Metastatic Melanoma
Conditions
Keywords
ILLUMINATE- 204, IMO-2125, tilsotolimod
Brief summary
The goal of the Phase 1 study was to find the recommended Phase 2 dose of the study drug IMO-2125 (tilsotolimod) that can be given in combination with ipilimumab (ipi) or pembrolizumab (pembro) to participants with metastatic melanoma and assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity when administered in combination with ipilimumab or pembrolizumab.
Detailed description
The open-label single-arm Phase 2 study was designed to assess the recommended dose for safety, tolerability, pharmacokinetics (PK), immunogenicity, and efficacy of 8 mg IMO-2125 (tilsotolimod) when administered in combination with ipilimumab.
Interventions
DRUGIMO-2125
Drug: IMO-2125 Intratumoral injection administered as 9 doses on Weeks 1, 2, 3, 5, 8, 11, 17, 23, and 29.
DRUGIpilimumab
4 doses administered intravenously at a dose of 3 mg/kg over 90 minutes on Weeks 2, 5, 8, and 11.
Sponsors
Idera Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have histologically confirmed metastatic melanoma with measurable, stage III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease. 2. Patients must have symptomatic or radiographic progression during or after treatment with a PD-(L)1 inhibitor administered either as monotherapy or in combination. 1. The interval between last PD-(L)1 directed treatment and start of study treatment should be at least 21 days. 2. Prior BRAF or MEK inhibitor treatment is not required. However, for patients with known BRAF status: * Those with BRAF wild type may have had a maximum of two previous systemic regimens for the treatment of melanoma. * Those with a BRAF mutation may have had a maximum of three previous systemic regimens for the treatment of melanoma. 3. Prior ipilimumab is permitted. 4. Previous treatment with either a PD-1 inhibitor (for patients enrolling on the IMO-2125 + pembrolizumab combination) or CTLA-4 inhibitor (for patients enrolling on the IMO-2125 + ipilimumab combination if applicable) should not have been accompanied by DLT for which permanent discontinuation is recommended (per USPI). * Patients with a history of Grade ≥2 gastrointestinal symptoms (e.g., diarrhea, colitis) during prior checkpoint inhibitor treatment should be discussed with the Idera Medical Monitor during the Screening Period before starting study treatment. 3. Phase 1 patients must have at least two measurable tumor lesions ≥ 1.0 cm that are accessible to biopsy. Phase 2 patients must have at least one measurable lesion (per RECIST v1.1) which may be the same site that is used for the intratumoral injections. 4. Patients must be ≥ 18 years of age. 5. Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2. 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 patients 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 IMO-2125, 3 months after the last dose of ipilimumab or at least 4 months after the last dose of pembrolizumab. 8. Patients must have an anticipated life expectancy \> 3 months.
Exclusion criteria
1. Patients who have received prior therapy with a TLR agonist, excluding topical agents. Patients who have received experimental vaccines or other investigational immune therapies should be discussed with the Medical Monitor to confirm eligibility. 2. Patients who have received systemic treatment with IFN-α within the previous 6 months prior to enrolling into this study. 3. Patients with known hypersensitivity to any oligodeoxynucleotide. 4. Patients with active autoimmune disease requiring disease-modifying therapy. 5. Patients requiring concurrent systemic steroid therapy higher than physiologic dose (7.5 mg/day of prednisone). 6. Patients with any form of active primary or secondary immunodeficiency. 7. Patients with another primary malignancy that has not been in remission for at least 3 years. 8. Patients with active systemic infections requiring antibiotics or active hepatitis A, B, or C. 9. Patients with a known diagnosis of human immunodeficiency virus (HIV) infection. 10. Patients who previously had a severe reaction to treatment with a human antibody. 11. Patients with known central nervous system, meningeal, or epidural disease. 12. Women who are pregnant or breastfeeding. 13. Patients with impaired cardiac function or clinically significant cardiac disease. 14. Patients with ocular melanoma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Number of Participants With Objective Response Rate (ORR) Using RECIST v1.1 | 33 weeks (29 weeks of treatment, 4 weeks follow up) | The following combined analysis populations were used for outcome measures (efficacy analysis N=53): * The Phase 2, 8 mg Tilso/Ipi efficacy evaluable population (N=44) * The Phase 1, 8 mg Tilso/Ipi evaluable population (N=9) The ORR for 49 evaluable (4 non-evaluable) participants who received the recommended Phase 2 dose (RP2D) of 8 mg Tilso/Ipi 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. Overall Response = CR or PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Progression-free Survival | 33 weeks (29 weeks of treatment, 4 weeks follow up) | The following combined analysis populations were used for outcome measures (efficacy analysis N=53): * The Phase 2, 8 mg Tilso/Ipi efficacy evaluable population N=40 (44 with 4 non-evaluable) * The Phase 1, 8 mg Tilso/Ipi evaluable population (N=9) Progression-free survival was defined as the number of months from the initiation of treatment to confirmed disease progression using RECIST v1.1 or death from any cause. |
| Phase 2: Overall Survival - 6 Months | 6 months | The following combined analysis populations were used for outcome measures (efficacy analysis N=53): * The Phase 2, 8 mg Tilso/Ipi efficacy evaluable population N=44 (40 with 4 non-evaluable) * The Phase 1, 8 mg Tilso/Ipi evaluable population (N=9) Overall survival was defined as the number of months from initiation of treatment to death from any cause. |
| Phase 2: Overall Survival - 12 Months | 12 months | The following combined analysis populations were used for outcome measures (efficacy analysis N=53): * The Phase 2, 8 mg Tilso/Ipi efficacy evaluable population N=40 (44 with 4 non-evaluable) * The Phase 1, 8 mg Tilso/Ipi evaluable population (N=9) Overall survival was defined as the number of months from initiation of treatment to death from any cause. |
Countries
United States
Participant flow
Recruitment details
The Phase 2 study was conducted at nine (9) academic cancer centers.
