A Phase I/II Study of 177Lu-HTK03170 in Metastatic, Castration-Resistant Prostate Cancer Subjects With Prostate-specific Membrane Antigen-positive Disease
试验速览
- 阶段
- 1 期
- 状态
- Enrolling By Invitation
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- To measure the radiation dosimetry of 177Lu-HTK03170 in subjects who have PSMA-positive mCRPC (confirmed by PSMA PET/CT) previously treated with ARAT
研究概览
简要总结
This study will determine the safe initial injected activity of the radioligand therapy 177Lu-HTK03170 for the measurement of dosimetry and initiation of treatment in subjects with PSMA-positive, metastatic castrate resistant prostate cancer, (mCRPC). Subjects will receive treatment which will be escalated between cycles and personalized based on dosimetry calculations and imaging. In addition, antitumour activity will be measured by radiographic response, and further assessments of the treatment will be measured by CT imaging, ctDNA/ctRNA, PSA, PSMA PET/CT, and quality of life questionnaires. Subjects will be followed for 2 years or until they have progression and are switched to another systemic treatment.
详细描述
Overall, up to 50 subjects will be enrolled to receive an injected activity (IA) of 177Lu-HTK03170. The IA's will be escalated based on personalized dosimetry at subsequent treatments (up to 5 cycles total).
Screening Phase: Subjects will be screened against the inclusion and exclusion criteria. A PSMA PET/CT scan using 68Ga-HTK03149 will be used to confirm PSMA positive disease. Those with confirmed PSMA positive disease with continue to one of the two Treatment Phases. Subjects will be informed which Phase they will be enrolled in.
Subjects will undergo a physical exam, complete a medical history questionnaire, a quality of life questionnaire, blood work, and a diagnostic CT.
Treatment summary per Phase:
The first 3 subjects will receive an initial Initial Acitivity (IA) of 1.1 GBq of 177Lu HTK03170, for the first cycle of treatment, assuming no toxicities occur requiring dose modification. Dosimetry will be performed to obtain absorbed organ dose and effective dose values. The initial IA used for dosimetry will be escalated to improve image quality, radiation dosimetry estimates, and potential efficacy. IA escalation will only occur on the initial dosimetry IA, with an increase of 30% over the initial IA (used for dosimetry) at each subsequent level (1.65 GBq, 2.5 GBq, 3.7 GBq) in up to 12 participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Each subject must meet all of the following inclusion criteria to be enrolled in the study:
- •Male subjects ≥ 18 years of age
- •Willing and able to provide consent
- •Life expectancy of > 6 months
- •Progression on treatment with abiraterone and/or enzalutamide, or similar next generation ARAT therapy, as determined by the investigator. Subjects who have received docetaxel in the castration-resistant setting are also eligible to participate. Prior treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor is permitted.
- •Pathologically confirmed prostate adenocarcinoma
- •Subjects must have evidence of biochemical or imaging progression. Progression is defined as any one of the following:
- •Prostate-specific antigen progression: two consecutive rising PSA values from a baseline measurement with an interval of ≥ 1 week between measurements. Minimum PSA at screening visit is ≥ 2.0 µg/L.
- •Soft tissue disease progression on chest, abdomen, pelvis CT or magnetic resonance imaging (MRI; RECIST v1.1)
- •Bone progression: ≥ 2 new lesions on bone scan
- •Eastern Cooperative Oncology Group (ECOG) performance score ≤2
- •Prior orchiectomy, or if on luteinizing hormone releasing hormone (LHRH) agonist/antagonist, then testosterone < 1.7 nmol/L or < 50 ng/dL
- •Adequate organ function:
- •a) Marrow i) Absolute neutrophil count ≥ 1.5 × 109 /L ii) Platelet count ≥ 100 ×109 /L iii) Hemoglobin ≥ 90 g/L with no transfusions in the past 2 weeks b) Kidney i) Estimated creatinine clearance ≥40 ml/min according to Cockroft-Gault equation: ((140 - age) × (weight in kg)) / (72 × (serum creatinine)) c) Liver: i) Bilirubin < 1.0 × upper limit of normal (ULN) (or if bilirubin is between 1.5 to 2 × ULN, must have a normal conjugated bilirubin) ii) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN in the absence of liver metastases, and) ≤ 5.0 × ULN in the presence of liver metastases.
- •Recovery from all previous cancer treatment toxicities to grade ≤ 2 (as per CTCAE 4.03)
- •Able to comply with scheduled visits, treatment plans, laboratory tests, imaging tests, and other procedures required and detailed in the protocol.
- •Must be surgically sterile or use adequate contraception for the duration of the therapy and 6 months after the end of therapy
排除标准
- •Subjects meeting any of the following exclusion criteria are not to be enrolled in the study.
- •Prior treatment with 225Ac-PSMA-617, 177Lu-PSMA, other radiolabeled therapeutic PSMA-ligands, or radio-immunotherapy
- •Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or targeted therapy) within 28 days prior to day of enrollment
- •Radiotherapy to target lesions (measurable disease) ≤ 4 weeks prior to enrolment
- •Known parenchymal brain metastases
- •Active epidural disease (treated epidural disease is permitted)
- •History of risk factors for xerostomia (ie, head and neck radiation, Sjögren's disease) or pre-existing xerostomia Grade ≥1
- •Other concomitant active invasive cancer (except superficial non-melanomatous, non-metastatic skin cancer or non-invasive superficial transitional cell carcinoma [TCC])
- •Clinically significant cardiac disease including:
- •History of unstable angina pectoris, symptomatic pericarditis, or myocardial infarction within 6 months prior to study entry.
