Melanoma-TBK1-inhibitor enhanced Immuno Therapy with Checkpoint Inhibitors: a Phase IB/II Trial in Unresectable Stage III or Stage IV Cutaneous Melanoma

Prior treatment

• Significant active or chronic bleeding event Grade 2 or higher (according to CTCAE 5.0) 4 weeks prior to randomization.
• Unstable angina pectoris 6 months prior to randomization.
• Symptomatic congestive heart failure and/or uncontrolled cardiac arrhythmia within 6 months prior to randomization.
• Contraindication to continue ICI therapy including immune-related AEs that have neither returned to baseline nor stabilized.
• Any underlying advanced, severe and uncontrolled concomitant medical condition, including infection, which, in the investigator's opinion, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy (including operation), or interfere with the interpretation of study results.
• Other malignancies (except if treated with curative intent and with a cancer-related LE of more than 5 years).
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Prior systemic anticancer therapy for unresectable stage III or metastatic stage IV melanoma; prior adjuvant or neoadjuvant melanoma therapy is permitted if related AEs either returned to baseline or stabilized.

Other illness

• Active human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
• Active Hepatitis B or Hepatitis C despite treatment.
• Current progressive thrombosis despite treatment.
• Active brain metastases or leptomeningeal metastases (treated and stable brain metastatic disease may be included).
• Any condition that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.

Lab values

• Abnormal safety laboratory results at screening or baseline (as per CTCAE v5).
• QT corrected interval >500 milliseconds unless attributed to bundle block.

Other

• Inability to understand given information or undergo study procedures according to protocol.
• Ocular melanoma including uveal and conjunctival sub-types.
• Women who are pregnant or breastfeeding.

• Participants must be at least 18 years of age.
• Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female patients of childbearing potential must be willing to use a highly effective method of contraception, for the course of the study through 150 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Highly effective methods of contraception include one or more of the following: a. male partner who is sterile (vasectomised) prior to the female study subject’s entry into the study and is the sole sexual partner for the female subject; b. hormonal (oral, intravaginal, transdermal, implantable or injectable) c. an intrauterine hormone-releasing system (IUS) d. an intrauterine device (IUD) with a documented failure rate of <1%.
• Male patients of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 150 days after the last dose of study therapy. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. A unique female sexual partner must be postmenopausal, permanently sterilized (e.g. hysterectomy or tubal ligation), or use a highly effective method of contraception.
• Can provide a signed informed consent as described in the protocol, including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• SD according to RECIST v1.1 at 6 months of ICI therapy in 1st line.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2.
• Patients must have: a. Histologically or cytologically confirmed unresectable stage III melanoma or metastatic stage IV melanoma. b. Patients with cutaneous, acral, or unknown primary melanomas are eligible for enrollment
• No drug insensitivity to ICIs or momelotinib.
• Known BRAF mutation status.
• Sample available to determine SAMHD1-status before study end, either with existing sample or new biopsy.
• Life expectancy (LE) > 3 months.