Clinical trial NCT04876651: The Present Study Aims to Compare Patients Who Receive the Investigational Product (177Lu-DOTA-rosopatamab) Plus Standard of Care, in Comparison to Standard of Care Only
Official title: A Multinational, Multicenter, Prospective, Randomized, Controlled, Open Label Phase 3 Study With Best Standard of Care With and Without 177Lu-DOTA-rosopatamab for Patients With PSMA Expressing Metastatic Castration-resistant Prostate Cancer Progressing Despite Prior Treatment With a Novel Androgen Axis Drug
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Metastatic Prostate Cancer
Keywords: prostate cancer
177Lu-DOTA-TLX591
progression free survival
overall survival
safety
gallium-68 labeled PSMA-11 (68Ga-PSMA-11) PET/CT Scan
novel androgen axis drug
Lead sponsor: Telix Pharmaceuticals (Innovations) Pty Limited
Sponsor class: INDUSTRY
First posted: 2021-05-06
Enrollment: 392
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Approximately 387 eligible patients will be randomized to one of two groups in a 2:1 ratio to receive one of the following treatments:

* Group A: Two single intravenous (IV) injections of 76 mCi each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA- rosopatamab, given 14 days apart, plus best SoC
* Group B: Best SoC.

Additionally, up to 10 patients, in New Zealand only, will be recruited for evaluation of biodistribution and dosimetry of 177Lu- DOTA-TLX591(m17 allotype) in combination with the SoC. These patients will receive two single intravenous (IV) injections of 76 mCi (±10%) each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA-TLX591 (m17), given 14 days apart, plus best SoC (abiraterone/prednisolone or enzalutamide or docetaxel). After the first dose, the patients will undergo single-photon emission computerized tomography/computerized tomography (SPECT/CT).
Primary purpose: TREATMENT

Brief summary: This multinational, multicenter, prospective, randomized, controlled, open label Phase 3 study is designed to investigate and confirm the benefits and risks associated with the PSMA-targeted antibody, 177Lu DOTA rosopatamab administered together with Standard of Care (SoC), as compared to the best SoC alone. The phase 3 will be conducted in patients with metastatic castration-resistant PC (mCRPC) that expresses PSMA and has progressed despite prior treatment with a novel androgen axis drug (NAAD).

Detailed description: This multinational, multicenter, prospective, randomized, controlled, open label Phase 3 study is designed to investigate and confirm the benefits and risks associated with 177Lu DOTA rosopatamab administered together with SoC, as compared to the best SoC alone, in patients with PSMA-positive, metastatic castration-resistant PC (mCRPC) that has progressed despite prior treatment with a novel androgen axis drug (NAAD).

PSMA positivity will be defined by gallium-68 labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography/computerized tomography (PET/CT) as at least one site of metastatic disease with intensity significantly greater than normal liver (i.e., standardized uptake value \[SUV\] max at least 1.5 times SUV of normal liver.

Approximately 392 eligible adult male will be part of this study. 387 patients will be randomized to one of two groups in a 2:1 ratio to receive one of the treatments below. 5 participants in New Zealand will be enrolled into a sub-study.

* Group A: Two single intravenous (IV) injections of 76 mCi each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA- rosopatamab, given 14 days apart, plus best SoC
* Group B: Best SoC.

In parallel to this, 5 participants in New Zealand site, will be enrolled into a sub-study to investigate the biodistribution, pharmacokinetics and dosimetry of 177Lu-DOTA-TLX591(m17). Participants will receive two doses of 177Lu-DOTA-TLX591(m17), 14 days apart.

Screening procedures will take up to 28 days prior to enrollment and randomization. Only patients with PSMA-positive metastatic PC and meeting all other inclusion/exclusion criteria were randomized in a 2:1 ratio to Group A or B OR allocated to Sub-study in New Zealand.

Participants in Group A or B will participate in the study for up to 5 years. During this period the participants will undergo imaging procedures approximately every 6-8 weeks until progression.

Participants in the sub-study will participate in the study up to 23 days. During this period participants will receive two doses of 177Lu-DOTA-TLX591(m17), 14 days apart, and undergo SPECT/CT imaging and blood collection for Pharmacokinetics at days 1,2,5,8, 13 and 15.

For all patients, the best SoC will be determined by the Principal Investigator (PI) and the medication will be provided until progression.

