A First-in-Human, Phase I/II PET Imaging Study of 64Cu-GRIP B, a Radiotracer Targeting Granzyme B, in Patients With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 91
- 试验地点
- 1
- 主要终点
- Change in SUVmax (Cohorts B, C, and D)
研究概览
简要总结
This phase I/II clinical trial evaluates if using a radiotracer targeting granzyme B, 64-copper granzyme targeting restricted interaction peptide specific to family member B (64 Cu-GRIP B) with positron emission tomography (PET) imaging can be safe and useful for detecting granzyme B (GrB) in patients with advanced cancers that has spread to nearby tissue or lymph nodes (advanced). Granzyme B (GrB) is a biomarker produced by immune cells in response to immunotherapy, which may highlight tumors that are more likely to respond to treatment. The study population is focused on genitourinary (GU) malignancies, including renal cell and urothelial cancer, two tumor types with high mutational burden and tumor infiltrating lymphocytes compared to other tumor types, and have a predictable response rate at the population level to immune checkpoint inhibitors. The information gained from this trial may allow researchers to develop future trials where 64Cu-GRIP B PET may serve as a biomarker to monitor early response to immunomodulatory therapies which are used to stimulate or suppress the immune system and may help the body fight cancer.
详细描述
PRIMARY OBJECTIVES:
I. To determine the safety, dosimetry, and pharmacokinetics of 64Cu-GRIP B PET in patients with solid tumor malignancy (3 males, 3 females). (Cohort A) II. To determine the mean percent change in both tumor maximum standardized uptake value (SUVmax) and ratio of SUVmax//blood average standardized uptake value (SUVave) on 64Cu-GRIP B PET in patients with participants with metastatic renal cell carcinoma (RCC) and urothelial carcinoma (UC) (Cohort B) or metastatic castration-resistant prostate cancer (mCRPC) (Cohort C).
SECONDARY OBJECTIVES:
I. To determine the safety and average organ dosimetry of 64Cu-GRIP B PET in patients with participants with metastatic RCC and UC (Cohort B), mCRPC (Cohort C) or other solid tumor malignancies (Cohort D).
II. To descriptively report the patterns of intra-tumoral uptake of 64Cu-GRIP B on whole body PET, including by site of disease, uptake by tumor type, inter-tumoral and inter-patient heterogeneity, and tumor-to-background signal in patients with participants with metastatic RCC and UC (Cohort B), mCRPC (Cohort C), or other solid tumor malignancies (Cohort D).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 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
- •Disease characteristics by cohort, as defined by:
- •Histologically-confirmed metastatic solid tumor malignancy (3 Male, 3 Female)
- •Locally advanced or metastatic disease on conventional imaging
- •Histologically-confirmed metastatic renal cell carcinoma (any histologic sub-type) or urothelial carcinoma
- •Locally advanced or metastatic disease on conventional imaging
- •Histologically-confirmed prostate adenocarcinoma
- •Metastatic castration resistant prostate cancer by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria
- •Planned treatment with immune checkpoint inhibitor (Cohorts B and C only)
- •Willing to undergo paired tumor biopsies and has safely accessible bone or soft tissue lesion (Cohorts B and C only)
- •The subject is able and willing to comply with study procedures and provide signed and dated informed consent.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
- •Age 18 years or older at the time of study entry.
- •Adequate organ function, as defined by:
- •Serum creatinine <= 1.5 x upper limit of normal (ULN) or estimated creatinine clearance > 60 mL/min
- •Total bilirubin <= 1.5 x ULN (< 3 x ULN in patients with documented or suspected Gilbert's).
- •Hemoglobin >= 8.0 g/dL
- •Platelet count >= 75,000/microliter
- •Absolute neutrophil count ≥ 1000/microliter
- •Patients must not be pregnant or breast feeding. Women of childbearing potential are required to obtain a negative pregnancy test within 14 days of PET Imaging scan. Effective contraception (men and women) must be used in subjects of child-bearing potential.
排除标准
- •Patients who because of age, general medical or psychiatric condition, or physiologic status cannot give valid informed consent.
- •Any condition that, in the opinion of the Principal Investigator, would impair the patient's ability to comply with study procedures.
- •Is currently pregnant or breastfeeding.
研究组 & 干预措施
Cohort A: 64Cu-GRIP B, Solid Tumor Malignancy participants
Participants with solid tumor malignancies (3 males, 3 females), dosimetry calculation will be performed by obtaining whole body (vertex to thighs) PET images up to five time points from 0.5 to 24 hours post 64Cu-GRIP B injections. An additional intravenous line will be placed in the contra-lateral arm to collect blood for this group.
干预措施: Copper-64 labeled Granzyme B (64Cu-GRIP B) (Drug)
Cohort A: 64Cu-GRIP B, Solid Tumor Malignancy participants
Participants with solid tumor malignancies (3 males, 3 females), dosimetry calculation will be performed by obtaining whole body (vertex to thighs) PET images up to five time points from 0.5 to 24 hours post 64Cu-GRIP B injections. An additional intravenous line will be placed in the contra-lateral arm to collect blood for this group.
