A study in men with advanced prostate cancer to determine the safety and effects of a test drug (Lutetium (177Lu) rhPSMA 10.1 injection)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Blue Earth Therapeutics Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Feb 2024 → ongoing

Decision date (initial)

2024-07-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Blue Earth Therapeutics Limited

External identifiers

EU CT number

2024-511537-35-00

EudraCT number

2022-002407-37

WHO UTN

U1111-1314-4775

ClinicalTrials.gov

NCT05413850

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

The primary objective in Phase 1 of the study is to establish the RP2D regimen by evaluation of the safety and tolerability of IV administration of Lutetium (177Lu) rhPSMA-10.1 Injection in subjects with mCRPC.
The primary objective in Phase 2 of the study is to evaluate the efficacy of Lutetium (177Lu) rhPSMA-10.1 Injection.

Secondary objectives 7

1. Phase 1: 1. To determine the whole-body radiation dosimetry and pharmacokinetics of Lutetium (177Lu) rhPSMA-10.1 Injection.
2. Phase 1: 2. To determine the organ-specific radiation dosimetry of Lutetium (177Lu) rhPSMA-10.1 Injection (organ exposure to radiation) after each administration.
3. Phase 1: 3. To describe observed anti-tumour activity of Lutetium (177Lu) rhPSMA-10.1 Injection.
4. Phase 2: 1. To evaluate the efficacy of Lutetium (177Lu) rhPSMA-10.1 Injection.
5. Phase 2: 2. To further evaluate the safety profile of Lutetium (177Lu) rhPSMA-10.1 Injection using the dosing regimen (RP2D) recommended by the Phase 1 results.
6. Phase 2: 3. To further characterise the whole-body distribution and dosimetry of Lutetium (177Lu) rhPSMA-10.1 Injection.
7. Phase 2: 4. To describe the influence of Lutetium (177Lu) rhPSMA-10.1 Injection on the health-related quality of life (HRQoL) of treated subjects using Functional Assessment of Cancer Therapy – Prostate (FACT-P).