Pre-assignment details
In the Phase 2 study, all participants were assigned to a single arm and received IMO-2125 (tilsotolimod \[tilso\]) at the recommended Phase 2 dose (RP2D) of 8 mg, in combination with ipilimumab (ipi).
Participants by arm
| Arm | Count |
|---|---|
| Phase 2, 8 mg Tilso/Ipi IMO-2125 intratumoral injection plus ipilimumab
IMO-2125: Drug: IMO-2125 (8 mg as the RP2D) Intratumoral injection administered as 9 doses on Weeks 1, 2, 3, 5, 8, 11, 17, 23, and 29.
Ipilimumab: 4 doses administered intravenously at a dose of 3 mg/kg over 90 minutes on Weeks 2, 5, 8, and 11. | 53 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 26 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive Disease | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Study Terminated by Sponsor | 4 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Phase 2, 8 mg Tilso/Ipi |
|---|---|
| Age, Continuous | 64.6 years STANDARD_DEVIATION 11.3 |
| Baseline BRAF Mutation No | 26 Participants |
| Baseline BRAF Mutation Unknown | 4 Participants |
| Baseline BRAF Mutation Yes | 23 Participants |
| Baseline Brain Metastases No | 49 Participants |
| Baseline Brain Metastases Unknown | 2 Participants |
| Baseline Brain Metastases Yes | 2 Participants |
| Baseline Elevated LDH No | 37 Participants |
| Baseline Elevated LDH Unknown | 2 Participants |
| Baseline Elevated LDH Yes | 14 Participants |
| Baseline Melanoma Characteristics Primary Histology - Cutaneous | 42 Participants |
| Baseline Melanoma Characteristics Primary Histology - Mucosal | 5 Participants |
| Baseline Melanoma Characteristics Primary Histology - Other | 6 Participants |
| Baseline Melanoma Stage IIIA | 2 Participants |
| Baseline Melanoma Stage IIIB | 2 Participants |
| Baseline Melanoma Stage IIIC | 13 Participants |
| Baseline Melanoma Stage IVM1A | 7 Participants |
| Baseline Melanoma Stage IVM1B | 6 Participants |
| Baseline Melanoma Stage IVM1C | 22 Participants |
| Baseline Melanoma Stage Other: IV | 1 Participants |
| Baseline Visceral Metastases No | 23 Participants |
| Baseline Visceral Metastases Unknown | 4 Participants |
| Baseline Visceral Metastases Yes | 26 Participants |
| Body Mass Index | 28.9 kg/m^2 STANDARD_DEVIATION 6.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Prior Melanoma Treatment BRAF Inhibitor | 9 prior treatments |
| Prior Melanoma Treatment Chemotherapy | 9 prior treatments |
| Prior Melanoma Treatment CTLA-4 Inhibitor | 17 prior treatments |
| Prior Melanoma Treatment Interferon | 9 prior treatments |
| Prior Melanoma Treatment MEK Inhibitor | 8 prior treatments |
| Prior Melanoma Treatment Other | 23 prior treatments |
| Prior Melanoma Treatment PD-(L)1 Inhibitor | 49 prior treatments |
| Prior Melanoma Treatment Radiation | 14 prior treatments |
| Prior Melanoma Treatment Therapeutic Lymph Node Dissection | 23 prior treatments |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 47 Participants |
| Region of Enrollment United States | 53 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 26 / 53 |
| other Total, other adverse events | 52 / 53 |
| serious Total, serious adverse events | 15 / 53 |
Outcome results
Primary
Phase 2: Number of Participants With Objective Response Rate (ORR) Using RECIST v1.1
The following combined analysis populations were used for outcome measures (efficacy analysis N=53): * The Phase 2, 8 mg Tilso/Ipi efficacy evaluable population (N=44) * The Phase 1, 8 mg Tilso/Ipi evaluable population (N=9) The ORR for 49 evaluable (4 non-evaluable) participants who received the recommended Phase 2 dose (RP2D) of 8 mg Tilso/Ipi 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. Overall Response = CR or PR
Time frame: 33 weeks (29 weeks of treatment, 4 weeks follow up)
Population: Per the SAP, section 6, Analysis Populations used for efficacy, the analysis populations utilize both PIIEE (Primary Ipilimumab + IMO-2125 Efficacy Evaluable) who are ipilimumab-naive and SIIEE (Secondary Ipilumumab + IMO-2125 Efficacy Evaluable) who are not ipilumumab-naive that were treated at the RP2D, regardless of phase, and received at least one dose of each study drug.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Number of Participants With Objective Response Rate (ORR) Using RECIST v1.1 | Complete Response | 2 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Number of Participants With Objective Response Rate (ORR) Using RECIST v1.1 | Partial Response | 9 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Number of Participants With Objective Response Rate (ORR) Using RECIST v1.1 | Stable Disease | 24 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Number of Participants With Objective Response Rate (ORR) Using RECIST v1.1 | Progressive Disease | 14 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Number of Participants With Objective Response Rate (ORR) Using RECIST v1.1 | Non-evaluable | 4 Participants |
