Clinical Trial 22350

• Overview

  Study Title:

  A Phase I/II Open Label Study to Evaluate the Safety, Cellular Kinetics, and Efficacy of AZD0754, a Chimeric Antigen Receptor (CAR) T-cell Therapy Directed Against STEAP2, in Adult Participants with Metastatic Prostate Cancer: APOLLO

  Summary:

  This is a first-time in human, multi-center, open label, Phase I/II study of AZD0754 autologous CAR T-cell therapy administered intravenously to participants with metastatic prostate cancer. The study is intended to assess the safety, cellular kinetics, pharmacodynamics, preliminary efficacy, and feasibility of manufacturing AZD0754 for patients with metastatic prostate cancer.

  Objective:

  Primary Objectives: *To evaluate the safety of AZD0754 and determine the OBD, the MTD and/or a RDE of AZD0754 in participants with mCRPC *To evaluate the safety of AZD0754 in participants with mCRPC. Secondary Objectives: *To estimate the antitumour activity of AZD0754 when administered to participants with mCRPC *To characterise the CK of AZD0754 transgene *To investigate STEAP2 expression and relationship to response to AZD0754

• Treatments

  Therapies:

  Autologous CAR T-cell therapy; Cell Therapy; Chemotherapy (NOS); monoclonal antibody

  Medications:

  AZD0754 (); AZD2287 (); cyclophosphamide (); cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate)

• Inclusion Criteria

  Inclusion Criteria:
  • A histologically confirmed diagnosis of metastatic adenocarcinoma of the prostate without known neuroendocrine differentiation or small cell features.
  • 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.
  • Measurable PSA greater than or equal to 1 ng/mL AND
  • 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 Tumors 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). (iii) Evidence of disease progression in bone according to PSMA PET scan results in tandem with PSA progression according to PCWG3 criteria."
  • 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.
  • For participants with pathogenic mutations in BRCA1 or BRCA2, they must also have received a PARP-inhibitor or be intolerant of this therapy. For participants with non-BRCA HRR deficiency disease, treatment with a PARP-inhibitor is at the discretion of the Investigator based on a risk/benefit analysis and discussion with the participant.
  • 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.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior to apheresis.
  • Minimum life expectancy of over 12 weeks prior to apheresis in the opinion of the Investigator
  • Adequate organ and marrow function.
  • Consent and provision of tumor 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 tumor sample will be required (age of biopsy cannot be greater than 10 years).

• Exclusion Criteria

  Exclusion Criteria:
  • Participants with weight less than 39 kg
  • 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.
  • Participants with known brain metastases.
  • Prior solid organ transplantation.
  • Active or prior documented autoimmune or inflammatory disorders. 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.
  • Stroke, intracranial haemorrhage, or seizure within 6 months of apheresis.
  • 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.
  • 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.
  • 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, known bleeding diathesis such as haemophilia, von Willebrand disease, etc.
  • Active, uncontrolled epilepsy. Participants without active/uncontrolled epilepsy in the last 5 years may be included.
  • 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.
  • Seropositive for human immunodeficiency virus (HIV).
  • Active hepatitis C infection (HCV). Participants testing positive for HCV antibody are eligible only if the polymerase chain reaction is negative for HCV RNA.
  • Other exclusions apply

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