Eligibility criteria: Inclusion Criteria:

1. Be a male, at least 18 years old, with metastatic adenocarcinoma of the prostate defined by histological / pathological confirmation of PC.
2. Be of ECOG Performance Status 0, 1, or 2 and have an estimated life expectancy of ≥6 months.
3. Have metastatic disease (≥1 metastatic lesions present on baseline CT, MRI, or bone scan imaging).
4. Have castration-resistant PC (defined as disease progressing despite castration by orchiectomy or ongoing use of luteinizing hormone-releasing hormone \[LHRH\]) and must have a castrate level of serum/plasma testosterone (\<50 ng/dL or \<1.7 nmol/L).
5. In the mCRPC setting, must have received a minimum of 12 weeks of prior therapy with a NAAD, either enzalutamide or abiraterone plus prednisone.
6. Should have received one line of prior taxane therapy or have refused or be ineligible for taxanes
7. Have a disease that is progressing at study entry, despite a castrate testosterone level (\<50 ng/dL or \<1.7 nmol/L), by the demonstration of at least one of the following:

   1. Rising PSA values done in sequence at least 1 week apart and with a minimal starting value of 2.0 ng/mL.
   2. Progressive disease or new lesion(s) in the viscera or lymph nodes as per RECIST1.1 or in bone as per Prostate Cancer Working Group 3 \[PCWG3; Scher et al., 2016\]). Any ambiguous results are to be confirmed by other imaging modality (e.g., CT or MRI scan).
8. Have disease that is PSMA positive, as demonstrated by a 68Ga-PSMA11 PET/CT scan and confirmed as eligible by the Sponsor's central reader (patient must have at least one site of metastatic disease with SUVmax ≥1.5 times the SUV of normal liver). If the disease meets the criteria for PSMA positivity, but there is one or more soft tissue lesion of ≥ 2 cm that is not PSMA positive, then the patient is to be excluded on the grounds that there is substantial disease which might not respond to the therapy.
9. Must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e., surgery, local radiotherapy, NAAD, chemotherapy, etc.).
10. Can be receiving a bisphosphonate or denosumab regimen provided that the patient has been receiving and tolerating this treatment for ≥30 days prior to randomization.
11. Have adequate organ function at Screening:

    a. Bone marrow: i. Platelets ≥150×109/L. ii. Absolute neutrophil count \>1.5×109/L. iii. Hemoglobin ≥10g/dL (no red blood cell transfusion in the previous 4 weeks).

    b. Liver function: i. Total bilirubin \< 1.5×the upper limit of normal (ULN). For patients with known Gilbert's Syndrome \<3×ULN is permitted. ii. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \<3×ULN OR \<5×ULN for patients with liver metastases. c. Renal function: i. Serum/plasma creatinine \<1.5×ULN or creatinine clearance ≥50 mL/min determined using the Cockcroft \& Gault formula.
12. Have the capacity to understand the study and be able and willing to comply with all protocol requirements.
13. Patients must comply with the radiation protection rules (including hospital admissions and isolation) that are used by the treating institution in order to protect their contacts and the general public, especially if a female partner of the patient is or could be pregnant.
14. Must agree to practice adequate precautions to prevent pregnancy in a partner and to avoid potential problems associated with radiation exposure to the unborn child (Refer to Clinical Trials Facilitation Group, 2020: Recommendations related to contraception and pregnancy testing in clinical trials Version 1.1, CTFG, 2020).

Exclusion Criteria:

