Phase I/II Dose−Escalation Trial of Combination Fractionated-dose 177Lu−J591 and 177Lu−PSMA−617 in Patients With Metastatic Castration−Resistant Prostate Cancer


Condition: Prostate Cancer

Intervention:

  • Drug: 177Lu−PSMA−617
  • Drug: 177Lu−J591
  • Drug: 68Ga−PSMA−HBED−CC

Purpose: Phase I dose escalation study with combination of 177Lu−J591 and 177Lu−PSMA−617 using a dose-fractionated regimen will be performed in patients with documented progressive metastatic CRPC. The cumulative 177Lu−J591 dose for each subject will be 2.7 GBq/m2 (73 mCi/m2) of 177Lu with 20 mg J591 and the cumulative 177Lu−PSMA−617 dose for each subject will vary (depending on the Cohort) from 3.7 GBq (100 mCi) to 18.5 GBq (500 mCi). The 177Lu−PSMA−617 dose will be escalated in up to 6 different dose levels (3+3 dose−escalation study / de-escalation design). For the phase II portion, a minimum number of 14 patients will be enrolled at MTD (including those enrolled at MTD in Phase I) and a maximum of 24.

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03545165

Sponsor: Weill Medical College of Cornell University

Primary Outcome Measures:

  • Measure: Dose limiting toxicity (DLT) of combination therapy in a 2−week dose−fractionation regimen
  • Time Frame: Approximately 3 months after enrollment
  • Safety Issue:
  • Measure: Cumulative maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of combination therapy in a 2−week dose−fractionation regimen
  • Time Frame: Approximately 3 months after enrollment
  • Safety Issue:
  • Measure: 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.
  • Time Frame: At baseline and at 2 weeks on therapy
  • Safety Issue:

Secondary Outcome Measures:

  • Measure: Radiographic response rate by RECIST 1.1 with PCWG3 modifications
  • Time Frame: At the efficacy (scan) visit time point (12 weeks)
  • Safety Issue:
  • Measure: Biomedical progression−free survival by PCWG3 criteria
  • Time Frame: At the efficacy (scan) visit time point (12 weeks)
  • Safety Issue:
  • Measure: Radiographic progression−free survival by PCWG3 criteria
  • Time Frame: At the efficacy (scan) visit time point (12 weeks)
  • Safety Issue:
  • Measure: Overall survival following treatment with the combination of 177Lu−J591 and 177Lu−PSMA−617 in a 2−week dose−fractionation regimen
  • Time Frame: Approximately 3 months after enrollment until study completion, approximately 36 months, or death
  • Safety Issue:
  • Measure: 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
  • Time Frame: Up to 6 months after first treatment
  • Safety Issue:
  • Measure: Changes in CTC count as measured by CellSearch
  • Time Frame: At the efficacy (scan) visit time point (12 weeks)
  • Safety Issue:
  • Measure: Rate of favorable CTC count as measured by Cell Search
  • Time Frame: At the efficacy (scan) visit time point (12 weeks)
  • Safety Issue:
  • Measure: Rate of favorable LDH count
  • Time Frame: During treatment phase, then every 4 weeks until radiographic progression, assessed up to 6 months
  • Safety Issue:
  • Measure: Patient reported outcomes using FACT−P
  • Time Frame: During treatment phase, then every 12 weeks until radiographic progression, assessed up to 6 months
  • Safety Issue:
  • Measure: Patient reported outcome using the Brief Pain Inventory short form
  • Time Frame: During treatment phase, then every 12 weeks until radiographic progression, assessed up to 6 months
  • Safety Issue:

Estimated Enrollment: 48

Study Start Date: April 18, 2018

Phase: Phase 1/Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

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

Contact:

  • GUONC Research Team
  • 212-746-7851

Location:

  • Weill Cornell Medical College
  • New York New York 10021 United States

View trial on ClinicalTrials.gov