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

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

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

Study Overview

• Status: Recruiting
• Conditions: Cervical Cancer; Breast Cancer; Glioblastoma; NSCLC; Nonsmall Cell Lung Cancer; Colon Cancer; mCRPC (Metastatic Castration-resistant Prostate Cancer)
• Intervention / Treatment: Drug: ²¹²Pb-DOTAM-GRPR1

Detailed Description

In this open-label, dose escalation and dose expansion single ascending dose (SAD) and multiple ascending dose (MAD) phase 1 study, participants 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 BOIN design for the MAD cohorts. Dose escalation may proceed until the recommended MAD dose is determined. Up to six (2 SAD and 4 MAD) cohorts are expected to be enrolled. Participants will be treated with up to four cycles administered every 4 or 6 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 participants part of the dose escalation.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Orano Med LLC; Phone Number: 469-638-0744; Email: clinicaltrials@oranomed.com

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Active, not recruiting
      • Northwestern University Robert H Lurie Medical Research
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Not yet recruiting
      • University of Iowa Health Care
      • Principal Investigator: David Bushness, MD
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • UK Markey Cancer Center
      • Principal Investigator: Eddy Yang, MD
      • Contact: Phone Number: 859-323-7628
  • Maryland
    • Glen Burnie, Maryland, United States, 21061
      • Recruiting
      • Advanced Molecular Imaging and Therapy
      • Principal Investigator: Michael Morris, MD
      • Contact: Phone Number: 443-333-1894
    • Glen Burnie, Maryland, United States, 21061
      • Not yet recruiting
      • United Theranostics - Chesapeake
      • Principal Investigator: Babak Saboury, MD
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Recruiting
      • XCancer Omaha / Urology Cancer Center
      • Principal Investigator: Luke Nordquist, MD
      • Contact: Phone Number: 402-697-2229
    • Omaha, Nebraska, United States, 68130
      • Recruiting
      • Nebraska Cancer Specialists (Midwest Cancer Center - Legacy)
      • Principal Investigator: Samuel Mehr, MD
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15219
      • Not yet recruiting
      • University of Pittsburg Medical Center (UPCM)
      • Principal Investigator: Neeta Pandit Taskar, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

1. Adult participants (age ≥ 18 years old) with any of the following advanced or metastatic solid tumors (documented history of histologically confirmed diagnosis):

   1. Metastatic castration-resistant prostate cancer (mCRPC) including neuroendocrine prostate cancer (NEPC) (enrolled only in SAD and MAD Q6W)
   2. HR+/HER2- breast cancer (estrogen receptor/ER expression >10% of tumor cell nuclei stain, regardless of progesterone receptor/PgR expression); HER2-negative including HER2-low (as per relevant ASCO/CAP guidelines)
   3. Colorectal cancer
   4. Cervical cancer
   5. Non-small-cell lung cancer (NSCLC)
   6. Recurrent glioblastoma (only enrolled in MAD Q4W cohorts) with evidence of recurrent disease (RD) demonstrated by disease progression using modified Response Assessment in Neuro-Oncology (RANO 2.0) criteria. Note: If surgery is performed for GBM recurrence, pre-surgery MRI will be used for confirmation of RD and residual and measurable disease post-surgery is not required but surgery must have confirmed the recurrence diagnosis by MRI.
2. Capable of giving signed informed consent
3. All participants must have progressed on at least 2 prior systemic therapies, except for recurrent GB
4. 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)
5. Presence of at least 1 measurable lesion per RECIST 1.1 as assessed by the Investigator (not applicable for GBM). At least 1 identified measurable lesion must show GRPR uptake in 203Pb-DOTAM-GRPR1 SPECT/CT (uptake greater than that of the background) as assessed by the Investigator.
6. For participants with prostate cancer that do not have measurable soft tissue disease, 203Pb-DOTAM-GRPR1 uptake in bone lesions > uptake in background is acceptable for eligibility.
7. Eastern Cooperative Oncology Group (ECOG) status 0-1. Participants with ECOG status of 2 may be approved on a case-by-case basis in discussion with the Sponsor.

8. Adequate bone marrow, hepatic, and renal function, as assessed by the following laboratory requirements:

   1. White blood cell (WBC) ≥3000/ mm3 (≥ 3 x 109/L)
   2. Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 x 109/L)
   3. Platelets ≥100,000/mm3 (≥ 100 x 109/L)
   4. Hemoglobin (Hb) ≥9.0 g/dL
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3x upper limit of normal (ULN) or ≤ 5 x ULN in the presence of liver metastases
   6. Total bilirubin: ≤1.5 x ULN, except if documented history of Gilbert's disease who are eligible if total bilirubin ≤ 3 x ULN
   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

9. For women of childbearing potential (WOCBP) and men with partners of childbearing potential: be willing to use highly effective methods of contraception or sexual abstinence, if part of participant's lifestyle, throughout the study and for 7 months for WOCBP, 4 months for men after the last [212Pb]Pb-DOTAM-GRPR1 administration or for 10 days following [203Pb]Pb-DOTAM-GRPR1 administration and participant is not proceeding to 212Pb-DOTAM-GRPR1 treatment, as outlined in protocol.

