| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with PSMA positive Metastatic Castration-resistant Prostate Cancer (mCRPC), and disease progression following previous systemic treatment for mCRPC. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prostate cancer that has spread to other parts of the body despite therapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10036908 |
| E.1.2 | Term | Prostatic neoplasms malignant |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I:
Determine the MTD and RP2D for 177Lu-PSMA-R2
Phase II:
Assess anti-tumor response based on PSA levels |
|
| E.2.2 | Secondary objectives of the trial |
Phase I:
Secondary Objectives:
·Characterize the safety and tolerability of 177Lu-PSMA-R2
·Assess preliminary anti-tumor response based on RECIST v1.1
·Assess preliminary anti-tumor response based on PSA levels
·Assess the pharmacokinetic profile of 177Lu-PSMA-R2
·Assess organ and lesion radiation uptake by dosimetry
·Assess preliminary patient reported outcomes related to xerostomia, xerophthalmia and pain
Phase II:
Secondary Objectives:
·Continued characterizations of the safety and tolerability of 177Lu-PSMA-R2
·Assess the antitumor response per RECIST v1.1
·Evaluate the efficacy of 177Lu-PSMA-R2 on prostate-specific antigen (PSA) response rate
·Estimate rPFS
·Estimate OS
·Estimate time to PSA progression
·Assess change from baseline in patient reported outcomes related to xerostomia, xerophthalmia, pain, and quality of life.
For information on exploratory endpoints, please refer to protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male patients, 18 years of age or older
2. Signed and dated written ICF by the patient prior to any study-specific procedures.
3. Histologically confirmed adenocarcinoma of the prostate.
4. Serum testosterone levels < 50 ng/dL after surgical or continued chemical castration
5. Metastatic disease documented by CT/MRI or bone scan revealing at least one metastatic lymph-node, visceral metastasis and/or bone metastasis
6. Positive 68Ga-PSMA-R2 PET/CT scan for central eligibility assessment. This scan must not be older than 28 days at enrollment and demonstrate metastatic disease. Patients who receive 68Ga-PSMA-R2 as part of separate clinical protocol are eligible (must meet all study eligibility criteria)
7. Documented progressive mCRPC after the last prior systemic treatment administered for metastatic disease. Disease progression is defined as increasing serum PSA (per PCWG3), radiological progression or ≥ 2 new bone lesions.
8.Must have received prior systemic therapy for mCRPC with CYP 17 inhibitors and/or androgen-pathway inhibitors (i.e. abiraterone and/or enzalutamide when available).
9.Must have received one but no more than one line of chemotherapy for the advanced disease or patients who were ineligible (unfit or unwilling) to receive chemotherapy.
10. At least 28 days elapsed between last anti-cancer treatment administration and the initiation of study treatment (except for Luteinizing Hormone-releasing Hormone [LHRH] or Gonadotropin-releasing Hormone [GnRH]), or resolution of all previous treatment related toxicities to CTCAE version 5.0 grade of ≤ 1 (except for chemotherapy induced alopecia and grade 2 peripheral neuropathy or grade 2 urinary frequency which are allowed). Prior major surgery must be at least 12 weeks prior to study entry.
11. Eastern cooperative oncology group (ECOG) performance status of 0-2 with a life expectancy ≥ 6 months
12. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, and biochemistry in blood and urine at baseline
a. Platelet count of >100 x10^9/L
b. White blood cell (WBC) count > 3,000/mL
c. Neutrophil count of > 1,500/mL
d. Hemoglobin ≥ 10 g/dL
e. Serum creatinine < 1.5 x ULN or estimated GFR > 50 mL/min based upon Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Patients with estimated GFR between 50 - 60 mL/min at baseline will require a 99mTc-DTPA GFR test and only patients with non-obstructive pathology will be included in the study.
f. Total bilirubin < 3 x ULN (except if confirmed history of Gilbert’s disease)
g. Baseline serum albumin > 30 g/L
h. Aspartate aminotransferase (AST) < 3 times the ULN
13. For male patients with partners of childbearing potential, agreement to use barrier contraceptive method (condom) and to continue its use for 6 months from receiving the last dose of IMP. |
|
| E.4 | Principal exclusion criteria |
1. Pathological finding consistent with small cell, neuroendocrine carcinoma of the prostate, or any other histology different than adenocarcinoma.
2. Diffuse bone-marrow involvement (i.e. “superscan” defined as bone scintigraphy in which there is excessive skeletal radioisotope uptake [>20 bone lesions] in relation to soft tissues along with absent or faint activity in the genitourinary tract due to diffuse bone/ bone marrow metastases).
3. Prior exposure to radioligand therapy, radioisotope therapy (e.g. 89Sr), systemic radiotherapy, or 223Ra-therapy.
4. Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any level of urinary obstruction requiring indwelling/condom catheters
5. Spinal cord compression or brain metastases
6. Uncontrolled pain that results in patient lack of compliance with the imaging procedures
7. Uncontrolled cardiovascular history, defined as:
• Congestive heart failure (New York Heart Association [NYHA] II, III, IV)
• Mean resting corrected QT interval (QTc) >450 millisecond (msec), obtained from 3 ECGs recordings, using the screening clinic ECG machine-derived QTc value.
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec).
• Any factor increasing the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives, or any concomitant medication known to prolong the QT interval.
8. Other known co-existing malignancies except non-melanoma skin or low grade superficial bladder cancer unless definitively treated and proven no evidence of recurrence for 5 years.
9. History of deep vein thrombosis and/or pulmonary embolism within 4 weeks of enrollment.
10. Known incompatibility to CT or PET scans.
11. Any evidence of severe or uncontrolled systemic or psychiatric diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
12. Active infection including human immunodeficiency virus (HIV) and untreated hepatitis B, and hepatitis C. Screening for chronic conditions is not required.
13. Patients who have received any investigational agent within the last 28 days.
14. Known allergies, hypersensitivity, or intolerance to the IP or its excipients
15. Known history of myelodysplastic syndrome/leukemia at any time
16. Patient is unlikely to comply with study procedures, restrictions and requirements and judged by the Investigator that the patient is not suitable for participation in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I: Dose Escalation
Incidence of dose limiting toxicities during the first cycle of the study treatment
Phase II: Dose Expansion
1. PSA response rate 50 (reduction ≥50% in PSA level from baseline at12 weeks after the first 177Lu-PSMA-R2 administration) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I:
1. Every visit
Phase II:
1. Baseline + week 13 |
|
| E.5.2 | Secondary end point(s) |
Phase I: Dose Escalation
1. Treatment emergent Adverse-event (TEAE) rate
2. Objective response rate (ORR)
3 . Duration of response (DoR)
4. PSA response of 30% and 50% decrease from baseline
5. Plasma concentration of 177Lu-PSMA-R2 and PK parameters including but not limited to Cmax, Cmin, AUC
6. Radiation (Gy, Gy/MBq) uptake by critical organs and metastatic lesions
7. Assess PROs with the use of the following instruments
- Xerostomia questionnaire
- Xerophthalmia questionnaire
- Brief pain inventory
Phase II: Dose Expansion
1. Treatment Emergent Adverse Event (TEAE) rate
2. Disease control rate (DCR)
3. Objective response rate (ORR)
4. Duration of response (DoR)
5. PSA response rate 30 (reduction ≥30% in PSA level from baseline at 12 weeks after the first 177Lu-PSMA-R2 administration)
6. rPFS per PCa working group 3 (PCWG3)
7. OS
8. Time to PSA progression
9. Change from baseline in PRO score using the following instruments:
- Xerostomia questionnaire,
- Xerophthalmia questionnaire
- Brief pain inventory
- Quality of life questionnaire for cancer patients (QLQ-C30),
- Quality of life questionnaire for patients with prostate cancer (QLQ-PR25)
For information on exploratory endpoint, please refer to protocol |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I
1. q visit
2&3. Baseline then q 12 w
4. Baseline + w 7, 13, 19, 25 and q 12 w during f/u until documented per PCWG3
5. Only in 18-24 patients/ before infusion, mid-point, before end of infusion, post infusion at 5, 15, 30 min, 1, 2, 4, 6, 8, 24, 40, 48 h and d4 and d8
6. Baseline then q 12 w until disease progression per PCWG3 or for 1 y after EOT
7. D 1 and q 12 w until 1 y after documented per PCWG3 or early termination
Phase II
1. q visit
2&3&4. Baseline then q 12 w
5&8. Baseline then w 7, 13, 19, 25 and q 12 w during f/u until documented per PCWG3
6. q 12 w until disease progression per PCWG3 or for 1 y after EOT visit
7. EOT + 5 y f/u
9- D 1 and q 12 w until 1 y after documented per PCWG3 or early termination
For info on exploratory endpoints, refer to protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of Study is defined as the moment when 5 years have elapsed since the date last patient was enrolled, or the trial is closed due to other reasons by the sponsor. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 48 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 48 |
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