MC1R-targeted Alpha-particle Therapy Trial in Adults With Advanced Melanoma
- Conditions
- Melanoma (Skin)Metastatic MelanomaMelanoma Stage IVMucosal MelanomaMelanoma Stage III
- Interventions
- Registration Number
- NCT05655312
- Lead Sponsor
- Perspective Therapeutics
- 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 in patients with unresectable and metastatic melanoma.
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 52
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Monotherapy-Dose Escalation [203Pb]VMT01 Enrolled subjects will be treated with increasing doses of \[212Pb\]VMT01 (up to 15 mCi) to determine MTD, MFD, and RP2D. Up to 32 subjects will be enrolled. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Monotherapy Dose-Escalation arm. Monotherapy-Dose Escalation [212Pb]VMT01 Enrolled subjects will be treated with increasing doses of \[212Pb\]VMT01 (up to 15 mCi) to determine MTD, MFD, and RP2D. Up to 32 subjects will be enrolled. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Monotherapy Dose-Escalation arm. Combination Therapy-Dose Escalation [203Pb]VMT01 Enrolled subjects will be treated with increasing radioactive doses of \[212Pb\]VMT01 (up to 15 mCi) in combination with nivolumab to determine MTD, MFD, and RP2D. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Combination Therapy-Dose Escalation. Combination Therapy-Dose Escalation [212Pb]VMT01 Enrolled subjects will be treated with increasing radioactive doses of \[212Pb\]VMT01 (up to 15 mCi) in combination with nivolumab to determine MTD, MFD, and RP2D. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Combination Therapy-Dose Escalation. Combination Therapy-Dose Escalation Nivolumab Enrolled subjects will be treated with increasing radioactive doses of \[212Pb\]VMT01 (up to 15 mCi) in combination with nivolumab to determine MTD, MFD, and RP2D. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Combination Therapy-Dose Escalation. Monotherapy - Dose Expansion [203Pb]VMT01 Up to 2 monotherapy expansion cohorts of up to 25 subjects will be enrolled at previously identified RP2D to confirm the RP2D and regimen for the Phase 2 dose-expansion cohort. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Monotherapy-Dose Expansion. Monotherapy - Dose Expansion [212Pb]VMT01 Up to 2 monotherapy expansion cohorts of up to 25 subjects will be enrolled at previously identified RP2D to confirm the RP2D and regimen for the Phase 2 dose-expansion cohort. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Monotherapy-Dose Expansion. Combination Therapy - Dose Expansion [203Pb]VMT01 Up to 2 Combination Therapy expansion cohorts of up to 25 subjects will be enrolled at RP2Ds previously identified to confirm the RP2D and regimen for the Phase 2 dose-expansion cohort. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Combination Therapy-Dose Expansion. Once the RP2D and regimen for the Phase 2 dose-expansion cohort is confirmed, up to 100 subjects will be enrolled to confirm the efficacy and safety of the RP2D and regimen. Combination Therapy - Dose Expansion [212Pb]VMT01 Up to 2 Combination Therapy expansion cohorts of up to 25 subjects will be enrolled at RP2Ds previously identified to confirm the RP2D and regimen for the Phase 2 dose-expansion cohort. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Combination Therapy-Dose Expansion. Once the RP2D and regimen for the Phase 2 dose-expansion cohort is confirmed, up to 100 subjects will be enrolled to confirm the efficacy and safety of the RP2D and regimen. Combination Therapy - Dose Expansion Nivolumab Up to 2 Combination Therapy expansion cohorts of up to 25 subjects will be enrolled at RP2Ds previously identified to confirm the RP2D and regimen for the Phase 2 dose-expansion cohort. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Combination Therapy-Dose Expansion. Once the RP2D and regimen for the Phase 2 dose-expansion cohort is confirmed, up to 100 subjects will be enrolled to confirm the efficacy and safety of the RP2D and regimen.
- Primary Outcome Measures
Name Time Method Number of subjects with treatment-related adverse events as assessed by CTCAE v4.0 42 days; up to 3 years Any untoward medical occurrence in a clinical investigational participant administered \[212Pb\]VMT01 as a monotherapy or in combination with nivolumab. Associated Adverse Events (AE) or Serious Adverse Event (SAE) is Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Number of subjects with laboratory abnormalities [Time Frame: Through 42 days following last dose of [212Pb]VMT01 as a monotherapy or in combination with nivolumab] up to 3 years Number of subjects with dose-limiting toxicities (DLTs) through 42 days following last dose of [212Pb]VMT01-T101 as a monotherapy or in combination with nivolumab. 42 days; up to 3 years Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 up to 3 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
- Secondary Outcome Measures
Name Time Method Determination of pharmacokinetic properties (PK) of [212Pb]VMT01: Area under the concentration versus time curve up to 3 years Blood radioactivity PK endpoint reported as Ci\*h/L
Determination of pharmacokinetic properties of [212Pb]VMT01]: Apparent terminal elimination half-life (T1/2) 42 days; up to 6 months Blood radioactivity PK endpoint (reported as time in minutes)
Determination of pharmacokinetic properties of [212Pb]VMT01 ]: Total urinary excretion of radioactivity Up to 6 months Urine radioactivity PK parameter reported as percentage of the injected (administered) dose (%ID)
Duration of response (DOR) following treatment with [212Pb]VMT01 as a monotherapy and in combination with nivolumab up to approximately 3 years Median DOR for subjects receiving at least 1 administration of \[212Pb\]VMT01 as a monotherapy and in combination with nivolumab, as assessed by RECIST v1.1 criteria.
Progression free survival (PFS) treatment with [212Pb]VMT01 as a monotherapy and in combination with nivolumab up to approximately 3 years For subjects receiving at least 1 administration of \[212Pb\]VMT01 as a monotherapy and in combination with nivolumab, PFS is assessed by RECIST v1.1 criteria.
Trial Locations
- Locations (10)
UPMC Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
Biogenix Molecular
🇺🇸Miami, Florida, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Saint Louis University Hospital
🇺🇸Saint Louis, Missouri, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Washington University of St. Louis
🇺🇸Saint Louis, Missouri, United States
Nebraska Cancer Specialists
🇺🇸Omaha, Nebraska, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
University of Wisconsin Carbone Cancer Center
🇺🇸Madison, Wisconsin, United States