Melanoma Stage III, Melanoma Stage IV, Metastatic Melanoma, Recurrent Melanoma (Skin)
Conditions
Keywords
Melanoma, Theranostic, Radiopharmaceutical, Radiotherapy, Alpha Particle, Melanocortin Receptor Sub-type 1 (MC1R), VMT01-T101, Pb-203, Pb-212, Ga-68, Nivolumab
Brief summary
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.
Detailed description
This is a prospective, multi-center open-label dose-finding, dose-expansion study of \[212Pb\]VMT01 as a monotherapy or in combination with nivolumab in up to 300 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-Finding Part 2: Combination-Therapy Dose-Finding Part 3: Dose Expansion Enrolled subjects in Monotherapy may receive up to 3 doses of \[212Pb\]VMT01 approximately 8 weeks apart and subjects in combination therapy may receive up to 3 doses of \[212Pb\]VMT01 along with nivolumab. Nivolumab will be administered every 4 weeks for up to 24 months. A Dosimetry sub-set 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.
Interventions
DRUG[203Pb]VMT01
\[203Pb\]VMT01 is administered intravenous (IV) as an imaging agent for SPECT/CT
DRUG[212Pb]VMT01
Subjects with positive uptake of \[203Pb\]VMT01 will receive a fixed dose of \[212Pb\]VMT01 administered IV every 8 weeks starting at Cycle 1 Day 1.
DRUGNivolumab
For all combination-therapy cohorts, 480 mg nivolumab will be administered every 4 weeks as an IV infusion.
Sponsors
Perspective Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase I/IIa First-in-Human Study of \[212Pb\]VMT01 Targeted Alpha-Particle Therapy for MC1R Positive Advanced Malignant Melanoma
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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 or recurrent melanoma * Previously progressed (radiological progression) on at least one approved systemic therapy for advanced 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 45 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects with dose-limiting toxicities (DLTs) after the first administration of [212Pb]VMT01 as a monotherapy or in combination with nivolumab. | Incidence of DLTs during the first 42 days of study Treatment will be assessed. | DLTs describe side effects of a drug that are serious enough to prevent an increase in dose |
| Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Up to approximately 2 years | Percentage of subjects with complete responses (CRs) or partial responses (PRs) to at least 1 administration of \[212Pb\]VMT01 as a monotherapy or in combination with nivolumab |
| Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) following administration of [212Pb]VMT01 as a monotherapy or in combination with nivolumab | Up to approximately 2 years | Any untoward medical occurrence in a clinical investigational participant administered \[212Pb\]VMT01 as a monotherapy or in combination with nivolumab. Associated AE or SAE is assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of response (DOR) following treatment with [212Pb]VMT01 as a monotherapy and in combination with nivolumab as assessed by RECIST v1.1 criteria | Up to approximately 2 years | DOR is time interval between the onset of a treatment response and the subsequent progression of disease or death |
| Progression free survival (PFS) for subjects receiving at least one administration of [212Pb]VMT01 as a monotherapy and in combination with nivolumab, as assessed by RECIST v1.1 criteria | Up to approximately 2 years | PFS a measure of how long a patient with a cancer lives without their cancer progressing or worsening. |
| Determination of pharmacokinetic properties (PK) of [212Pb]VMT01: Area under the concentration versus time curve | Up to week 16 | Blood radioactivity PK endpoint reported as Ci\*h/L |
| Determination of pharmacokinetic properties of [212Pb]VMT01]: Apparent terminal elimination half-life (T1/2) | Up to week 16 | Blood radioactivity PK endpoint (reported as time in minutes) |
Countries
United States
Contacts
CONTACTClinicalTrials at Perspectivetherapeutics
Outcome results
None listed