A Study to Assess the Safety and Efficacy of Intratumoral IMO-2125 in Combination With Ipilimumab or Pembrolizumab in Patients With Metastatic Melanoma

This is an open-label Phase 1/2 study to determine the recommended dose and assess the
safety, tolerability, pharmacokinetics (PK), immunogenicity, and efficacy of IMO-2125 when
administered in combination with ipilimumab or pembrolizumab. The study will be conducted in
2 parts; a dose-escalation portion (Phase 1) to evaluate safety and tolerability of multiple
dose levels and a Phase 2 portion to assess efficacy.

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.