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

Phase 1

Recruiting

• Conditions: Cervical Cancer; Colon Cancer; NSCLC; Breast Cancer; Cutaneous Melanoma; Prostate Cancer Metastatic
• Interventions: Drug: ²¹²Pb-DOTAM-GRPR1

• Registration Number: NCT05283330
• Lead Sponsor: Orano Med LLC

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2022-02-13
• Study First Submitted QC: 2022-03-11
• Study First Posted: 2022-03-16
• Study Start: 2022-12-22
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-17
• Last Update Posted: 2023-10-19
• Primary Completion: 2024-08
• Study Completion: 2025-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Male or female ≥18 years old with the following histologically confirmed metastatic or recurrent GRPR-expressing tumors:

  1. Metastatic castrate resistant prostate cancer (mCRPC);
  2. HR+/HER2- breast cancer;
  3. Colorectal cancer;
  4. Cervical cancer;
  5. Cutaneous melanoma;
  6. 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:

  1. White blood cell (WBC) ≥2,500/ mm³
  2. Absolute neutrophil count (ANC) ≥1500/mm³
  3. Platelets ≥75,000/mm³
  4. 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:

  1. New York Heart Association (NYHA) class III or IV;
  2. QTc > 470 msec for females and QTc >450 msec for males on screening electrocardiogram (ECG) or congenital long QT syndrome;
  3. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
²¹²Pb-DOTAM-GRPR1	²¹²Pb-DOTAM-GRPR1	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
To assess half-live(s) (t½) of ²¹²Pb-DOTAM-GRPR1	24 months	Blood and urine samples will be drawn to determine half-live(s) (t½) of ²¹²Pb-DOTAM-GRPR1
To assess the safety and tolerability of ²¹²Pb-DOTAM-GRPR1 in subjects with gastrin-releasing peptide receptor (GRPR)-expressing tumors;	24 months	Measured as the number of AEs per CTCAE v5 and changes in laboratory values compared to baseline.
To assess the volume of distribution (Vd) of ²¹²Pb-DOTAM-GRPR1	24 months	Blood and urine samples will be drawn to determine the volume of distribution (Vd) of ²¹²Pb-DOTAM-GRPR1
To evaluate the preliminary anti-tumor activity of the RP2D of ²¹²Pb-DOTAM-GRPR1	24 months	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.
To assess the area under the curve (AUC) from time 0 to the time of the last quantifiable concentration of ²¹²Pb-DOTAM-GRPR1	24 months	Blood and urine samples will be drawn to determine AUC of ²¹²Pb-DOTAM-GRPR1
To assess maximum concentration (Cmax) of ²¹²Pb-DOTAM-GRPR1	24 months	Blood and urine samples will be drawn to determine maximum concentration (Cmax) of 212Pb-DOTAM-GRPR1
To assess the clearance (CL) of ²¹²Pb-DOTAM-GRPR1	24 months	Blood and urine samples will be drawn to determine the clearance (CL) of ²¹²Pb-DOTAM-GRPR1

Trial Locations

Locations (4)

UK Markey Cancer Center; 🇺🇸 Lexington, Kentucky, United States

Northwestern University Robert H Lurie Medical Research; 🇺🇸 Chicago, Illinois, United States

Advanced Molecular Imaging and Therapy; 🇺🇸 Glen Burnie, Maryland, United States

XCancer Omaha / Urology Cancer Center; 🇺🇸 Omaha, Nebraska, United States