Title
A Phase I/IIa, First-in-Human, Multicenter Dose Escalation and Dose Expansion Study of [203/212Pb]VMT01 Receptor-Targeted, Image Guided Alpha-Particle Therapy in Patients with Previously Treated Unresectable or Metastatic Melanoma

Description
This is a prospective, multi-center open-label dose escalation, dose expansion study of [212Pb]VMT01 in up to 52 subjects with histologically confirmed melanoma and a positive MC1R imaging scan ([203Pb]VMT01 or [68Ga]VMT02).

MC1R is a receptor that is expressed on the surface of melanoma cells. As such MC1R represents a potentially useful means of targeting therapeutics to melanoma. Lead-212 ([212Pb]-) based peptide-radiopharmaceuticals are an emerging class of targeted alpha-particle cancer therapies which have the potential to improve delivery of a highly effective form of radiation.

Patients may be eligible to receive up to 3 administrations of [212Pb]VMT01 approximately 8 weeks apart.

The first part of the study is an dose-escalation study to determine the Maximum Tolerated radioactivity Dose (MTD) or Maximum Feasible radioactivity Dose (MFD) following a single administration of [212Pb]VMT01.

The second part of the study is a dose expansion based on the identified MTD/MFD for the selection of [212Pb]VMT01 dose(s) for further clinical development.

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

Objective
Primary Objectives:
-To determine the MTD or MFD of [212Pb]VMT01
-To determine the safety and tolerability of single and repeated administrations of [212Pb]VMT01
-To investigate the anti-tumor efficacy of [212Pb]VMT01 in terms of tumor response

Secondary Objectives:
- To investigate the duration of response (DOR) following treatment with [212Pb]VMT01
-To investigate the progression free survival (PFS) treatment with [212Pb]VMT01
-To investigate the overall survival (OS) following treatment with [212Pb]VMT01
-To determine the pharmacokinetic properties of [212Pb]VMT01
-To assess the tumor uptake of [68Ga]VMT02
-To assess the tumor uptake of [203Pb]VMT01 in a subset of subjects
-To estimate radiation dosimetry for [203Pb]VMT01 and [212Pb]VMT01 in a subset of subjects

Exploratory Objectives:
-Correlation of uptake of [203Pb]VMT01 with observed toxicities following therapeutic administration of [212Pb]VMT01
-Correlation of uptake of [68Ga]VMT02 and [203Pb]VMT01 with observed efficacy following therapeutic administration of [212Pb]VMT01

Treatment Experimental: Dose Escalation
Dose Escalation to determine MTD/MFD among 4 different dose levels in up to 32 patients receiving up to 3 administrations of [212Pb]VMT01 approximately 8 weeks apart.
The second part of the study is a dose expansion based on the identified MTD/MFD for the selection of [212Pb]VMT01 dose(s) in up to 20 additional subjects.
A dosimetry sub-study utilizing [203Pb]VMT01 has been incorporated
Drug: [203Pb]VMT01
[203Pb]VMT01 IV administered as Image agent for SPECT/CT
Drug: [212Pb]VMT01
Patients with positive uptake of [203Pb]VMT01 will receive a fixed dose of [212Pb]VMT01 IV administered every 8 weeks for a maximum of three doses. Doses range between 111 MBq to 555 MBq (3 mCi to 15 mCi)

Experimental: Dose Expansion with RPh2D
Up to 20 patients with advanced or metastatic melanoma
Drug: [212Pb]VMT01
Patients with positive update of [203Pb]VMT01 receive a fixed dose of [212Pb]VMT01 IV administered every 8 weeks at the RPh2D and schedule determined in Phase I

Key Eligibility Inclusion Criteria:

Ability to understand and willingness to provide informed consent, willingness to comply with all study procedures for the duration of the study

Male or female, aged >/=18 years

Diagnosed with Stage IV metastatic melanoma, or unresectable Stage III

Previously progressed (clinical or radiological progression) on at least one prior 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., BRAF or MEK inhibitors) who demonstrate MC1R positivity during screening are eligible for enrollment, provided that they undergo a wash-out period of 21 days, or 14 days, respectively, prior to Day 1 treatment with [212Pb]VMT01.

Presence of measurable disease by RECIST v1.1 criteria assessed within 30 days prior to the start of 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: use of highly effective contraception for at least one month prior to screening, and agreement to use such a method during study participation and for an additional four weeks after the last administration of an investigational product

For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner during study participation and for an additional four weeks after the last administration of an investigational product

ECOG performance score of < 2 at Screening

Life expectancy of at least 3 months

Evidence of sufficient organ function as determined by all of the following:



Oxygen saturation > 90% on room air eGFR > 50 mL/min/1.73m2 by CKD-EPI equation Complete blood count with differential, within 7 calendar days prior to therapy and off Growth Factors White blood cells (WBC) > 2500/mm3 Hemoglobin (Hgb) > 9.0 g/dL Platelets > 60,000/mm3 Absolute Neutrophil Count (ANC) > 1,250/mm3

The comprehensive metabolic panel, within seven calendar days prior to Day 1, demonstrating values within the site's upper limit of normal (ULN), with the following exceptions:

Alanine aminotransferase (ALT) < 3x ULN Aspartate aminotransferase (AST) < 3x ULN Alkaline phosphatase (ALP) < 2.5x ULN

Applicable Disease Sites
Melanoma/Skin cancer

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital