A Phase 1 Open-label, Dose-finding Multi-center Trial of [177Lu]Ludotadipep in Metastatic Castration-resistant Prostate Cancer Patients, Followed by an Open-label, Repeat Dose, Multi-center Phase 2a Trial to Assess Safety and Efficacy
Overview
- Phase
- Phase 1
- Intervention
- [177Lu]Ludotadipep 3.7 GBq
- Conditions
- Metastatic Castration-resistant Prostate Cancer
- Sponsor
- FutureChem
- Enrollment
- 26
- Locations
- 4
- Primary Endpoint
- Dose Limiting Toxicities (DLT) with a single fixed dose of [177Lu]Ludotadipep during the first cycle (8 [±1] weeks) (Phase 1)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
Phase 1: The objective of the Phase 1 part of the clinical trial is to verify safety and tolerability (dose-limiting toxicity [DLT], maximum tolerated dose [MTD]) of a single 3.7 Giga-Becquerel (GBq) dose with the potential for one dose level de-escalation to 2.775 GBq if necessary, to determine the recommended [177Lu]Ludotadipep dose for use in the Phase 2a part of the trial.
Phase 2a: The objective of the Phase 2a part of the trial is to evaluate safety and efficacy for repeated administration of the recommended [177Lu]Ludotadipep dose. The Recommended Phase 2 dose (RP2D) will be based on the study results from the Phase 1 trial in South Korea upon consultation with the FDA.
Detailed Description
Phase 1: The patient will attend a Screening visit (-28 to -1 days) prior to study treatment, where it will be determined if the patient is eligible to, and consents to, participate in the trial based on the inclusion/exclusion criteria. \[Ga-68\]PSMA-11 positron emission tomography (PET)/CT scan will be performed at screening. Patients who are finally registered for trial participation will be injected with a single dose of \[177Lu\]Ludotadipep. Ice packs and other cooling therapies will be applied to the major salivary glands from 30 minutes before the administration of \[177Lu\]Ludotadipep to 60 minutes after the administration to prevent side effects such as sialadenitis. Amino acid solution will be administered slowly intravenously for renal protection over approximately 4 hours from 30 minutes before treatment to 3.5 hours after treatment. 500 mL of 0.9% sodium chloride (NaCl) will be administered slowly intravenously for hydration over approximately 90 minutes from 30 minutes before treatment to 60 minutes after treatment. Adverse events and DLTs will be assessed continuously for the duration of the 8 \[±1\] week study period. Other measurements, corresponding to secondary outcomes, are detailed in the Schedule of Assessments and include concomitant medications, laboratory tests, physical examination, vital signs, Eastern cooperative oncology group performance status (ECOG PS), imaging (positron emission tomography-computed tomography \[PET/CT\], bone scan and Whole Body Scan (WBS)). Follow-up will occur at scheduled visits 1, 2, 4 and 8 weeks after investigational product (IP) administration. Patients who show a clinical response and who the PI considers will likely benefit from retreatment can be so treated after consultation and agreement of the medical monitor and the sponsor. Phase 2a: The patient will attend a Screening visit (-28 to -1 days) prior to treatment with IP, where it will be determined if the patient is eligible to, and consents to, participate in the trial based on the inclusion/exclusion criteria. \[Ga-68\]PSMA-11 PET/CT and \[F-18\]FDG-PET scans will be performed at screening. Patients who are finally registered for trial participation will be injected with a single dose of \[177Lu\]Ludotadipep. Ice packs and other cooling therapies will be applied to the major salivary glands 30 minutes before and up to 60 minutes after the administration of \[177Lu\]Ludotadipep to prevent side effects such as sialadenitis. Amino acid solution will be administered slowly intravenously for renal protection over approximately 4 hours from 30 minutes before treatment to 3.5 hours after treatment. 500 mL of 0.9% NaCl will be administered slowly intravenously for hydration over approximately 90 minutes from 30 minutes before treatment to 60 minutes after treatment. WBS or single photon emission computed tomography (SPECT) images will be obtained 24 hours after each administration and Day 7, and AE information will also be captured. Other measurements are detailed in the Schedule of Assessments. Patients will receive \[177Lu\]Ludotadipep every 8 \[±1\] weeks (4 to 6 times). Patients will be contacted by phone 2 weeks after the first administration for a safety check-up. Four and six weeks after each administration the patient will attend the clinic for a follow-up visit. The following assessments will be performed: * PSA and other laboratory blood tests (4 and 6 weeks) * AEs (4 and 6 weeks) * Urinalysis, physical examination, vital signs, ECOG PS, EORTC QLQ-C30 and Pain Response questionnaires (4 weeks only) The decision on whether to proceed with additional administrations will be determined every 6 weeks after administration of the IP, based on investigator's assessment of tolerability. If a patient does not progress to the next dose administration at 8 weeks, a PSA blood sample will be taken. A tumor response assessment by CT and bone scan, and additional \[Ga-68\]PSMA-11 PET/CT and FDG-PET scans will be conducted at end of treatment (EOT). All follow up assessments are detailed in the Schedule of Assessments. All patients will have long term follow-up every 6 months for 2 years after the last dose of IP unless there is death, withdrawal of consent, or loss to follow-up. Patients who are alive at \>2 years after the last dose of IP, unless there is death, withdrawal of consent, or loss to follow-up will be offered participation in a long-term follow-up protocol for up to 10 years. In the long-term survival follow-up, the long-term outcome of the known serious risk of myelosuppression, renal failure, xerostomia, xerophthalmia, and their complications; the potential serious signals of secondary malignancies including myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML); and other serious adverse reactions, will be monitored.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must meet the following criteria in order to be included in both the Phase 1 and Phase 2a parts of the trial:
- •Male and ≥ 18 years
- •Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features at initial diagnosis
- •Disease progression on any one of the following: prior enzalutamide, abiraterone, apalutamide or related agent therapy as defined by meeting at least one of the following criteria per the investigator in accordance with the Prostate Cancer Working Group 3 (PCWG3) criteria \[Scher et al, 2016\]:
- •PSA progression as defined by a minimum of two rising PSA levels at least 1 week apart, ideally three successive measurements
- •Soft tissue disease progression defined as \>20% increase in sum of diameters of all target lesions based on sum of diameters since treatment started or the appearance of 1 or more new lesions by RECIST 1.1
- •Bone disease progression defined by two or more new lesions on bone scan
- •Serum testosterone level \< 50 ng/dL (\< 0.5 ng/mL, \< 1.7 nmol/L). Patients may have ongoing androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) "super-agonist" or antagonist, and/or be surgically or medically castrated.