- •History of documented congestive heart failure (New York Heart Association [NYHA] functional classification III-IV) or cardiomyopathy.
- •Major surgery within 4 weeks of starting study treatment.
- •Unmanageable urinary tract obstruction or hydronephrosis
研究组 & 干预措施
177Lu HTK03170 Phase I/II
Phase I, the administered activity will be 1.1 GBq ± 10% as an intravenous infusion over a time of 10 to 30 minutes. Initial Activity (IA) escalation will only occur on the initial dosimetry IA, with an increase of 30% over the initial IA (used for dosimetry) at each subsequent level ( 1.65 GBq, 2.5 GBq, 3.7 GBq) in up to 12 participants. Personalized dosimetry will be calculated for each subject.
Phase II, subjects will be treated with an initial IA of 177Lu-HTK03170 at the MTIA as determined during Phase I or 13.7 GBq whichever is lower. Treatment is administered as an intravenous infusion over a time of 10 - 30 minutes. Personalized dosimetry will be calculated for each subject so that subsequent treatments will be estimated to remain within the absorbed cumulative dose limits of 28Gy and 35Gy for kidneys and salivary glands, adjusted iteratively over the 4 remaining treatment cycles separated by 8 weeks. Up to 32 subjects will be enrolled to continue efficacy evaluation.
干预措施: 177Lu HTK03170 (Drug)
177Lu HTK03170 Phase I/II
Phase I, the administered activity will be 1.1 GBq ± 10% as an intravenous infusion over a time of 10 to 30 minutes. Initial Activity (IA) escalation will only occur on the initial dosimetry IA, with an increase of 30% over the initial IA (used for dosimetry) at each subsequent level ( 1.65 GBq, 2.5 GBq, 3.7 GBq) in up to 12 participants. Personalized dosimetry will be calculated for each subject.
Phase II, subjects will be treated with an initial IA of 177Lu-HTK03170 at the MTIA as determined during Phase I or 13.7 GBq whichever is lower. Treatment is administered as an intravenous infusion over a time of 10 - 30 minutes. Personalized dosimetry will be calculated for each subject so that subsequent treatments will be estimated to remain within the absorbed cumulative dose limits of 28Gy and 35Gy for kidneys and salivary glands, adjusted iteratively over the 4 remaining treatment cycles separated by 8 weeks. Up to 32 subjects will be enrolled to continue efficacy evaluation.
干预措施: 68Ga-HTK03149 (Drug)
结局指标
主要结局
To measure the radiation dosimetry of 177Lu-HTK03170 in subjects who have PSMA-positive mCRPC (confirmed by PSMA PET/CT) previously treated with ARAT
时间窗: Within 8 weeks of treatments per cycle (cycle durations = 8 weeks)
Phase I: Absorbed doses to organs and tumors per unit of administered activity (Gy/MBq)
To determine the number of subjects with AEs, Grade 3 or above AEs, drug-related AEs, and SAEs, based on CTCAE v4.03.
时间窗: Within 8 weeks of treatments per cycle (cycle durations = 8 weeks)
Proportion and distribution of adverse events (AE) is done via the analysis of frequencies for treatment emergent Adverse Event and Serious Adverse Event through the monitoring of relevant clinical and laboratory safety parameters.
To determine the MTIA or a recommended safe initial IA of 177Lu-HTK03170 to measure dosimetry and initiate treatment
时间窗: Within 8 weeks of treatments per cycle (cycle durations = 8 weeks)
Phase I: Occurrence of dose limiting toxicity (DLT) per protocol
To determine the antitumour effect of 177Lu-HTK03170 therapy measured by radiographic ORR per RECIST v1.1 in subjects who have PSMA-positive mCRPC
时间窗: up to 24 months subsequent follow up evaluations
Proportion of subjects achieving a PR, or CR, based on RECIST v1.1
To determine the number of subjects with AEs leading to discontinuation
时间窗: up to 8 weeks post treatment cycle up to 14 weeks post cycle
Proportion of subjects who permanently discontinue 177Lu-HTK03170 due to toxicity or hypersensitivity
Determine the number of subjects with markedly abnormal laboratory tests (including ECG) at least once post-injection
时间窗: up to 8 weeks post treatment cycle
Analysis of the number of subjects with abnormal labs or ECG data parameters as determined by lab assessment reports and 12-lead electrocardiogram (ECG) reporting
次要结局
- Duration of PSA responses(From date of first documented PSA response till 4 weeks follow up, assessed up to 24 months post end of last cycle)
- Duration of radiographic response(From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 24 months from end of last cycle)
- Progression free survival at 6 months(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 6 months)
- Progression-free Survival (PFS)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 24 months post end of treatment cycle)
- Overall Response Rate (ORR)(at least 6 months subsequent follow-up evaluations)
- Percentage of Participants Achieving Prostate-specific Antigen (PSA) Response(from date of baseline assessment to at least 4 weeks post treatment cycle Within 8 weeks of treatments per cycle (cycle durations = 8 weeks))
- Time to First Symptomatic Skeletal Event (SSE)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 24 months post end of treatment cycle)
- Change From Baseline in the European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) Utility Score(Baseline (week 0), Cycle 3 (Day 1), Follow up (Day 84 of last treatment) (cycle duration for Cycle 1-5 = 8 weeks)