177Lu−J591 and 177Lu−PSMA−617 Combination for mCRPC
Märksõnad
Abstraktne
Kirjeldus
This is an open−label, single−center Phase I dose−escalation study designed to determine the dose−limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combination of 177Lu−J591 and 177Lu−PSMA−617 in a two−week dose−fractionation regimen. 177Lu−J591 will be given at a moderate dose previously demonstrated to be safe x2 infusions two weeks apart. For 177Lu−PSMA−617 the dose escalation will start at 3.7 GBq (100 mCi) and escalate in increments of 1.85 GBq (50 mCi) for each dose to a planned maximum of 9.25 GBq (250 mCi) x2 doses, 2 weeks apart. Should there be unacceptable toxicity at the initial dose level, we will de-escalate to dose level -1 (1.85 GBq / 50 mCi per dose). After the phase I study has established a MTD, the Phase II, single-arm trial will start.
Patients must have documented progressive metastatic CRPC disease based on Prostate Cancer Working Group 3 (PCWG3) criteria in order to be eligible for enrollment. Upon meeting the inclusion and exclusion criteria and signing the informed consent and HIPPA form, subjects will undergo the screening. As part of the screening, subjects will get a single dose of 68Ga−PSMA−HBED−CC and will have a PET/CT. Nuclear Medicine physician(s) will review the PET/CT scans to document PSMA expression at tumor site(s).
Subjects will have Lutetium−177 Planar/SPECT Imaging on Day 8 (±1 day) after the first dose of 177Lu−J591 + 177Lu−PSMA−617. Optimal images will be performed on selected consenting subjects between the initial treatment visit #1 on Day 1 and Day 4 and prior to treatment visit #2 on D15 ±1. Subjects will be closely monitored for AEs (weekly x2 weeks, then every 2 weeks for one month, at 8 and 12 weeks, and then every 4 weeks for next 3 months).
Upon completion of investigational treatment with dose−fractionation regimen of the combination of 177Lu−J591 + 177Lu−PSMA−617, subjects will undergo 68Ga−PSMA−HBED−CC injection and same day PET/CT at the end of study visit to document treatment response. Subsequently survival data and additional treatment(s) information will be captured from their routine Standard of care (SOC) visits.
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Kuupäevad
| Viimati kinnitatud: | 06/30/2020 |
| Esmalt esitatud: | 05/03/2018 |
| Hinnanguline registreerumine on esitatud: | 05/30/2018 |
| Esmalt postitatud: | 06/03/2018 |
| Viimane värskendus on esitatud: | 07/16/2020 |
| Viimati värskendus postitatud: | 07/20/2020 |
| Õppe tegelik alguskuupäev: | 04/17/2018 |
| Eeldatav esmane lõpetamise kuupäev: | 07/14/2020 |
| Eeldatav uuringu lõpetamise kuupäev: | 07/14/2020 |
Seisund või haigus
Sekkumine / ravi
Drug: All Subjects
Drug: All Subjects
Drug: All Subjects
Faas
Käerühmad
| Arm | Sekkumine / ravi |
|---|---|
| Experimental: All Subjects 177Lu−PSMA−617 [1.85 GBq (50 mCi) - 9.25 GBq (250 mCi)] x2 doses, 2 weeks apart (Treatment Visit #1 and #2), IV administration
177Lu−J591 [1.35 GBq/m2 or 36.5 mCi/m2] x2 doses, 2 weeks apart (Treatment Visit #1 and #2), IV administration
68Ga−PSMA−HBED−CC [185 ±74 MBq or 5 ±2 mCi] intravenous during screening and at 12 weeks (±1 week) with standard imaging | Drug: All Subjects [1.85 GBq (50 mCi) - 9.25 GBq (250 mCi)] |
Abikõlblikkuse kriteeriumid
| Õppimiseks sobivad vanused | 18 Years To 18 Years |
| Uuringuks kõlblikud sood | Male |
| Võtab vastu tervislikke vabatahtlikke | Jah |
| Kriteeriumid | Inclusion Criteria 1. Histologically or cytologically confirmed adenocarcinoma of prostate 2. Documented progressive metastatic CRPC based on Prostate Cancer Working Group 3 (PCWG3) criteria, which includes at least one of the following criteria: i. PSA progression ii. Objective radiographic progression in soft tissue iii. New bone lesions 3. ECOG performance status of 0−2 4. Have serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone bilateral orchiectomy. 5. Have previously been treated with at least one of the following: - Androgen receptor signaling inhibitor (such as enzalutamide) - CYP 17 inhibitor (such as abiraterone acetate) 6. Have previously received taxane chemotherapy, been determined to be ineligible for taxane chemotherapy by their physician, or refused taxane chemotherapy. 7. Age > 18 years 8. Patients must have normal organ and marrow function as defined below: - Absolute neutrophil count >2,000 cells/mm3 - Hemoglobin ≥9 g/dL - Platelet count >150,000 x 109/L - Serum creatinine <1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft−Gault - Serum total bilirubin<1.5 x ULN (unless due to Gilbert's syndrome in which case direct bilirubin must be normal) - Serum AST and ALT<1.5 x ULN in the absence of liver metastases; <3 x ULN if due to liver metastases (in both circumstances bilirubin must meet entry criteria) 9. