time frame: OS is measured from the date of randomization to the date of death from any cause (up to 36 months).
Population: All percentages were based on the number of participants in the Intent-to-Treat (ITT) analysis set within each group.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Ipilimumab | Summary of Overall Survival | Died | 166 Participants |
| Arm A: Ipilimumab | Summary of Overall Survival | Alive (Censored) | 77 Participants |
| Arm B: IMO-2125 Plus Ipilimumab | Summary of Overall Survival | Died | 165 Participants |
| Arm B: IMO-2125 Plus Ipilimumab | Summary of Overall Survival | Alive (Censored) | 73 Participants |
p-value: 0.677595% CI: [0.77, 1.186]Log Rank