   Participants with Recurrent Glioblastoma:

10. Having first or second glioblastoma recurrence, after standard therapy that includes prior radiation therapy (RT) and at least 12 weeks from completion of RT prior to first administration of 212Pb-DOTAM-GRPR1. In case surgery has been performed for GBM recurrence, the surgery has to be completed at least 4 weeks prior to 212Pb-DOTAM-GRPR1 treatment start, with post-surgery recovery without any complications related to surgical procedure.
11. Presence of 203Pb-DOTAM-GRPR1 uptake by SPECT/CT scan in the tumor lesion(s).
12. Presence of Gadolinium enhancement in the MRI in the tumor lesion(s) shown at the time of diagnosis of tumor recurrence.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ²¹²Pb-DOTAM-GRPR1; In the dose escalation portion, a classic 3+3 design will be utilized for the SAD cohorts and a 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 5.5 mCi +/- 10%.	Drug: ²¹²Pb-DOTAM-GRPR1; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the Recommended Phase 2 Dose (RP2D) of ²¹²Pb-DOTAM-GRPR1	Incidence of DLTs.	14 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the safety and tolerability of 212Pb-DOTAM-GRPR1.	Measured as Incidence and severity of TEAEs and TESAEs.	24 months
To assess the safety and tolerability of 203Pb-DOTAM-GRPR1.	Measured as Incidence and severity of TEAEs and TESAEs.	24 months
To assess PK of ²¹²Pb-DOTAM-GRPR1	212Pb-DOTAM-GRPR1 radioactivity concentration as a function of time in whole blood, plasma and urine	24 months
To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1.	ORR by RECIST1.1, DOR, PFS by Investigator assessment and OS.	24 months
To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1	For participants with mCRPC, by Investigator assessment of ORR which is defined as a proportion of participants having a 'best overall response' (BOR) assessment of Complete Response (CR) or Partial Response (PR) as per PCWG3 guidelines.	24 months
To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1	For participants with mCRPC, by Investigator assessment of DOR which is defined as the time from the first documented objective response of PR or CR by PCWG3, whichever occurs earlier, to disease progression or death.	24 months
To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1	For participants with mCRPC, by Investigator assessment of PFS which is defined as the time from the start of study intervention to the date of first observed disease progression (Investigator's radiological assessment), clinical disease progression (Investigator's assessment) or death due to any cause as per PCWG3 guidelines.	24 months
To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1	For participants with mCRPC, as Overall Survival (OS) is defined as the time from the date of the start of study intervention to the date of death due to any cause.	24 months
To evaluate the preliminary antitumor activity of 212-PbDOTAM-GRPR1.	For participants with recurrent GBM, by Investigator assessment of ORR which is defined as a proportion of participants having a 'best overall response' (BOR) assessment of Complete Response (CR) or Partial Response (PR) as per RANO 2.0 criteria.	24 Months
To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1.	For participants with recurrent GBM, by Investigator assessment of DOR defined as the time from the first documented objective response of PR or CR by RANO v 2.0, whichever occurs earlier, to disease progression or death	24 months
To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1.	For participants with recurrent GBM, Investigator assessment of PFS defined as the time from the start of study intervention to the date of first observed disease progression (Investigator's radiological assessment), clinical disease progression (Investigator's assessment) or death due to any cause as per RANO 2.0 criteria.	24 months
To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1.	For participants with recurrent GBM, Overall Survival (OS) is defined as the time from the date of the start of study intervention to the date of death due to any cause.	24 months

Collaborators and Investigators

• Sponsor: Orano Med Theranostics, SAS
• Investigators: Study Director: Jason D Hurt, MD, Orano Med

Publications and helpful links

General Publications

• Taunk NK, Escorcia FE, Lewis JS, Bodei L. Radiopharmaceuticals for Cancer Diagnosis and Therapy: New Targets, New Therapies-Alpha-Emitters, Novel Targets. Cancer J. 2024 May-Jun 01;30(3):218-223. doi: 10.1097/PPO.0000000000000720.
• Kunos CA, Fabian D, Napier D, Stonecypher MS, Duncan RM, Hurt J. Human gastrin- releasing peptide receptor expression in women with uterine cervix cancer. Front Oncol. 2023 Jan 25;13:1126426. doi: 10.3389/fonc.2023.1126426. eCollection 2023.

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2022
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): May 1, 2032

Study Registration Dates

• First Submitted: February 13, 2022
• First Submitted That Met QC Criteria: March 11, 2022
• First Posted (Actual): March 16, 2022

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Non-Small Cell Lung Cancer; Cervical Cancer; Colorectal Cancer; Advanced Cancer; Metastatic Cancer; Radioligand Therapy; Recurrent Cancer; Metastatic Prostate Cancer; SPECT/CT; Targeted Alpha Therapy; Targeted Radiation Therapy; Glioblastoma, Recurrent; Prostate Cancer, Castration-Resistant; Breast Cancer, Hormone Receptor Positive; Gastrin-Releasing Peptide Receptor or Bombesin receptor subtype-2; Lead-212 Radiopharmaceutical Therapy; Lead-203 Radiopharmaceutical Diagnostic
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pathologic Processes; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Intestinal Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Uterine Diseases; Genital Diseases, Female; Lung Diseases; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Neoplastic Processes; Lung Neoplasms; Genital Neoplasms, Female; Skin Diseases; Breast Diseases; Uterine Cervical Diseases; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Carcinoma, Bronchogenic; Bronchial Neoplasms; Uterine Neoplasms; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Prostatic Neoplasms; Recurrence; Colorectal Neoplasms; Colonic Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Glioblastoma; Carcinoma, Non-Small-Cell Lung; Uterine Cervical Neoplasms
• Other Study ID Numbers: OM-GRPR1-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No