MC1R-targeted Alpha-particle Monotherapy and Combination Therapy Trial With Nivolumab in Adults With Advanced Melanoma

In this first-in human, phase I/IIa study, the safety and efficacy of \[212Pb\]VMT01, an alpha-particle emitting therapeutic agent targeted to melanocortin sub-type 1 receptor (MC1R) is being evaluated as a monotherapy and in combination with Nivolumab in subjects with unresectable and metastatic melanoma.

This is a prospective, multi-center open-label dose-escalation, dose-expansion study of \[212Pb\]VMT01 as a monotherapy or in combination with Nivolumab in up to 264 subjects with histologically confirmed melanoma and a positive MC1R imaging scan with imaging agents \[203Pb\]VMT01 or \[68Ga\]VMT02.

MC1R is a receptor that is expressed on the surface of melanoma cells and therefore is an attractive therapeutic target for melanoma treatment. Lead-212 (\[212Pb\]-) based peptide-radiopharmaceuticals are an emerging class of targeted alpha-particle cancer therapies that have potential to improve delivery of a highly effective form of radiation.

This study will be conducted in 3 parts:

Part 1: Monotherapy Dose-Escalation: \[212Pb\]VMT01 is administered alone in escalating doses to determine the Maximum Tolerated radioactivity Dose (MTD), Maximum Feasible radioactivity Dose (MFD), and potential recommended Phase 2 doses (RP2Ds)

Part 2: Combination-Therapy Dose-Escalation: \[212Pb\]VMT01 and Nivolumab are administered in escalating doses to determine MTD, MFD, and RP2Ds.

Part 3: Dose Expansion: This part will enroll subjects in monotherapy and combination-therapy expansion cohorts based on the identified MTD, MFD, and RP2D for the selection of \[212Pb\]VMT01 alone and \[212Pb\]VMT01-Nivolumab combination doses for further clinical development.

Enrolled subjects in Monotherapy part may receive up to 3 doses of \[212Pb\]VMT01 approximately 8 weeks apart and subjects in combination therapy may receive nivolumab every 4 weeks for up to 24 months.

A Dosimetry sub-study utilizing an imaging surrogate, \[203Pb\]VMT01, has been incorporated into the study in order to assess organ biodistribution and tumor uptake of the investigational products. This study will also estimate radiation dosimetry and correlate uptake of the investigation products with observed toxicities and efficacy.

Eligibility Criteria:
Inclusion Criteria:

* Ability to understand and willingness to provide informed consent, willingness to comply with all study procedures for the duration of the study
* Aged ≥ 18 years
* Diagnosed with unresectable Stage III or Stage IV metastatic melanoma
* Previously progressed (clinical or radiological progression) on at least one approved first-line therapy for metastatic melanoma
* Uptake of \[68Ga\]VMT02 or \[203Pb\]VMT01 by PET or SPECT imaging observed in at least one melanoma tumor site using quantitative imaging analysis compared to reference normal tissue
* Subjects on prior intravenous therapy (e.g., chemotherapy or checkpoint inhibitors), or prior oral therapy (e.g.,proto-oncogene B-RAF or mitogen-activated extracellular signal-regulated kinase inhibitors) who demonstrate MC1R positivity during screening are eligible for enrollment, provided that they undergo a wash-out period of 21 days, or 7 days, respectively, prior to Cycle 1 Day 1 treatment with \[212Pb\]VMT01.
* Presence of measurable disease by RECIST v1.1 assessed within 30 days prior to the first dose of \[212Pb\]VMT01 on Cycle 1 Day 1
* Ability to lie flat and still for up to two hours for imaging scans; moderate conscious sedation allowed if indicated
* For females of reproductive potential: agree to use of highly effective contraception and refrain from donating eggs (ova, oocytes) for the purpose of reproduction starting from screening, during treatment with \[212Pb\]VMT01 and/or nivolumab, and for at least 6 months after the last dose of \[212Pb\]VMT01 and/or nivolumab, whichever is administered last
* For males of reproductive potential: agree to use of condoms or other methods to ensure effective contraception and refrain from donating sperm starting from screening, during treatment with \[212Pb\]VMT01 and/or nivolumab, and for at least 6 months after the last dose of \[212Pb\]VMT01 and/or nivolumab, whichever is administered last
* Eastern Cooperative Oncology Group performance score of \< 2 at Screening
* Life expectancy of at least 3 months after Cycle 1 Day 1
* Satisfactory organ function determined by laboratory testing

Exclusion Criteria:

* Active secondary malignancy
* Prior systematic treatment with radioactive nuclides. Subjects who had localized treatment with radioactive nuclides or imaging using radioactive imaging agents may be enrolled
* Pregnancy or breastfeeding a child
* Any serious/active/uncontrolled infection requiring parenteral antibiotics within 2 weeks before the first administration of \[212Pb\]VMT01
* Febrile illness within 48 hours of any scheduled investigational product (\[212Pb\]VMT01, \[203Pb\]VMT01, or \[68Ga\]VMT02) administration; subjects should be rescheduled \> 48 hours after resolution of fever
* Treatment with another investigational drug product (therapeutic IND agents) within the last 45 days before the first dose of \[212Pb\]VMT01 on C1D1.
* Current abuse of alcohol or illicit drugs
* Existence of any medical or social issues likely to interfere with study conductor that may cause increased risk to the subject or to others, e.g., lack of ability to follow radiation safety precautions

Additional exclusion criteria for subjects who will receive combination therapy with nivolumab:

* Untreated central nervous system (CNS) metastasis or metastasis requiring acute therapy of any modality. Subjects must have been either off corticosteroids, or on a stable or decreasing dose of prednisone (or equivalent) for at least 2 weeks prior to the first dose of \[212Pb\]VMT01
* Concurrent malignancy requiring treatment or history of prior malignancy active within 2 years prior to the first dose of \[212Pb\]VMT01
* Subjects with an active, known, or suspected autoimmune disease
* Subjects with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications
* Acute or chronic hepatitis B (e.g., Hepatitis B surface antigen reactive), hepatitis C (e.g., HCV RNA \[qualitative\] is detected) or known history of Human Immunodeficiency Virus (HIV) with an acquired immunodeficiency syndrome
* Treatment with complementary medications (e.g., herbal supplements or traditional Chinese medicines)
* Existence of abnormal laboratory values in hematology, liver, and renal function
* Treatment with any live/attenuated vaccine within 30 days prior to the first dose of \[212Pb\]VMT01
* Any treatment-related toxicities from prior systemic immune therapy with the exception of those unlikely to re-occur with standard countermeasures
* History of allergy or hypersensitivity to nivolumab or its components