177Lu-HTK03170 in MCRPC with PSMA Positive Disease

This study will determine the safe initial injected activity of the radioligand therapy 177Lu-HTK03170 for the measurement of dosimetry and initiation of treatment in subjects with PSMA-positive, metastatic castrate resistant prostate cancer, (mCRPC). Subjects will receive treatment which will be escalated between cycles and personalized based on dosimetry calculations and imaging. In addition, antitumour activity will be measured by radiographic response, and further assessments of the treatment will be measured by CT imaging, ctDNA/ctRNA, PSA, PSMA PET/CT, and quality of life questionnaires. Subjects will be followed for 2 years or until they have progression and are switched to another systemic treatment.

Overall, up to 50 subjects will be enrolled to receive an injected activity (IA) of 177Lu-HTK03170. The IA's will be escalated based on personalized dosimetry at subsequent treatments (up to 5 cycles total).

Screening Phase: Subjects will be screened against the inclusion and exclusion criteria. A PSMA PET/CT scan using 68Ga-HTK03149 will be used to confirm PSMA positive disease. Those with confirmed PSMA positive disease with continue to one of the two Treatment Phases. Subjects will be informed which Phase they will be enrolled in.

Subjects will undergo a physical exam, complete a medical history questionnaire, a quality of life questionnaire, blood work, and a diagnostic CT.

Treatment summary per Phase:

The first 3 subjects will receive an initial Initial Acitivity (IA) of 1.1 GBq of 177Lu HTK03170, for the first cycle of treatment, assuming no toxicities occur requiring dose modification. Dosimetry will be performed to obtain absorbed organ dose and effective dose values. The initial IA used for dosimetry will be escalated to improve image quality, radiation dosimetry estimates, and potential efficacy. IA escalation will only occur on the initial dosimetry IA, with an increase of 30% over the initial IA (used for dosimetry) at each subsequent level (1.65 GBq, 2.5 GBq, 3.7 GBq) in up to 12 participants.

IA escalation will cease when a maximum tolerated injected activity (MTIA) is determined or a recommended safe initial IA has been identified based on an integrated assessment of safety, pharmacokinetics (PK), dosimetry, and preliminary antitumour activity data, if available.

Treatment Phase I: During the treatment phase, subjects will undergo up to 5 cycles of treatment. Each treatment cycle will be followed by dosimetry SPECT/CT scans on day 3 (72 +/- 24 hours) after treatment administration, and day 10 (10 days +/- 72 hours) after treatment administration. Additional dosimetry SPECT/CT scans will be completed during Cycle 1, on the day of treatment, and on day 1 (24 hours after treatment). After Cycle 3, a quality of life questionnaire will be completed again.

Treatment Phase II: During the treatment phase, subjects will be treated with an initial IA of 177Lu-HTK03170 at the MTD as determined during Phase I, or 1625 MBq, whichever is lower. Personalized dosimetry will be calculated for each subject as in Phase 1 so that subsequent treatments will be estimated to remain within the absorbed cumulative dose limits of 28Gy and 35Gy for kidneys and salivary glands, respectively, adjusted iteratively over the 3 remaining treatment cycles separated by 8 weeks. Each treatment cycle IA will be further adjusted to ensure a single dose exposure of 2Gy or less to the bone marrow, as needed. Fifteen (15) subjects will be enrolled in the first stage. When 6 or more subjects achieve objective radiographic response based on RECIST v1.1 , the study will proceed to the 2nd stage, where additional 17 subjects will be enrolled to continue efficacy evaluation.

Subjects will undergo up to 5 cycles of treatment. Each treatment cycle will be followed by dosimetry SPECT/CT scans on day 1 (18 - 32 hours after treatment administration) and day 3 (64 - 80h after treatment administration). Additional dosimetry SPECT/CT scans will be completed during Cycle 1, on the day of treatment, and on day 10. A repeat After cycle 5 a quality of life questionnaire will be completed again.

