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 Open-Label, First-in-human, Dose Escalation and Expansion Study to Determine the Safety, Tolerability, Dosimetry, Pharmacokinetics, and Preliminary Efficacy of 212Pb-DOTAM-GRPR1 in Adult Participants with Recurrent or Metastatic 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 for the SAD cohorts and a TITE Boin design for the MAD cohorts. Dose escalation may proceed until the recommended MAD dose is determined. Up to four (2 SAD and 2 MAD) cohorts are expected to be enrolled. Subjects will be treated with up to four cycles administered every 8 weeks. Once the recommended MAD dose is determined, the expansion cohorts of the study will commence. A dosimetry sub study will also be conducted in which participants will receive a single injection of 203Pb-DOTAM-GRPR1 with 1 week follow-up.

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: 2025-06
• Last Update Submitted: 2025-06-23
• Last Update Posted: 2025-06-26
• Primary Completion: 2026-08
• Study Completion: 2027-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 55

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).

• Subjects with recurrent disease must have progressed on at least 2 prior systemic therapies.

  • For participants with mCRPC: Prior orchiectomy and/or ongoing androgen deprivation therapy and a castrate level of serum testosterone (<50 ng/dL or <1.7 nmol/L).
  • Presence of at least 1 site of measurable disease per RECIST 1.1. At least 1 identified measurable lesion must show GRPR expression in 203Pb-DOTAM-GRPR1 imaging (uptake greater than that of the liver).

• Eastern Cooperative Oncology Group (ECOG) status 0-1.

• Sufficient bone marrow, hepatic and renal function, as assessed by the following laboratory requirements:

  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;

  5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x upper limit of normal (ULN) or ≤ 5 x ULN in the presence of liver metastases.

  6. Total bilirubin: ≤1.5 x ULN, except if history of Gilbert's disease.

  7. Adequate renal function defined by creatinine clearance (CLCR) ≥ 60 mL/min calculated as follows: CLCR = eGFR in ml/min/1.73 m2 calculated by the Modified Diet in Renal Disease (MDRD) x participant body surface area (BSA) in m2 ÷ 1.73.

  8. Serum amylase and/or lipase ≤1.5 x ULN.

     • For women of childbearing potential (WOCBP) and men with partners of childbearing potential: be willing to use highly effective methods of contraception throughout the study and for 7 months (for WOCBP, 4 months for men) after discontinuation of study intervention, as outlined in Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information.

Exclusion Criteria

1. Impaired cardiac function or clinically significant cardiac disease, including any of the following:

   1. Congestive heart failure New York Heart Association (NYHA) class II, III or IV.
   2. Left ventricular ejection fraction (LVEF) <50%.
   3. Clinically significant arrhythmias, cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin or digitalis compounds.
   4. Fridericia-corrected QT (QTcF) interval >480 ms (Common Terminology Criteria for Adverse Events [CTCAE] v5.0 Grade >1).
   5. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months before start of study intervention).
   6. Myocardial infarction less than 6 months before the start of study intervention.
   7. Uncontrolled hypertension, defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg, despite optimal medical management.

2. Known brain metastases or spinal cord compression.

3. History of myelodysplastic syndrome (MDS)/leukemia.

4. A known additional malignancy that has required active treatment within the past 3 years before the start of study intervention, except for adequately treated basal or squamous cell carcinoma of the skin, or carcinomas in situ that have undergone curative therapy.

5. Current infections requiring systemic therapy or infected non-healing wound.

6. Clinically significant toxicities related to prior anticancer therapies not recovered to ≤ Grade 1 CTCAE v5.0 or that have not returned to baseline. Chronic toxic effects of CTCAE Grade ≤2 from prior anticancer therapy where no further resolution is expected do not require exclusion with agreement between the Investigator and Sponsor (e.g., chemotherapy-induced neuropathy, fatigue, alopecia, anorexia, etc.).

7. Known or expected hypersensitivity or intolerance to the study intervention (including excipients).

8. Known human immunodeficiency virus (HIV) infection without established antiretroviral therapy and control of viral load (more than 400 copies/mL cells/µL) or a history of acquired immunodeficiency syndrome (AIDS) defining opportunistic infection.

9. Known active or symptomatic viral hepatitis.

10. Major surgery (defined as the opening of a body cavity), open biopsy, or significant trauma within 4 weeks before start of study intervention.

11. Any of the following:

    1. Prior exposure to any other GRPR-targeting therapeutic agents.
    2. Prior treatment with any systemic anticancer therapy including chemotherapy, biologic therapy, immunotherapy, or investigational therapies within 4 weeks of the start of study intervention, except luteinizing hormone-releasing hormone (LHRH) or gonadotropin releasing hormone (GnRH) for patients with mCRPC.
    3. Prior EBRT completed less than 6 weeks before the start of study intervention. Note that palliative radiotherapy completed less than 6 weeks before the start of study intervention will be allowed if: (i) no more than 10% of the participants' bone marrow is irradiated, (ii) it does not encompass all potential target/measurable lesions.
    4. Prior systemic therapeutic radiopharmaceutical treatments.
    5. Previous high-dose chemotherapy needing hematopoietic-stem-cell-rescue, or autologous or allogeneic stem-cell transplantation.
    6. Prior external beam radiation therapy to more than 25% of the bone marrow.
    7. Granulocyte colony-stimulating factor (G-CSF), erythropoietin or transfusions within 4 weeks before start of study intervention.
    8. Chronic systemic corticosteroids greater than the equivalent dose of 10 mg of prednisone/ prednisolone per day for at least 4 weeks before the first administration of 212Pb-DOTAM-GRPR1.

12. Any other condition which, in the opinion of the Investigator, would preclude participation in this study.

13. Participants with diabetes inadequately controlled on current treatment as judged by the Investigator or with hyperglycemia ≥ CTCAE Version 5.0 Grade 2.

14. History of or ongoing acute or chronic pancreatitis.

15. Concurrent bladder outflow obstruction or unmanageable urinary incontinence.

16. Female participants who are pregnant or breastfeeding.

17. For participants with mCRPC: Diffuse bone or bone marrow involvement, i.e., a "superscan": defined as bone scans in which there is excessive skeletal radioisotope uptake in relation to soft tissues along with absent or faint activity in the genitourinary tract due to diffuse bone / bone marrow metastases.

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 for the SAD cohorts and a TITE Boin design for the MAD cohorts. Doses will be increased by approximately 30% in subsequent cohorts. The maximum total dose that may be administered to a subject per cycle is 6.0 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 the safety and tolerability of ²¹²Pb-DOTAM-GRPR1 in subjects with gastrin-releasing peptide receptor (GRPR)-expressing tumors;	24 months	Measured as the number and severity of TEAEs and SAEs per CTCAE v5 and changes in laboratory values compared to baseline.
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 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 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 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 clearance (CL) of ²¹²Pb-DOTAM-GRPR1	24 months	Blood and urine samples will be drawn to determine the clearance (CL) of ²¹²Pb-DOTAM-GRPR1
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

Trial Locations

Locations (4)

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

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

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

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