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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Melanoma Stage IV, Melanoma (Skin), Metastatic Melanoma, Melanoma, Uveal, Mucosal Melanoma, Melanoma Stage III

Intervention / Treatment
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* Drug: [203Pb]VMT01
* Drug: [212Pb]VMT01
* Drug: [212Pb]VMT01


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase I/IIa First-in-Human Study of [212Pb]VMT01 Targeted Alpha-Particle Therapy for MC1R Positive Advanced Malignant Melanoma Dose
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>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<br>* [203Pb]VMT01 IV administered as Image agent for SPECT/CT<br>Drug: [212Pb]VMT01<br>* 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)<br>|
| Experimental: Dose Expansion with RPh2D<br>Up to 20 patients with advanced or metastatic melanoma | Drug: [212Pb]VMT01<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Theranostic, Radiopharmaceutical, Radiotherapy, Alpha Particle, Melanocortin Receptor Sub-type 1 (MC1R), VMT01-T101, Pb-203, Pb-212, Ga-68