Overview

The purpose of this study is to evaluate the safety, tolerability, and antitumour activity of AZD0754 CAR T-cell therapy in participants with metastatic prostate cancer.

Eligibility

Inclusion Criteria:

Age

1. Participant must be 18 years or older at the time of signing the informed consent form.

   Type of Participant and Disease Characteristics

2. Participants with:
   1. A histologically confirmed diagnosis of metastatic adenocarcinoma of the prostate without known neuroendocrine differentiation or small cell features.
   2. Castration-resistant prostate cancer as defined by disease progression despite castration by orchiectomy or ongoing luteinising hormone-releasing hormone analogue. Participants receiving medical castration therapy with gonadotropin releasing hormone analogues should continue this treatment during the study.
   3. Measurable PSA >/=1 ng/mL AND
   4. Evidence of progression within 6 months prior to screening according to one of the following:

             (i) Radiographic disease progression in soft tissue based on Response Evaluation
             Criteria in Solid Tumours Version 1.1 criteria with or without PSA progression as per
             Prostate Cancer Working Group Criteria 3 (PCWG3) (ii) Radiographic disease progression
             in bone defined as the appearance of 2 or more new bone lesions on bone scan as per
             Prostate Cancer Working Group Criteria 3 (PCWG3).
          3. Participant has previously received a NHA (ie, abiraterone, enzalutamide, apalutamide,
             darolutamide) and taxane as part of their treatment for prostate cancer (whether
             before or in the metastatic castration-resistant setting) or be ineligible for or
             refuse taxanes.
          4. For participants with HRR deficiency disease or breast cancer gene mutated disease,
             they disease must also have received a PARP inhibitor or be intolerant of this
             therapy.
          5. For participants who have high microsatellite instability or deficient DNA mismatch
             repair they must also have received at least one line of checkpoint inhibitors (ie,
             pembrolizumab), not be eligible for, or be intolerant to therapy as per NCCN or local
             treatment guidelines.
          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior to
             apheresis.
          7. Minimum life expectancy of > 12 weeks prior to apheresis in the opinion of the
             Investigator
          8. Adequate organ and marrow function.
          9. Consent and provision of tumour material to assess STEAP2 expression and other
             correlative biomarkers retrospectively with pre- and post-treatment biopsies. Fresh
             baseline and on-treatment biopsies are required unless these are deemed medically
             unfeasible. If the participant is unable to undergo fresh biopsy, an archival tumour
             sample will be required (age of biopsy cannot be greater than 10 years).
        Exclusion Criteria:
          1. Participants with weight less than 42 kg
          2. History of another primary malignancy except for malignancy treated with curative
             intent with no known active disease (≥ 2 years) before the first dose of study
             intervention and of low potential risk for recurrence. Such exceptions include
             non-melanoma cancer of the skin that has undergone curative therapy or adequately
             treated carcinoma in situ without evidence of disease.
          3. Participants with known brain metastases.
          4. Prior solid organ transplantation.
          5. Active or prior documented autoimmune or inflammatory disorders (including but not
             limited to inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis,
             systemic lupus erythematosus, Wegener's syndrome, myasthenia gravis, Graves' disease,
             rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune
             nephritis, or nephropathy, etc). The following are exceptions to this criterion:
               1. Participants with vitiligo or autoimmune alopecia.
               2. Participants with autoimmune hypothyroidism (eg, following Hashimoto thyroiditis)
                  stable on hormone replacement.
               3. Any chronic inflammatory or autoimmune skin condition that does not require
                  systemic therapy.
               4. Participants without active disease in the last 5 years may be included, but only
                  after consultation with the Sponsor.
               5. Participants with coeliac disease controlled by diet alone.
          6. Stroke, intracranial haemorrhage, or seizure within 6 months of apheresis.
          7. Cardiac arrhythmias, (such as multifocal premature ventricular contractions, bigeminy,
             trigeminy, ventricular tachycardia), which are symptomatic or require treatment
             (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3) unless controlled by
             pacemaker (discussion with the Study Physician required); symptomatic or uncontrolled
             atrial fibrillation despite treatment, or asymptomatic sustained ventricular
             tachycardia.
          8. Investigator judgement of one or more of the following:
               1. Mean resting corrected QT interval > 470 ms, obtained from triplicate
                  electrocardiograms (ECGs) performed at screening.
               2. History of QT prolongation associated with other medications that required
                  discontinuation of that medication, or any current concomitant medication known
                  to prolong the QT interval.
               3. Congenital long QT syndrome, family history of long QT syndrome, or unexplained
                  sudden death under 40 years of age in first-degree relatives.