Follow up Phase: At the end of treatment or after discontinuation of any cause, subjects will be followed for 2 years to continue data collection for the other objectives. Objective tumour response will be assessed every 4 months by diagnostic CT according to the RECIST 1.1 criteria. A final quality of life questionnaire will be completed again within 28 days after the last treatment.

Eligibility Criteria:
Inclusion Criteria:

Each subject must meet all of the following inclusion criteria to be enrolled in the study:

1. Male subjects ≥ 18 years of age
2. Willing and able to provide consent
3. Life expectancy of \> 6 months
4. Progression on treatment with abiraterone and/or enzalutamide, or similar next generation ARAT therapy, as determined by the investigator. Subjects who have received docetaxel in the castration-resistant setting are also eligible to participate. Prior treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor is permitted.
5. Pathologically confirmed prostate adenocarcinoma
6. Subjects must have evidence of biochemical or imaging progression. Progression is defined as any one of the following:

   1. Prostate-specific antigen progression: two consecutive rising PSA values from a baseline measurement with an interval of ≥ 1 week between measurements. Minimum PSA at screening visit is ≥ 2.0 µg/L.
   2. Soft tissue disease progression on chest, abdomen, pelvis CT or magnetic resonance imaging (MRI; RECIST v1.1)
   3. Bone progression: ≥ 2 new lesions on bone scan
7. Eastern Cooperative Oncology Group (ECOG) performance score ≤2
8. Prior orchiectomy, or if on luteinizing hormone releasing hormone (LHRH) agonist/antagonist, then testosterone \< 1.7 nmol/L or \< 50 ng/dL
9. Adequate organ function:

   a) Marrow i) Absolute neutrophil count ≥ 1.5 × 109 /L ii) Platelet count ≥ 100 ×109 /L iii) Hemoglobin ≥ 90 g/L with no transfusions in the past 2 weeks b) Kidney i) Estimated creatinine clearance ≥40 ml/min according to Cockroft-Gault equation: ((140 - age) × (weight in kg)) / (72 × (serum creatinine)) c) Liver: i) Bilirubin \< 1.0 × upper limit of normal (ULN) (or if bilirubin is between 1.5 to 2 × ULN, must have a normal conjugated bilirubin) ii) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN in the absence of liver metastases, and) ≤ 5.0 × ULN in the presence of liver metastases.
10. Recovery from all previous cancer treatment toxicities to grade ≤ 2 (as per CTCAE 4.03)
11. Able to comply with scheduled visits, treatment plans, laboratory tests, imaging tests, and other procedures required and detailed in the protocol.
12. Must be surgically sterile or use adequate contraception for the duration of the therapy and 6 months after the end of therapy

Exclusion Criteria:

Subjects meeting any of the following exclusion criteria are not to be enrolled in the study.

1. Prior treatment with 225Ac-PSMA-617, 177Lu-PSMA, other radiolabeled therapeutic PSMA-ligands, or radio-immunotherapy
2. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or targeted therapy) within 28 days prior to day of enrollment
3. Radiotherapy to target lesions (measurable disease) ≤ 4 weeks prior to enrolment
4. Known parenchymal brain metastases
5. Active epidural disease (treated epidural disease is permitted)
6. History of risk factors for xerostomia (ie, head and neck radiation, Sjögren's disease) or pre-existing xerostomia Grade ≥1
7. Other concomitant active invasive cancer (except superficial non-melanomatous, non-metastatic skin cancer or non-invasive superficial transitional cell carcinoma \[TCC\])
8. Clinically significant cardiac disease including:

   1. History of unstable angina pectoris, symptomatic pericarditis, or myocardial infarction within 6 months prior to study entry.
   2. History of documented congestive heart failure (New York Heart Association \[NYHA\] functional classification III-IV) or cardiomyopathy.
9. Major surgery within 4 weeks of starting study treatment.
10. Unmanageable urinary tract obstruction or hydronephrosis