Safety and Tolerability of ²¹²Pb-DOTAM-GRPR1 in Adult Subjects With Recurrent or Metastatic GRPR-expressing Tumors

Study Overview
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Brief Summary
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A Phase 1 SAD/MAD dose escalation and expansion study to determine the safety and effectiveness of ²¹²Pb-DOTAM-GRPR1 in subjects with various GRPR-expressing Tumors

Detailed Description
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In this open-label, dose escalation and dose expansion single ascending dose (SAD) and multiple ascending dose (MAD) phase 1 study, adult subjects with recurrent or metastatic histologically confirmed GRPR-expressing tumors will be enrolled. In the dose escalation portion, a classic 3+3 design will be utilized. Dose escalation may proceed until the recommended MAD dose is determined. Up to four cohorts are expected to be enrolled. Once the recommended MAD dose is determined, no additional subjects will be enrolled in the SAD escalation portion and the MAD portion of the study will commence. Subjects will be treated with up to four cycles administered every 8 weeks.

Official Title
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A Phase 1 Open-Label Dose Escalation and Expansion Study to Determine the Safety, Tolerability, Dosimetry, and Preliminary Efficacy of ²¹²Pb-DOTAM-GRPR1 in Adult Subjects With Recurrent or Metastatic GRPR-expressing Tumors

Conditions
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Cervical Cancer, Prostate Cancer Metastatic, Breast Cancer, Colon Cancer, NSCLC, Cutaneous Melanoma

Intervention / Treatment
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* Drug: ²¹²Pb-DOTAM-GRPR1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years old with the following histologically confirmed metastatic or recurrent GRPR-expressing tumors: Metastatic castrate resistant prostate cancer (mCRPC); HR+/HER2- breast cancer; Colorectal cancer; Cervical cancer; Cutaneous melanoma; Non-small-cell lung cancer (NSCLC). Biopsies must demonstrate the following on immunohistochemistry (IHC): 51-80% positively staining cells; and Moderate intensity of staining. Subjects with recurrent disease must have progressed on at least 2 prior systemic therapies. Presence of at least 1 site of measurable disease per RECIST 1.1 within 1 month prior to Cycle 1 Day 1. For subjects with prostate cancer, bone lesions may be used to fulfill the eligibility requirements per PCWG3 in lieu of measurable disease per RECIST 1.1. Eastern Cooperative Oncology Group (ECOG) status 0-2. Sufficient bone marrow capacity and organ function as defined by: White blood cell (WBC) ≥2,500/ mm³ Absolute neutrophil count (ANC) ≥1500/mm³ Platelets ≥75,000/mm³ Hemoglobin (HgB) ≥9.0 g/dL; Exclusion Criteria: Previous whole-body radiotherapy or peptide receptor radionuclide therapy (PRRT) with either alpha or beta emitters, or subjects with mCRPC who have received radium-223 (²²³Ra). Known hypersensitivity to any component of ²¹²Pb-DOTAM-GRPR1. Exposure to any other GRPR-targeting therapeutic agents. History of chronic pancreatitis History of pneumonitis. Impaired cardiac function defined as: New York Heart Association (NYHA) class III or IV; QTc > 470 msec for females and QTc >450 msec for males on screening electrocardiogram (ECG) or congenital long QT syndrome; Acute myocardial infarction or unstable angina pectoris < 3 months prior to study enrollment. Cyclical chemotherapy, radiotherapy, or biologic therapy (e.g. antibodies), continuous or intermittent, small molecule therapeutics, or any investigational agents within a period which is ≤ 5 half-lives or ≤ 4 weeks (whichever is longer) prior to Day 1.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ²¹²Pb-DOTAM-GRPR1<br>In the dose escalation portion, a classic 3+3 design will be utilized. Doses will be increased by approximately 30% in subsequent cohorts. The maximum total dose that may be administered to a subject per cycle is 5.5 mCi +/- 10%. The maximum total dose that may be administered to a subject in the MAD regimen is 24 mCi over 4 cycles. | Drug: ²¹²Pb-DOTAM-GRPR1<br>* ²¹²Pb-DOTAM-GRPR1 is a radioimmunoconjugate comprised of ²¹²Pb, the metal chelator DOTAM (1,4,7,10-Tetrakis(carbamoylmethyl)-1,4,7,10- tetraazacyclododecane) and a GRPR-targeted antagonist.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the Recommended Phase 2 Dose (RP2D) of ²¹²Pb-DOTAM-GRPR1 | RP2D is defined as the dose at which MAD dose escalation ceases | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety and tolerability of ²¹²Pb-DOTAM-GRPR1 in subjects with gastrin-releasing peptide receptor (GRPR)-expressing tumors; | Measured as the number of AEs per CTCAE v5 and changes in laboratory values compared to baseline. | 24 months | 
| To evaluate the preliminary anti-tumor activity of the RP2D of ²¹²Pb-DOTAM-GRPR1 | PFS is defined as the number of days from the first dose of study drug to documented tumor progression per RECIST 1.1 criteria or death due to any cause and OS will be defined as the number of days from the first dose of study drug to the date of death due to any cause or the date of last contact (censored observations) at the data cut-off date. | 24 months | 
| To assess maximum concentration (Cmax) of ²¹²Pb-DOTAM-GRPR1 | Blood and urine samples will be drawn to determine maximum concentration (Cmax) of 212Pb-DOTAM-GRPR1 | 24 months | 
| To assess the area under the curve (AUC) from time 0 to the time of the last quantifiable concentration of ²¹²Pb-DOTAM-GRPR1 | Blood and urine samples will be drawn to determine AUC of ²¹²Pb-DOTAM-GRPR1 | 24 months | 
| To assess half-live(s) (t½) of ²¹²Pb-DOTAM-GRPR1 | Blood and urine samples will be drawn to determine half-live(s) (t½) of ²¹²Pb-DOTAM-GRPR1 | 24 months | 
| To assess the clearance (CL) of ²¹²Pb-DOTAM-GRPR1 | Blood and urine samples will be drawn to determine the clearance (CL) of ²¹²Pb-DOTAM-GRPR1 | 24 months | 
| To assess the volume of distribution (Vd) of ²¹²Pb-DOTAM-GRPR1 | Blood and urine samples will be drawn to determine the volume of distribution (Vd) of ²¹²Pb-DOTAM-GRPR1 | 24 months |