          9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             known infection, cardiomyopathy of any aetiology, symptomatic congestive heart failure
             defined by New York Heart Association class ≥ 3), interstitial lung disease,
             uncontrolled hypertension, uncontrolled diabetes mellitus, unstable angina pectoris,
             history of myocardial infarction within the past 6 months prior to apheresis.
         10. Active, uncontrolled epilepsy. Participants without active/uncontrolled epilepsy in
             the last 5 years may be included.
         11. Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anticancer therapy,
             excluding alopecia. Participants with irreversible toxicity that is not reasonably
             expected to be exacerbated by study intervention may be included (eg, hearing loss)
             after consultation with the Study Physician or Medical Monitor. Participants with
             Grade 2 neuropathy will be evaluated on a case-by-case basis after consultation with
             the Study Physician or Medical Monitor.
         12. Seropositive for human immunodeficiency virus (HIV).
         13. Active hepatitis C infection (HCV). Participants testing positive for HCV antibody are
             eligible only if the polymerase chain reaction is negative for HCV RNA.
         14. Participants with hepatitis B virus (HBV) may be included under the following
             circumstances:
               1. Negative for hepatitis B surface antigen (HbsAg) and positive for anti-HBc
                  antibody
               2. Positive for HbsAg, but for > 6 months have had normal transaminases and HBV DNA
                  levels between 0 - 2000 IU/mL (inactive carrier state) and willing to start and
                  maintain antiviral treatment for at least the duration of the study.
               3. HBV DNA levels > 2000 IU/mL but on prophylactic antiviral treatment for the past
                  3 months and will maintain the antiviral treatment during the study.
         15. Local requirements for the testing for infectious diseases and exclusions of
             applicable participants should be followed per local regulations.
             Prior/Concomitant Therapy
         16. Participants may not receive full-dose long acting oral or parenteral anticoagulants
             or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose from the
             time of informed consent to 28-days post infusion of AZD0754. Use of short acting
             direct oral anticoagulants for therapeutic and prophylactic purposes are permitted.
         17. Any concomitant medications known to be associated with Torsades de Points within 14
             days prior and 28 days after AZD0754 infusion.
         18. Received the following:
               1. Major surgery within 2 weeks prior to apheresis, or planned major surgery within
                  4 weeks of the study treatment administration (Note: participants with planned
                  surgical procedures to be conducted under local anaesthesia may participate after
                  discussion with the Sponsor).
               2. Steroids (except inhaled steroids) or other immunomodulators (including
                  interleukins, interferons, and thymosins) of systemic therapeutic dose, and
                  systemic corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent
                  < 7 days prior to apheresis.
         19. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
             therapy targeted therapy, biologic therapy, tumour embolisation, or monoclonal
             antibodies, investigational product) within 5 half-lives or ≤ 21 days (whichever is
             shorter) prior to apheresis. Radiotherapy within 14 days. However, if the radiation
             portal covered ≤ 5% of the bone marrow reserve, the participant is eligible
             irrespective of the end date of radiotherapy. If sufficient washout time has not
             occurred due to the schedule or PK properties of an agent, a longer washout period
             will be required, as agreed by AstraZeneca and the Investigator.
         20. Any concurrent anticancer treatment with the following exceptions:
               1. Protocol-defined LDC
               2. Hormonal therapy for non cancer-related conditions (eg, hormone replacement
                  therapy)
               3. Androgen deprivation therapy with a luteinising-hormone replacement hormone
                  agonist/antagonist is required if needed to maintain testosterone level in the
                  castration range (levels < 50 ng/dL) and should be continued (unless bilateral
                  orchiectomy) throughout the trial. Following apheresis, bridging therapy is
                  permitted (if required) as outlined in Section 6.1.2
         21. Participants should not have received any live vaccines within 30 days prior to
             apheresis. Participants can receive coronavirus (COVID)-19 vaccines, at the discretion
             of the Investigator, following a benefit/risk evaluation for the individual
             participant and in accordance with local rules and regulations and vaccination
             guidelines. Note: If a COVID-19 vaccine is administered, it should ideally be done at
             least one week prior to LDC or after completion of the DLT period.
             Prior/Concurrent Clinical Study Experience
         22. Prior treatment with a CAR-T therapy directed at any target or any therapy that is
             targeted to STEAP2.
         23. Participants with a known life-threatening allergy, hypersensitivity, or intolerance
             to AZD0754 or any of the excipients of the product, including dimethylsulfoxide.