An Open-Label, Multicentre Phase 1b/2a Clinical Trial of BI-1607, an Fc-Engineered Monoclonal Antibody to FcγRIIB (CD32b), in Combination with Ipilimumab and Pembrolizumab in Participants with Unresectable or Metastatic Melanoma

Prior treatment

• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated CNS metastases may participate provided they are radiologically stable , are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention.
• Is at high medical risk because of non-malignant systemic disease including severe active infections on treatment with antibiotics, antifungals, or antivirals.
• Has severe hypersensitivity to pembrolizumab and/or any of its excipients. Has known or suspected hypersensitivity to BI-1607, ipilimumab or any of their excipients. Previous isolated infusion related reactions are not to be considered a reason for exclusion unless Grade 4 in severity.
• Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher irAE or was discontinued from that treatment due to Grade 2 myocarditis or recurrent Grade 2 pneumonitis.
• Has received the following: a. Chemotherapy or small molecule products within 4 weeks of first dose of BI-1607. b. Radiotherapy within 2 weeks of first dose of BI-1607, or has radiation-related toxicities, requiring corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) for non-central nervous system (CNS) disease. Participants who have previously had radiation pneumonitis are not allowed. c. Immunotherapy or biological anti-cancer therapy or an investigational agent or an investigational device within 4 weeks prior to the first dose of BI-1607.
• Has received a live or live-attenuated vaccine within 30 days prior to the first dose of trial intervention.
• Is participating or planning to participate in another interventional clinical trial or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to first dose of trial intervention. Participants who have entered the follow-up phase of an investigational trial may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Participation in an observational trial is acceptable.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial intervention. During the Screening period, doses of up to 20 mg/day may be given but the dose must be reduced to 10 mg/day within 7 days prior to the first dose of trial intervention.

Other illness

• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has a known history of human immunodeficiency virus infection. No HIV testing is required unless mandated by local health authority.
• Has cardiac or renal amyloid light-chain amyloidosis.
• Has uncontrolled or significant cardiovascular disease.
• Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the trial.
• Has an active autoimmune disease that has required systemic treatment in past 2 years Replacement therapy is not considered a form of systemic treatment and is allowed.
• Has history of allogeneic tissue/solid organ transplant.

Lab values

• Has received previous lines of treatment containing anti-CTLA-4 mAb or anti-LAG3 mAb (anti-Lymphocyte Activation Gene 3).
• Is a female participant and has the possibility to become pregnant (or already pregnant or lactating/breastfeeding). However, those female participants who have a negative serum or urine pregnancy test before enrolment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial, and for 12 months after last dose of BI-1607 are considered eligible.
• Has a history or there is current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or in the opinion of the treating Investigator is not in the best interest of the participant to participate.

Other

• Is a male participant with partner(s) of childbearing potential (unless he agrees to use a barrier method of contraception [condom plus spermicidal gel] with the female partner(s) who are using one highly effective method of contraception during the trial and for 12 months after completing treatment). Men with pregnant or lactating partners should be advised to use barrier methods of contraception to prevent exposure to the foetus or neonate. All males should refrain from sperm donation for 12 months after last dose of trial intervention.

• Is willing and able to provide written informed consent for the trial.
• Has a life expectancy of ≥ 12 weeks.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Has adequate organ function as confirmed by laboratory values listed in the protocol.
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrolment. Note: Participants should remain on antiviral therapy throughout trial intervention and follow local guidelines for HBV antiviral therapy post completion of trial intervention. Hepatitis B screening tests are not required unless: a. Known history of HBV infection. b. As mandated by local health authority
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening. Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to enrolment. Hepatitis C screening tests are not required unless: a. Known history of HCV infection. b. As mandated by local health authority.
• Is ≥ 18 years of age on the day of signing informed consent.
• Has histologically confirmed advanced melanoma (unresectable or metastatic melanoma) with established disease progression.
• Participants must have progressed on treatment with an anti-PD-1/L1 mAb. Subjects with uveal melanoma are not required to have received any prior anti-PD-1/L1 treatment. PD-1 treatment progression is defined by meeting all of the following criteria: a. Has received at least 2 doses of an approved anti-PD-1/L1 mAb. b. Has demonstrated disease progression after anti PD-1/L1 as defined by RECIST v1.1. The initial evidence of disease progression is to be confirmed by a second assessment no less than four weeks from the date of the first documented disease progression, in the absence of rapid clinical progression. c. Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb. i. Progressive disease is determined according to iRECIST. ii. This determination is made by the Investigator. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.
• Has at least 1 measurable disease lesion as defined by RECIST v1.1 criteria.
• Must be willing to provide tumour biopsies as specified in the schedule of assessments (SoA) unless otherwise discussed and agreed with the Sponsor in case a biopsy cannot be taken for a medical/safety reason. The Screening biopsy must be performed prior to the first dose of BI-1607 (on non-previously irradiated lesions only), and at least 4 weeks following the last dose of tumour directed therapy. The biopsy at Screening can be replaced with a formalin fixed archival tumour tissue sample collected from a previous standard of care biopsy, provided that the biopsy was recent, performed after the participant’s last tumour directed therapy and prior to trial entry.