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

Официальное название

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

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат 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.

Первичные конечные точки

• To determine the Recommended Phase 2 Dose (RP2D) of ²¹²Pb-DOTAM-GRPR1 [Срок оценки: 14 months]

Вторичные конечные точки (12)

• To assess the safety and tolerability of 212Pb-DOTAM-GRPR1. [Срок оценки: 24 months]
• To assess the safety and tolerability of 203Pb-DOTAM-GRPR1. [Срок оценки: 24 months]
• To assess PK of ²¹²Pb-DOTAM-GRPR1 [Срок оценки: 24 months]
• To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1. [Срок оценки: 24 months]
• To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1 [Срок оценки: 24 months]
• To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1 [Срок оценки: 24 months]
• To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1 [Срок оценки: 24 months]
• To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1 [Срок оценки: 24 months]
• To evaluate the preliminary antitumor activity of 212-PbDOTAM-GRPR1. [Срок оценки: 24 Months]
• To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1. [Срок оценки: 24 months]
• To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1. [Срок оценки: 24 months]
• To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1. [Срок оценки: 24 months]

Критерии участия

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

• Metastatic castration-resistant prostate cancer (mCRPC) including neuroendocrine prostate cancer (NEPC) (enrolled only in SAD and MAD Q6W)
• 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)
• Colorectal cancer
• Cervical cancer
• Non-small-cell lung cancer (NSCLC)
• 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.
• Capable of giving signed informed consent
• All participants must have progressed on at least 2 prior systemic therapies, except for recurrent GB
• 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 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.
• 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.
• 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.
• Adequate bone marrow, hepatic, and renal function, as assessed by the following laboratory requirements:

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

• 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.
• Presence of 203Pb-DOTAM-GRPR1 uptake by SPECT/CT scan in the tumor lesion(s).
• Presence of Gadolinium enhancement in the MRI in the tumor lesion(s) shown at the time of diagnosis of tumor recurrence.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 8 центров

• Northwestern University Robert H Lurie Medical Research — Chicago
• University of Iowa Health Care — Iowa City
• UK Markey Cancer Center — Lexington
• Advanced Molecular Imaging and Therapy — Glen Burnie
• United Theranostics - Chesapeake — Glen Burnie
• Nebraska Cancer Specialists (Midwest Cancer Center - Legacy) — Omaha
• XCancer Omaha / Urology Cancer Center — Omaha
• University of Pittsburg Medical Center (UPCM) — Pittsburgh

Публикации

• 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. PMID 38753757
• 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. PMID 36761980

Идентификаторы

NCT: NCT05283330 · OM-GRPR1-02

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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