Conditions and MedDRA coding

Metastatic castration-resistant prostate cancer (mCRPC)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 01. Male subjects, 18 years of age or older.
2. 12. Adequate bone marrow reserve and organ function as demonstrated by blood count, and serum biochemistry at baseline: For Phase 1 only: • Platelet count ≥150 × 10^9/L • White blood cell (WBC) count ≥3.0 × 10^9/L • Neutrophil count of ≥1.5 × 10^9/L • Haemoglobin ≥10 g/dL • Estimated glomerular filtration rate (using Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation [2009]) (Levey 2009) ≥60 mL/min • Total bilirubin <1.5× ULN (except if confirmed history of Gilbert's disease) • Serum albumin ≥30 g/L • AST <2× the ULN • ALT <2× the ULN For Phase 2 only: Bone marrow reserve: • Platelet count ≥150 × 10^9/L • WBC count ≥3.0 × 10^9/L • Neutrophil count of ≥1.5 × 10^9/L • Haemoglobin ≥9 g/dL Renal: • Estimated glomerular filtration rate (using Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation [2009]) (Levey 2009) ≥60 mL/min Hepatic: • Total bilirubin <2 × the institutional ULN. For subjects with known Gilbert's Syndrome, ≤3 × ULN is permitted • AST <3 × the ULN (<5 × ULN in the presence of confirmed liver metastasis) • ALT <3 × the ULN (<5 × the ULN in the presence of confirmed liver metastasis) • Serum albumin ≥30 g/L
3. 13. Male subjects must not father children or donate sperm during the study and for at least 6 months after the last study treatment. In addition, they must agree to use condoms and highly effective contraception for this same period to protect partners from any exposure to the IMP. For fertile males with partners who are women of childbearing potential, highly effective contraception should be used during the study and for at least 6 months after the last study treatment. Highly effective methods of contraception include: • combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) • progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) • intrauterine device • intrauterine hormone-releasing system • bilateral tubal occlusion • vasectomised partner • sexual abstinence, only where this is the preferred and usual lifestyle of the subject. A woman is considered of childbearing potential i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A man is only considered to be infertile if he has had bilateral orchidectomy or successful vasectomy with laboratory confirmed aspermia.
4. 02. Willing to provide signed and dated written informed consent form (ICF) prior to any study-specific procedures.
5. 03. Willing to comply with required lifestyle restrictions following administration of the IMP per local regulations.
6. 04. Histologically confirmed adenocarcinoma of the prostate.
7. 05. Serum testosterone levels <50 ng/dL (1.73 nmol/L) after surgical or continued chemical castration. Note: If a sample has been taken within the last 3 months before the screening date and there has been no change to medication it can be used to confirm eligibility.
8. 06. Presence of disease target or non-target lesions (per RECIST v1.1) on CT/MRI and/or Presence of disease on full body 99mTc bone scan. Note: Imaging scans obtained no more than 28 days prior to informed consent may be used to determine imaging eligibility, if available for submission to the central reader
9. 07. Positive disease expression of PSMA as confirmed on PSMA PET/CT scan. Note: For Phase 1 only: Positive disease is defined as having at least 1 PSMA-positive lesion of any size with higher uptake than normal liver using visual assessment. The lesion can be bone, lymph node or viscera. At least one PSMA-positive lesion should be visible on the CT/MRI and ≥1.5 cm in the short axis. Further details regarding the interpretation of the diagnostic images can be found in the Image Acquisition Guidelines. For Phase 2 only: Positive disease is defined as: • Having at least 1 PSMA-positive lesion of any size with a higher uptake than normal parotid using visual assessment. The lesion can be bone, lymph node or viscera, and • Having the majority of PSMA-expressing disease with equivalent or higher uptake than normal liver using visual assessment. PSMA PET/CT scans obtained no more than 28 days prior to informed consent may be used to determine PSMA eligibility, if available for submission to the central reader. Further details regarding this inclusion criterion can be found in the Image Review Charter.
10. 08. At least 28 days or 5 half-lives (whichever is longer) elapsed between last anti-cancer treatment administration and the initiation of study treatment (except for Luteinising Hormone-releasing Hormone or GnRH).
11. 09. 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).
12. 10. Prior major surgery must be at least 12 weeks prior to study entry.
13. 11. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with a life expectancy ≥6 months.
14. 14. Study phase-specific inclusion criteria: a) For Phase 1 mCRPC only: Subjects who have experienced disease progression on or after at least 1 NAAD (e.g. abiraterone, enzalutamide) and at least 1 course (but no more than 2 courses) of taxane-based chemotherapy. b) For Phase 2 mCRPC only: Subjects who have experienced disease progression on or after at least 1 NAAD (e.g. abiraterone, enzalutamide, apalutamide, darolutamide), but have not received previous taxane-based chemotherapy for the treatment of mCRPC. • Prior NAAD can be given as part of doublet or triplet therapy during treatment for metastatic hormone sensitive prostate cancer, or during the castrate resistant phase of disease. • Prior chemotherapy as part of the treatment of metastatic hormone sensitive disease is permitted. • Prior first-generation androgen receptor inhibitors (i.e. bicalutamide) are permitted but do not count as prior NAAD for eligibility in this trial. Notes: Subjects must have progressive mCRPC. Disease progression is defined by the “criteria for progression at trial entry” (Table 3 in PCWG3 guidelines; Scher 2016; Appendix 2 to protocol). Taxane exposure is defined as a minimum of 2 cycles.