1. Are unable to understand or are unwilling to sign a written informed consent document or to follow investigational procedures in the opinion of the Investigator.
2. Have PC associated with pathological findings consistent with small cell or any histology other than adenocarcinoma of the prostate. If there are minor elements of neuroendocrine histology, this is acceptable.
3. Uncontrolled pain.
4. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, patients with a prior history of malignancy that has been adequately treated and who have been disease-free for more than 3 years are eligible, as are patients with adequately treated non-melanoma skin cancer, and superficial bladder cancer.
5. Are at increased risk of hemorrhage or bleeding, or with a recent history of a thrombolytic event (e.g., deep vein thrombosis \[DVT\]/ pulmonary embolism \[PE\]) and have been administered long-term anti-coagulant or anti-platelet agents.
6. Have received prior treatment with monoclonal antibody (mAb) J591 or HuJ591 or any other PSMA targeted therapy.
7. Have known allergies, hypersensitivity, or intolerance to the investigational drug or its excipients.
8. Have received prior systemic anti-cancer therapy (e.g., chemotherapy, immunotherapy, or biological therapy) and/or radiation therapy within 4 weeks of randomization OR if any significant AEs have not resolved to National Cancer Institute (NCI) AE Criteria ≤2; OR are receiving other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.
9. Have received prior treatment with radioisotopes, including but not limited to: 89Strontium, 153Samarium, 186Rhenium, 188Rhenium, 223Radium, or hemi-body irradiation within 6 months prior to randomization.
10. Have received other investigational therapy within 4 weeks of randomization.
11. Have known brain metastases or hepatic metastases.
12. Have a history of seizure and/or stroke within past 6 months.
13. Have clinical or radiologic findings indicative of impending cord compression or experience symptomatic cord compression.
14. Have a serious active or sub-clinical infection or angina pectoris (New York Heart Association \[NYHA\] Class III or IV), significantly prolonged QT interval or other serious illness(es) involving the cardiac, respiratory, central nervous system, renal, hepatic or hematological organ systems, which might impair the ability to complete this study or could interfere with determination of causality of any adverse effects experienced in this study, or which require treatment that could interact with study treatment, particularly with enzalutamide.
15. Have received treatment with any PARP inhibitors (i.e., Olaparib) or with any platinum based anti-neoplastic drugs.
16. Have a known alteration in breast cancer genes (BRCA) BRCA1, BRCA2, or Ataxia Telangiectasia Mutated Gene (ATM) gene and are eligible to receive Olaparib therapy according to their institution's SoC

Primary outcomes:
measure: Comparison of radiographic progression-free survival (rPFS)
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
Secondary outcomes:
measure: Overall survival
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Tumour objective response rate (ORR)
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Time to a first Symptomatic Skeletal Event (SSE)
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Progression-free survival
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Adverse events of special interest (AESI)
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Health-related quality of life by ECOG
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Health-related quality of life by FACT-P
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Health-related quality of life by BPI-SF
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Health-related quality of life by EQ-5D-5L
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Health-related quality of life by EORTC/QQ-C30
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Assessment of changes in prostate specific antigen (PSA)
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Time to radiographic soft tissue progression (TTSTP)
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Biochemical response as indicated by PSA levels, lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Development of anti-drug antibodies (ADA) to 177Lu-DOTA-TLX591
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Titer of anti-drug antibodies (ADA) to 177Lu-DOTA-TLX591
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Duration of positiveness in the development of anti-drug antibodies (ADA) to 177Lu-DOTA-TLX591
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: Neutralizing anti-drug antibodies (NAb) to 177Lu-DOTA-TLX591
timeFrame: Day 1 to 5 years after two administrations of 177Lu-DOTA-rosopatamab
measure: To determine whole body biodistribution (BD) of administered activity 177Lu-DOTATLX591(m17)
timeFrame: Day 1 to day 23 after two administrations of 177Lu-DOTA-rosopatamab
measure: To determine organ radiation dosimetry of tracer levels of administered activity 177Lu-DOTATLX591(m17)
timeFrame: Day 1 to day 23 after two administrations of 177Lu-DOTA-rosopatamab
measure: To determine pharmacokinetics (PK) of administered activity 177Lu-DOTATLX591
timeFrame: Day 1 to day 23 after two administrations of 177Lu-DOTA-rosopatamab
measure: Demonstrate comparability of whole body biodistribution dosimetry of the 177Lu-DOTA-TLX591
timeFrame: Day 1 to day 23 after two administrations of 177Lu-DOTA-rosopatamab
measure: Demonstrate comparability of organ uptake dosimetry of the 177Lu-DOTA-TLX591
timeFrame: Day 1 to day 23 after two administrations of 177Lu-DOTA-rosopatamab
measure: Demonstrate organ radiation dosimetry comparability of the 177Lu-DOTA-TLX591
timeFrame: Day 1 to day 23 after two administrations of 177Lu-DOTA-rosopatamab
Other outcomes:
Locations:
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Melbourne
country: Australia
facility: Austin Health
state: Victoria
city: Murdoch
country: Australia
facility: 'GenesisCare Murdoch'
state: Western Australia
city: Auckland
country: New Zealand
facility: Auckland City Hospital
Study officials:
References: