MC1R-targeted Alpha-particle Therapy Trial in Adults With Advanced Melanoma

A Phase I/IIa, First-In-Human, Multi-Center 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

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 in patients with unresectable and metastatic melanoma.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Melanoma; Melanoma (Skin); Mucosal Melanoma; Melanoma Stage IV; Melanoma Stage III; Melanoma, Uveal
• Intervention / Treatment: Drug: [203Pb]VMT01; Drug: [212Pb]VMT01; Drug: [212Pb]VMT01

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Markus Puhlmann, MD; Phone Number: 319-665-2151; Email: mpuhlmann@perspectivetherapeutics.com

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa
      • Principal Investigator: Yusuf Menda, MD
      • Sub-Investigator: Yousef Zakharia, MD
      • Contact: Kristin West,, RN, BSN; Phone Number: 319-394-5489
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • University of Kentucky
      • Principal Investigator: Ruta Arays, MD
      • Contact: Yvonne O Taul; Phone Number: 859-323-2354; Email: yvonne.taul@uky.edu
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic Rochester
      • Sub-Investigator: Geoffrey B Johnson, MD, PhD
      • Principal Investigator: Matthew S Block, MD, PhD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University of St. Louis
      • Principal Investigator: Richard Wahl, MD
      • Contact: John Crandall; Phone Number: 314-747-5561; Email: jcrandall@wustl.edu
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Saint Louis University Hospital
      • Principal Investigator: Medhat Osman, MD
      • Contact: Chelsea Webb; Phone Number: 314-617-2899; Email: chelsea.may@health.slu.edu
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Recruiting
      • Nebraska Cancer Specialists
      • Principal Investigator: Samuel Mehr, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Recruiting
      • Fox Chase Cancer Center
      • Contact: Phone Number: 203-785-5102
      • Principal Investigator: Anthony Olszanski, MD
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • University of Wisconsin Carbone Cancer Center
      • Principal Investigator: Zachary S Morris, MD, PhD
      • Sub-Investigator: Vincent Ma, MD
      • Contact: Cancer Connect; Phone Number: 800-622-8922; Email: clinicaltrials@cancer.wisc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Exclusion Criteria:

• Active secondary malignancy
• Prior treatment (for any reason) with radioactive nuclides; however, imaging tracers are acceptable
• Pregnancy or breastfeeding a child
• Active infection
• Brain metastasis requiring acute therapy of any modality (i.e., surgical or external beam radiotherapy) within two weeks of enrollment or clinical instability, including signs or symptoms of brain edema. Subjects must demonstrate stable or decreasing brain metastasis by a noninvasive imaging scan and must be off steroids or on decreasing doses prior to enrollment.
• Treatment with another investigational drug product (therapeutic IND agents) within the last 30 days.
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / 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 for further clinical development. A dosimetry sub-study utilizing [203Pb]VMT01 has been incorporated into the study.	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); Drug: [212Pb]VMT01; Patients with positive update of [203Pb]VMT01 will receive a fixed dose of [212Pb]VMT01 IV administered every 8 weeks at the RPh2D and schedule determined in Phase I dose escalation
Experimental: Dose Expansion with RPh2D; Up to 20 patients with advanced or metastatic melanoma	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); Drug: [212Pb]VMT01; Patients with positive update of [203Pb]VMT01 will receive a fixed dose of [212Pb]VMT01 IV administered every 8 weeks at the RPh2D and schedule determined in Phase I dose escalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Any untoward medical occurrence in a clinical investigational participant administered [212Pb]VMT01 and Associated Adverse Events (AE) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0	42 days; up to 3 years
Number of patients with laboratory abnormalities [Time Frame: Through 42 days following last dose of [212Pb]VMT01; up to 3 years]		up to 3 years
Number of participants with dose-limiting toxicities (DLTs) through 42 days following last dose of [212Pb]VMT01-T101		42 days; up to 3 years
Objective response rate (ORR) per RECIST 1.1 [Time Frame: up to approximately 3 years]		up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the concentration-time curve (AUC) [Time Frame: Through 42 days following last dose of [212Pb]VMT01; up to 3 years]	Pharmacokinetic (PK) endpoint	up to 3 years
Apparent terminal elimination half-life (T1/2) [Time Frame: Through 42 days following last dose of [212Pb]VMT01; up to 6 months]	PK endpoint	up to 6 months
Duration of response (DOR) following treatment with [212Pb]VMT01	Median DOR for subjects receiving at least 1 administration of[212Pb]VMT01, as assessed by RECIST v1.1 criteria.	up to approximately 3 years
Progression free survival (PFS) treatment with [212Pb]VMT01	For subjects receiving at least 1 administration of [212Pb]VMT01, assessed by RECIST v1.1 criteria.	up to approximately 3 years
Overall survival (OS) following treatment with [212Pb]VMT01	Median OS for subjects receiving at least 1 administration of [212Pb]VMT01.	up to approximately 3 years

Collaborators and Investigators

• Sponsor: Perspective Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2023
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: November 15, 2022
• First Submitted That Met QC Criteria: December 8, 2022
• First Posted (Actual): December 19, 2022

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Radiotherapy; Melanoma; Theranostic; Radiopharmaceutical; Melanocortin Receptor Sub-type 1 (MC1R); Pb-203; Ga-68; Pb-212; Alpha Particle; VMT01-T101
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma
• Other Study ID Numbers: VMT01-T101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Protocol, CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No