Exclusion criteria 20

1. 01. Known hypersensitivity to the therapeutic IMP, PSMA PET/CT tracer, or diagnostic IMP (for Phase 1 only) or any of its constituents.
2. 02. Presence of PSMA-negative disease: Note: For Phase 1 only: defined as any large PSMA-negative lymph node >1 cm in the short axis and/or a PSMA-negative bone metastasis which has a significant soft tissue component suggesting ongoing disease activity and/or a PSMA-negative solid organ metastasis >1 cm in the long axis. In addition, subjects with significant low PSMA-expressing disease should be excluded. Further details are provided in the Image Acquisition Guidelines. For Phase 2 only: defined as any large PSMA- negative lymph node >2.5 cm in the short axis and/or a PSMA negative bone metastasis which has a significant soft tissue component suggesting ongoing disease activity and/or a PSMA-negative solid organ metastasis >1 cm in the long axis. Further details are provided in the Image Review Charter.
3. 03. Diffuse marrow infiltration of disease (‘superscan’ appearance on full body 99mTc bone scan). A superscan is defined as bone scintigraphy in which there is excessive skeletal radioisotope uptake in relation to soft tissues along with absent or faint activity in the genitourinary tract and soft tissues due to diffuse bone/bone marrow metastases.
4. 04. Symptomatic spinal cord compression, or clinical or radiological findings that are indicative of impending spinal cord compression.
5. 05. Known history of haematological malignancy.
6. 06. Known history of central nervous system (CNS) metastases. Exception: Subjects with a history of CNS metastases who have received and completed therapy (e.g. surgery, radiotherapy), and are neurologically stable, asymptomatic and do not require corticosteroids or anti-convulsants to control neurological symptoms will be eligible. Discrete dural metastases are permitted but diffuse leptomeningeal disease is not. For subjects with a history of CNS metastases, baseline imaging and subsequent radiological imaging for assessing treatment response must include MRI or ceCT evaluation of the brain.
7. 07. Histological findings consistent with neuroendocrine phenotype of prostate cancer.
8. 08. Known history of other solid malignancy that may reduce life expectancy and/or may interfere with disease assessment. Exception: Subjects with histopathologically confirmed prior malignancy that has been treated, and who have been disease-free for >3 years. Subjects with treated non-melanoma skin cancer and non-muscle invasive bladder cancer will be eligible.
9. 09. Unresolved urinary tract obstruction defined as radiographic evidence of hydronephrosis with or without ureteric stent/nephrostomy. Where the clinical team judges that the subject’s hydronephrosis is not obstructing, and renal function meets the inclusion criteria, the subject may undergo 99mTc mercaptoacetyltriglycerine scanning during the screening period and if the result is non-obstructed, the subject can be eligible for the study.
10. 10. Any uncontrolled significant medical, psychiatric, or surgical condition or laboratory finding that would pose a risk to subject safety or interfere with study participation or interpretation of individual subject results. For cardiac conditions, this includes, but is not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, and myocardial infarction diagnosed within 6 months prior to enrolment.
11. 11. Ongoing treatment with bisphosphonates for bone-targeted therapy. Exception: Subjects will be eligible if they have received a stable dose of bisphosphonates for at least 6 weeks prior to enrolment. These subjects must have had renal function monitored since initiation of bisphosphonate therapy, with a stable pattern observed, and must have an estimated glomerular filtration rate ≥ 60 mL/min.
12. 12. Severe urinary incontinence that would preclude safe disposal of radioactive urine.
13. 13. Single kidney, renal transplant, or any concomitant nephrotoxic therapy, that in the judgement of the investigator might put the subject at high risk of renal toxicity during the study.
14. 14. Based on the judgement of the investigator, clinically significant abnormalities on a single 12-lead electrocardiogram (ECG) at screening.
15. 15. Previously received external beam irradiation to a field that includes more than 30% of the bone marrow or kidneys.
16. 16. Sponsor employees or investigator site personnel directly affiliated with this study, and their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
17. 17. Previous treatment with any of the following: PSMA-targeted radionuclide therapy, Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation.
18. 18. Subjects with bilateral hip replacements or any significant metallic implants or objects, which may in the opinion of the investigator, affect image quality and/or dosimetry calculations (for Phase 1 only).
19. 19. Transfusion of blood products for the sole purpose of meeting the eligibility criteria for this clinical study.
20. 20. Participation in other studies involving IMP(s) within 28 days or 5 half-lives (whichever is longer) prior to study entry and/or during study participation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Phase 1: 1. Incidence of DLTs during the DLT observation period. The definition of DLTs in this study is described in protocol section 4.1.1.4.
2. Phase 1: 2. Frequency and nature of treatment-emergent adverse events (TEAEs).
3. Phase 2: The number of subjects with an anti-tumour response defined as a ≥50% reduction in PSA level from baseline to the End of Treatment (EoT).