- •Patients must have PSMA positive lesions. These are defined as having Ga 68-PSMA-11 uptake greater than that of liver parenchyma in one or more metastatic lesions of any size in any organ system. PSMA-negative lesions are defined as having PSMA uptake equal to or lower than that of liver parenchyma in any lymph node with a short axis of at least 2.5 cm, in any metastatic solid-organ lesions with a short axis of at least 1.0 cm, or in any metastatic bone lesion with a soft-tissue component of at least 1.0 cm in the short axis.
- •Patients receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to Day 1
Exclusion Criteria
- •Patients will be excluded from the study if they meet any of the following criteria (applies to both Phase 1 and Phase 2a):
- •Impaired organ function as evidenced by the following laboratory values at Screening:
- •Absolute neutrophil count \< 1500/μL
- •Platelet count \< 100,000/μL
- •Hemoglobin \< 9.0 g/dL Note: the patient cannot have received blood transfusion or growth factor support in the 2 weeks prior to screening laboratory hematology assessments.
- •Albumin \< 3.0 g/dL (30 g/L)
- •Total bilirubin \> 2 x upper limit of normal (ULN) unless in instances of known or suspected Gilbert's disease
- •aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 x ULN
- •Calculated creatinine clearance \< 60 mL/min (Cockroft-Gault equation), or currently on renal dialysis
- •QT interval corrected for heart rate (QTcF) \> 470 msec
Arms & Interventions
[177Lu]Ludotadipep 3.7 GBq
If investigators observed one or no DLT in 6 patients at the 3.7 GBq dose level, the study can advance to the Phase 2a part of the trial after the safety review committee (SRC) review.
Intervention: [177Lu]Ludotadipep 3.7 GBq
Outcomes
Primary Outcomes
Dose Limiting Toxicities (DLT) with a single fixed dose of [177Lu]Ludotadipep during the first cycle (8 [±1] weeks) (Phase 1)
Time Frame: Single dose and 8 weeks follow up (Screening up to 28 days)
Determination of Maximum Tolerated Dose (MTD)
Objective Response Rate (Phase 2a)
Time Frame: up to 40 weeks (4 to 6 doses at 8-weekly intervals [± 1 week], with 6 week follow-up after each dose (Screening up to 28 days)
Complete Response \[CR\] Rate + Partial Response \[PR\] Rate
Secondary Outcomes
- Safety assessments (Phase 1)(Single dose and 8 weeks follow up (Screening up to 28 days))
- Whole-body absorbed dose (Phase 1)(Single dose and 8 weeks follow up (Screening up to 28 days))
- Biodistribution: assessment of the absorption (uptake) into the blood, lungs, liver, spleen, pancreas, kidneys, muscle, stomach, and tumor based on the level obtained from whole body scan (WBS) 2 hours, 24 hours, 48 hours, and 7 days post-dose (Phase 1)(Single dose and 8 weeks follow up (Screening up to 28 days))
- Disease Control Rate (Phase 2a)(up to 40 weeks (4 to 6 doses at 8-weekly intervals [± 1 week], with 6 week follow-up after each dose (Screening up to 28 days))
- Safety assessments (Phase 2a)(up to 40 weeks (4 to 6 doses at 8-weekly intervals [± 1 week], with 6 week follow-up after each dose (Screening up to 28 days))
- Prostate Specific Antigen Response Rate (PSA RR) (Phase 2a)(up to 40 weeks (4 to 6 doses at 8-weekly intervals [± 1 week], with 6 week follow-up after each dose (Screening up to 28 days))
- Tumor response rate (Phase 2a)(up to 40 weeks (4 to 6 doses at 8-weekly intervals [± 1 week], with 6 week follow-up after each dose (Screening up to 28 days))
- Pain response rate (Phase 2a)(up to 40 weeks (4 to 6 doses at 8-weekly intervals [± 1 week], with 6 week follow-up after each dose (Screening up to 28 days))
- European Organization for Research and Treatment of Cancer quality of life (EORTC QLQ-C30) questionnaire (Phase 2a)(up to 40 weeks (4 to 6 doses at 8-weekly intervals [± 1 week], with 6 week follow-up after each dose (Screening up to 28 days))
- Time to death for any reason (Overall Survival [OS]) (Phase 2a)(up to 40 weeks (4 to 6 doses at 8-weekly intervals [± 1 week], with 6 week follow-up after each dose (Screening up to 28 days))