NCT05283330招募中1 期
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
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 48
- 试验地点
- 8
- 主要终点
- To determine the Recommended Phase 2 Dose (RP2D) of ²¹²Pb-DOTAM-GRPR1
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-
- •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-GRPR
- •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.
排除标准
- •Impaired cardiac function or clinically significant cardiac disease, including any of the following:
- •Congestive heart failure New York Heart Association (NYHA) class II, III or IV.
- •Left ventricular ejection fraction (LVEF) <50%.
- •Clinically significant arrhythmias, cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin or digitalis compounds.
- •Fridericia-corrected QT (QTcF) interval >480 ms (Common Terminology Criteria for Adverse Events [CTCAE] v5.0 Grade >1).
- •Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months before start of study intervention).
- •Myocardial infarction less than 6 months before the start of study intervention.
- •Uncontrolled hypertension, defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg, despite optimal medical management.
- •Known brain metastases or spinal cord compression.
- •History of myelodysplastic syndrome (MDS)/leukemia.
- •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.
- •Current infections requiring systemic therapy or infected non-healing wound.
- •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.).
- •Known or expected hypersensitivity or intolerance to the study intervention (including excipients).
- •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.
- •Known active or symptomatic viral hepatitis.
- •Major surgery (defined as the opening of a body cavity), open biopsy, or significant trauma within 4 weeks before start of study intervention.
- •Any of the following:
- •Prior exposure to any other GRPR-targeting therapeutic agents.
- •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.
- •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.
- •Prior systemic therapeutic radiopharmaceutical treatments.
- •Previous high-dose chemotherapy needing hematopoietic-stem-cell-rescue, or autologous or allogeneic stem-cell transplantation.
- •Prior external beam radiation therapy to more than 25% of the bone marrow.
- •Granulocyte colony-stimulating factor (G-CSF), erythropoietin or transfusions within 4 weeks before start of study intervention.
- •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-GRPR
- •Any other condition which, in the opinion of the Investigator, would preclude participation in this study.
- •Participants with diabetes inadequately controlled on current treatment as judged by the Investigator or with hyperglycemia ≥ CTCAE Version 5.0 Grade
- •History of or ongoing acute or chronic pancreatitis.
- •Concurrent bladder outflow obstruction or unmanageable urinary incontinence.
- •Female participants who are pregnant or breastfeeding.
- •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.
研究组 & 干预措施
²¹²Pb-DOTAM-GRPR1
Experimental
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%.
干预措施: ²¹²Pb-DOTAM-GRPR1 (Drug)
结局指标
主要结局
To determine the Recommended Phase 2 Dose (RP2D) of ²¹²Pb-DOTAM-GRPR1
时间窗: 14 months
Incidence of DLTs.
次要结局
- To assess the safety and tolerability of 212Pb-DOTAM-GRPR1.(24 months)
- To assess the safety and tolerability of 203Pb-DOTAM-GRPR1.(24 months)
- To assess PK of ²¹²Pb-DOTAM-GRPR1(24 months)
- To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1.(24 months)
- To evaluate the preliminary antitumor activity of 212Pb-DOTAM-GRPR1(24 months)
- To evaluate the preliminary antitumor activity of 212-PbDOTAM-GRPR1.(24 Months)
研究者
研究点 (8)
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