Comparison: Testing the best overall confirmed response rate against the historical control rate of 0.11 (extracted from the literature review).p-value: 0.0158One-sided Clopper-Pearson test
Secondary
Phase 2: Overall Survival - 12 Months
The following combined analysis populations were used for outcome measures (efficacy analysis N=53): * The Phase 2, 8 mg Tilso/Ipi efficacy evaluable population N=40 (44 with 4 non-evaluable) * The Phase 1, 8 mg Tilso/Ipi evaluable population (N=9) Overall survival was defined as the number of months from initiation of treatment to death from any cause.
Time frame: 12 months
Population: Per the SAP, section 6, Analysis Populations used for efficacy, the analysis populations utilize both PIIEE (Primary Ipilimumab + IMO-2125 Efficacy Evaluable) who are ipilimumab-naive and SIIEE (Secondary Ipilumumab + IMO-2125 Efficacy Evaluable) who are not ipilumumab-naive that were treated at the RP2D, regardless of phase, and received at least one dose of each study drug.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Overall Survival - 12 Months | Participants who died at or before 12 months | 19 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Overall Survival - 12 Months | Participants who did not die at or before 12 months | 30 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Overall Survival - 12 Months | Non-evaluable | 4 Participants |
95% CI: [44.7, 72.4]
Secondary
Phase 2: Overall Survival - 6 Months
The following combined analysis populations were used for outcome measures (efficacy analysis N=53): * The Phase 2, 8 mg Tilso/Ipi efficacy evaluable population N=44 (40 with 4 non-evaluable) * The Phase 1, 8 mg Tilso/Ipi evaluable population (N=9) Overall survival was defined as the number of months from initiation of treatment to death from any cause.
Time frame: 6 months
Population: Per the SAP, section 6, Analysis Populations used for efficacy, the analysis populations utilize both PIIEE (Primary Ipilimumab + IMO-2125 Efficacy Evaluable) who are ipilimumab-naive and SIIEE (Secondary Ipilumumab + IMO-2125 Efficacy Evaluable) who are not ipilumumab-naive that were treated at the RP2D, regardless of phase, and received at least one dose of each study drug.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Overall Survival - 6 Months | Participants who died at or before 6 months | 6 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Overall Survival - 6 Months | Participants who did not die at or before 6 months | 43 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Overall Survival - 6 Months | Non-evaluable | 4 Participants |
95% CI: [74.3, 94.2]
Secondary
Phase 2: Progression-free Survival
The following combined analysis populations were used for outcome measures (efficacy analysis N=53): * The Phase 2, 8 mg Tilso/Ipi efficacy evaluable population N=40 (44 with 4 non-evaluable) * The Phase 1, 8 mg Tilso/Ipi evaluable population (N=9) Progression-free survival was defined as the number of months from the initiation of treatment to confirmed disease progression using RECIST v1.1 or death from any cause.
Time frame: 33 weeks (29 weeks of treatment, 4 weeks follow up)
Population: Per the SAP, section 6, Analysis Populations used for efficacy, the analysis populations utilize both PIIEE (Primary Ipilimumab + IMO-2125 Efficacy Evaluable) who are ipilimumab-naive and SIIEE (Secondary Ipilumumab + IMO-2125 Efficacy Evaluable) who are not ipilumumab-naive that were treated at the RP2D, regardless of phase, and received at least one dose of each study drug.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Progression-free Survival | Participants with disease progression or death | 41 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Progression-free Survival | Participants who did not progress or die | 8 Participants |
| Phase 2, 8 mg Tilso/Ipi | Phase 2: Progression-free Survival | Non-evaluable | 4 Participants |
95% CI: [3.65, 7]