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria 1. Implantation of investigational medical device ≤4 weeks of Treatment visit #1 (Day 1) or current enrollment in oncologic investigational drug or device study 2. Use of investigational drugs ≤4 weeks or <5 half−lives of Treatment visit # 1(Day 1) or current enrollment in investigational oncology drug or device study 3. Prior systemic beta−emitting bone−seeking radioisotopes 4. Known active brain metastases or leptomeningeal disease 5. History of deep vein thrombosis and/or pulmonary embolus within 1 month of Treatment visit #1 6. Other serious illness(es) involving the cardiac, respiratory, CNS, renal, hepatic or hematological organ systems which might preclude completion of this study or interfere with determination of causality of any adverse effects experienced in this study 7. Radiation therapy for treatment of PC ≤4 weeks of Treatment visit #1 8. Patients on stable dose of bisphosphonates or denosumab, which have been started no less than 4 weeks prior to treatment start, may continue on this medication, however patients are not allowed to initiate bisphosphonate/Denosumab therapy during the DLT−assessment period of the study. 9. Having partners of childbearing potential and not willing to use a method of birth control deemed acceptable by the principle investigator and chairperson during the study and for 1 month after last study drug administration 10. Currently active other malignancy other than non−melanoma skin cancer. Patients are considered not to have "currently active" malignancy if they have completed any necessary therapy and are considered by their physician to be at less than 30% risk of relapse. 11. Known history of known myelodysplastic syndrome |
Tulemus
Esmased tulemusnäitajad
1. Dose limiting toxicity (DLT) of combination therapy in a 2−week dose−fractionation regimen [Approximately 3 months after enrollment]
2. Cumulative maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of combination therapy in a 2−week dose−fractionation regimen [Approximately 3 months after enrollment]
3. The proportion with PSA decline following the dose−fractionated combination therapy by comparing the change in PSA levels after therapy to the baseline, pre−treatment PSA. [At baseline and at 2 weeks on therapy]
Sekundaarsed tulemusmõõdud
1. Radiographic response rate by RECIST 1.1 with PCWG3 modifications [At the efficacy (scan) visit time point (12 weeks)]
2. Biomedical progression−free survival by PCWG3 criteria [At the efficacy (scan) visit time point (12 weeks)]
3. Radiographic progression−free survival by PCWG3 criteria [At the efficacy (scan) visit time point (12 weeks)]
4. Overall survival following treatment with the combination of 177Lu−J591 and 177Lu−PSMA−617 in a 2−week dose−fractionation regimen [Approximately 3 months after enrollment until study completion, approximately 36 months, or death]
5. Safety of treatment with the combination of 177Lu−J591 and 177Lu−PSMA−617 in a 2−week dose−fractionation regimen as assessed by CTCAE 4.0 [Up to 6 months after first treatment]
6. Changes in CTC count as measured by CellSearch [At the efficacy (scan) visit time point (12 weeks)]
7. Rate of favorable CTC count as measured by Cell Search [At the efficacy (scan) visit time point (12 weeks)]
8. Rate of favorable LDH count [During treatment phase, then every 4 weeks until radiographic progression, assessed up to 6 months]
9. Patient reported outcomes using FACT−P [During treatment phase, then every 12 weeks until radiographic progression, assessed up to 6 months]
10. Patient reported outcome using the Brief Pain Inventory short form [During treatment phase, then every 12 weeks until radiographic progression, assessed up to 6 months]
Muud tulemusmeetmed
1. Disease assessment with PSMA−ligand based imaging prior to and following investigational treatment [Up to 12 weeks]
2. Immune effects of PSMA−targeted radionuclide therapy [Up to 12 weeks]
3. Genomic DNA repair pathways in relationship to outcome following treatment with the combination of 177Lu−J591 and 177Lu−PSMA−617 in a 2−week dose−fractionation regimen [Up to 12 weeks]
4. Whole body distribution of combination therapy [Up to 12 weeks]
5. Radiation dosimetry of combination therapy [Up to 12 weeks]