干预措施: Positron Emission Tomography (PET) (Procedure)
Cohort B: 64Cu-GRIP B, RCC and UC participants
Participants with renal cell and urothelial carcinoma will have longitudinal imaging performed prior to treatment outside of this study with anti-programmed death-1 (PD-1)/anti-PD-1 ligand 1 (PD-L1) blockade (with or without concomitant anti-CTLA4 treatment), after 8 weeks of checkpoint blockade, and again at the time of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
干预措施: Copper-64 labeled Granzyme B (64Cu-GRIP B) (Drug)
Cohort B: 64Cu-GRIP B, RCC and UC participants
Participants with renal cell and urothelial carcinoma will have longitudinal imaging performed prior to treatment outside of this study with anti-programmed death-1 (PD-1)/anti-PD-1 ligand 1 (PD-L1) blockade (with or without concomitant anti-CTLA4 treatment), after 8 weeks of checkpoint blockade, and again at the time of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
干预措施: Positron Emission Tomography (PET) (Procedure)
Cohort C: 64Cu-GRIP B, mCRPC participants
Participants with metastatic castration resistant prostate cancer (mCRPC)) will have longitudinal imaging performed prior to treatment outside of this study, 8 weeks following initiation of treatment outside of this study, and at the time of disease progression by Prostate Cancer Working Group 3 (PCWG3) criteria.
干预措施: Copper-64 labeled Granzyme B (64Cu-GRIP B) (Drug)
Cohort C: 64Cu-GRIP B, mCRPC participants
Participants with metastatic castration resistant prostate cancer (mCRPC)) will have longitudinal imaging performed prior to treatment outside of this study, 8 weeks following initiation of treatment outside of this study, and at the time of disease progression by Prostate Cancer Working Group 3 (PCWG3) criteria.
干预措施: Positron Emission Tomography (PET) (Procedure)
Cohort D: 64Cu-GRIP B, Advanced malignancies
participants with solid tumor malignancies will have longitudinal imaging performed prior to treatment outside of this study, 8 weeks following initiation of treatment, and the opportunity to have an optional scan at the time of progression.
干预措施: Copper-64 labeled Granzyme B (64Cu-GRIP B) (Drug)
Cohort D: 64Cu-GRIP B, Advanced malignancies
participants with solid tumor malignancies will have longitudinal imaging performed prior to treatment outside of this study, 8 weeks following initiation of treatment, and the opportunity to have an optional scan at the time of progression.
干预措施: Positron Emission Tomography (PET) (Procedure)
结局指标
主要结局
Change in SUVmax (Cohorts B, C, and D)
时间窗: Up to 8 weeks
For Cohorts B, C and D, descriptive statistics will be used to summarize the change in SUVmax from baseline to 8 weeks at lesion level for participants in Cohorts B \& C.
Frequency of treatment-emergent adverse events (Cohort A)
时间窗: Up to 8 weeks
For Cohort A, the frequency and severity of adverse events following 64Cu-GRIP B injection will be descriptively reported, using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Apparent terminal elimination rate constant (Cohort A)
时间窗: Up to 8 weeks
PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the apparent terminal elimination rate constant.
Apparent terminal elimination half-life (Cohort A)
时间窗: Up to 8 weeks
PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute apparent terminal elimination half-life (t1/2; min).
Percent of injected activity (Cohort A)
时间窗: Up to 8 weeks
For Cohort A, the tracer kinetics is measured in the organs and total-body, and the % of injected activity for each time point will be recorded for participants in Cohort A. This information is used as input for organ and whole-body effective dose calculation using Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM). This will provide the data of whole-body effective dose (millisievert (mSv)/megabecquerels (MBq)), and organ doses.
Time to maximum observed concentration (Tmax) (Cohort A)
时间窗: Up to 8 weeks
Pharmacokinetic (PK) parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the time it takes for a drug to reach the maximum concentration (Cmax) after administration of a drug that needs to be absorbed.
Maximum observed concentration (Cmax) (Cohort A)
时间窗: Up to 8 weeks
PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the maximum concentration (Cmax) after administration of a drug that needs to be absorbed.
Area under the concentration-time curve (AUC) (Cohort A)
时间窗: Up to 8 weeks
PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the area under the concentration-time curve (AUC) from hour 0 to the last measurable concentration (AUC0-t; min\*unit/mL)
AUC extrapolated to infinity (Cohort A)
时间窗: Up to 8 weeks
PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the AUC extrapolated to infinity (AUC0-∞; min\*unit/mL)
Median clearance (Cohort A)
时间窗: Up to 8 weeks
PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the volume of plasma which is completely cleared of a substance per minute (mL/min).
Change in SUVmax/SUVave (Cohorts B, C, and D)
时间窗: Up to 8 weeks
For Cohorts B, C and D, descriptive statistics will be used to summarize the change in the ratio of SUVmax/SUVave from baseline to 8 weeks at lesion level for participants in Cohorts B \& C.
次要结局
- Frequency of treatment-emergent adverse events (Cohorts B, C, and D)(Up to 8 weeks)
- Mean SUVmax in metastatic lesions by disease site (Cohorts B, C and D)(Up to 2 years)
- Association of baseline uptake with object response (ORR) (Cohorts B, C and D)(Up to 2 years)
- Association of baseline uptake with progression-free survival (PFS) (Cohorts B, C and D)(Up to 2 years)
- Association of baseline uptake with reported PSA50 response (Cohort C)(Up to 2 years)
- Percent of lesions detected for metastatic participants (Cohorts B, C and D)(Up to 8 weeks)
- Median change in SUVmax from baseline with reported immune-related adverse event (Cohort B)(Up to 2 years)
- Median change in SUVmax-ave from baseline with reported immune-related adverse event (Cohorts B)(Up to 2 years)
- Association of baseline uptake with reported immune-related adverse events (irAEs)(Cohorts B, C and D)(Up to 2 years)
研究者
Rahul Aggarwal
Principal Investigator
University of California, San Francisco