A Randomized Phase 3 Comparison of IMO-2125 with Ipilimumab versus Ipilimumab Alone in Subjects with Anti-PD-1 Refractory Melanoma

1. Subjects must be willing and able to sign the informed consent and comply
with the study protocol.
2. Must be * 18 years of age.
3. Histologically confirmed metastatic melanoma with measurable (by Response
Evaluation Criteria in Solid Tumors [RECIST] v1.1}, Stage III (lymph node or in
transit lesions) or Stage IVA, IVB, or IVC disease that is accessible for
injection. Stage should be determined using the American Joint Committee on
Cancer (AJCC) Cancer staging Manual, Seventh Edition
4. Confirmed progression during or after treatment with either nivolumab or
pembrolizumab. Confirmed progression is defined as:
* Radiological progression (confirmed at least 4 weeks after the initial scan
showing progressive disease); 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:
a) No intervening anti-cancer therapy between the last course of nivolumab or
pembrolizumab and the first dose of study treatment is allowed except for local
measures (e.g., surgical excision or biopsy, focal radiation therapy).
b) The interval between last nivolumab or pembrolizumab and start of study
treatment should be at least 21 days with no residual anti-PD-1-related immunie
toxicities in excess of Grade 1 severity.
c) Prior BRAF inhibitor treatment (alone or in combination with a MEK
inhibitor) is required if the tumor carries a BRAF V600E or V600K mutation.
5. Eastern Cooperative Oncology Group (ECOG) Peformance Status *1.
6. Adequate baseline organ function as defined by:
a) Absolute neutrophil count (ANC) * 1.5 x 109/L (1500/mm3)
b) Platelet count *100 x 109/L (100,000/mm3)
c) Hemoglobin *8.0 g/dL (4.96 mmol/L)
d) Serum creatinine *1.5 x upper limit of normal (ULN) or 24-hour creatinine
clearance *60 mL/minute (*Grade 1)
e) Aspartate aminotransferase (AST) *2.5 x ULN; alanine aminotransferase (ALT)
*2.5 x ULN; AST/ALT <5 x ULN if liver involvement (*Grade 1)
f) Serum bilirubin *1.5 x ULN, except in subjects with Gilbert*s Syndrome who
must have a total bilirubin <3 mg/dL (*Grade 1)
7. Women of childbearing potential (WOCBP) and men must agree to use effective
contraceptive methods from screening until at least 3 months after the last
dose of ipilimumab (Arm A) and at least 4 weeks after the last dose of IMO-2125
(Arm B).
Non-childbearing potential is defined as a woman who meets either of the
following criteria: a) postmenopausal state defined as no menses for 12 months
without an alternative medical cause, or b) documented hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy.
Effective contraception methods are defined as one of the following:
a) True abstinence, defined as refraining from heterosexual intercourse, when
this is in line with the preferred and usual lifestyle of the subject. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods),
declaration of abstinence for the duration of a trial, and withdrawal are not
acceptable methods of contraception.
b) Condoms and spermicide
c) Diaphragm and spermicide
d) Oral or implanted hormonal contraceptive (e.g., Implanon*)
NOTE: For subjects in Sweden, low dose oral contraceptives are not permitted
e) An intra-uterine device
8. WOCBP must have a negative pregnancy test (serum or urine) according to the
Schedule of Evaluations

1. Ocular melanoma.
2. Prior therapy with a TLR agonist, excluding topical agents.
3. Prior ipilimumab with the exception of adjuvant treatment completed *6
months prior to enrollment.
4. Systemic treatment with IFN-* 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 with a requirement for receiving more than physiologic doses of
systemic steroids (>10 mg/day of prednisone or equivalent) for the 2 weeks
preceding start of study treatment.
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. Known active, hepatitis A, B, or C infection.
11. Known diagnosis of human immunodeficiency virus (HIV) infection.
12. Women who are pregnant or breast-feeding.
13. Prior anaphylactic or other severe infusion reaction associated with human
antibody administration 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.