Secondary endpoints 28

1. Phase 1: 1. Terminal half-life of activity concentrations in blood.
2. Phase 1: 2. Specific whole-body absorbed dose (Gy/GBq), specific absorbed dose to the tumour lesions (Gy/GBq), specific absorbed dose per organ (Gy/GBq) and cumulative absorbed organ and whole-body absorbed doses (Gy).
3. Phase 1: 3. Number of subjects with ≥50% reduction in PSA level from baseline at 12 weeks after first therapeutic IMP administration.
4. Phase 1: 4. Number of subjects with best response in PSA level ≥50% from baseline to the end of the dosing period.
5. Phase 1: 5. PSA Progression-free survival (PFS): Time interval from first cycle of therapeutic IMP administration to PSA progression as defined by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria, or death, whichever comes first.
6. Phase 1: 6. Number of subjects who remain PSA progression-free at fixed 6-month intervals throughout the study.
7. Phase 1: 7. Duration of response as defined by time interval from achieving a ≥50% reduction in PSA compared to baseline to the PSA returning to baseline or evidence of radiological progression, as defined by PCWG3, or death.
8. Phase 1: 8. Radiographic PFS (rPFS): Time interval from first therapeutic IMP administration to the date when the first site of disease is found to progress radiographically, or death, whichever occurs first, as defined by PCWG3.
9. Phase 1: 9. Number of subjects who remain radiographic progression-free at fixed 6-month intervals throughout the study.
10. Phase 1: 10. Number of subjects with confirmed complete response (CR) or partial response (PR) based on PCWG3-recommended application of the Response Evaluation Criteria in Solid Tumours v1.1 (RECIST v1.1) criteria.
11. Phase 1: 11. Evaluation of PSMA PET/CT defined disease response after 2 treatment cycles.
12. Phase 1: 12. Overall survival at fixed 6 month intervals throughout the study.
13. Phase 1: 13. Time to PSA progression: Time interval from first cycle of therapeutic IMP administration to PSA progression as defined by the PCWG3 criteria.
14. Phase 1: 14. Time to radiographic progression: Time interval from first therapeutic IMP administration to the date when the first site of disease is found to progress radiographically as defined by PCWG3.
15. Phase 2: 1. Number of subjects with ≥50% reduction in PSA level from baseline at 12 weeks after first IMP administration.
16. Phase 2: 2. PSA PFS: Time interval from first cycle of IMP administration to PSA progression as defined by PCWG3 criteria, or death.
17. Phase 2: 3. Number of subjects who remain PSA progression-free at fixed 6-month intervals throughout the study.
18. Phase 2: 4. Duration of response as defined by time interval from achieving a ≥50% reduction in PSA compared to baseline to the PSA returning to baseline or evidence of radiological progression, as defined by PCWG3.
19. Phase 2: 5. Radiographic PFS: Time interval from first cycle of IMP administration to the date when the first site of disease is found to progress radiographically, or death, whichever occurs first, as defined by PCWG3.
20. Phase 2: 6. Number of subjects who remain radiographic progression-free at fixed 6-month intervals throughout the study.
21. Phase 2: 7. Number of subjects with confirmed CR or PR based on PCWG3-recommended application of RECIST v1.1.
22. Phase 2: 8. Overall survival, defined as the time interval from first cycle of IMP administration to death.
23. Phase 2: 9. Overall survival at fixed 6-month intervals throughout the study.
24. Phase 2: 10. Time to PSA progression: Time interval from first cycle of IMP administration to PSA progression as defined by PCWG3 criteria.
25. Phase 2: 11. Time to radiographic progression: Time interval from first cycle of IMP administration to the date when the first site of disease is found to progress radiographically as defined by PCWG3.
26. Phase 2: 12. Frequency and nature of TEAEs.
27. Phase 2: 13. Specific absorbed dose to the tumour lesions (Gy/GBq), specific absorbed dose per organ (Gy/GBq).
28. Phase 2: 14. Changes in patient-reported outcomes (PROs) assessed by FACT-P. The PROs will be measured from baseline up to the EoT: • Change from baseline in FACT-P total score. • Proportion of subjects with improvement or worsening in the FACT-P total score and subscales. • Time to worsening in the FACT-P total score and subscales, defined as the time from first cycle of IMP administration to worsening, clinical progression, or death, whichever occurs first.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Blue Earth Therapeutics Limited

Sponsor organisation

Blue Earth Therapeutics Limited

Address

The Oxford Science Park, Magdalen Centre, 1 Robert Robinson Avenue Magdalen Centre 1 Robert Robinson Avenue

City

Oxford

Postcode

OX4 4GA

Country

United Kingdom

Scientific contact point

Organisation

Blue Earth Therapeutics Limited

Contact name

Study Manager

Public contact point

Organisation

Blue Earth Therapeutics Limited

Contact name

Study Manager

Third parties 6

Locations

3 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 27 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications