Study of AZD0754 in Participants With Metastatic Prostate Cancer (APOLLO)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Prostate Cancer
• Intervention / Treatment: Biological: AZD0754

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Australia
  • East Melbourne, Australia, 3002
    • Recruiting
    • Research Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • Research Site
  • Florida
    • Tampa, Florida, United States, 33612
      • Not yet recruiting
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Not yet recruiting
      • Research Site
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Recruiting
      • Research Site
  • New York
    • New York, New York, United States, 10065
      • Not yet recruiting
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Not yet recruiting
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: AZD0754; AZD0754 monotherapy for treatment of participants with metastatic prostate cancer.

Biological: AZD0754; Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to produce AZD0754. During AZD0754 production, subjects may receive bridging therapy for disease control. Upon successful generation of AZD0754 product, subjects will receive treatment with AZD0754 therapy. Study treatment will include lymphodepleting chemotherapy followed by one dose of AZD0754 administered by intravenous (IV) infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of participants with Dose-limiting Toxicity (DLTs)/DLT-like events, Adverse Events (AEs), including Adverse Events of Special Interest (AESIs) and Serious Adverse Events (SAEs).	Determine if treatment with AZD0754 is safe and tolerable through assessment of DLTs/DLT-like events, AEs, AESIs, SAEs, and changes from baseline in laboratory parameters, vital signs, and ECGs.	Through study completion, an average of 2 years
Presence of replication-competent lentivirus (RCL) in peripheral blood samples	Number of patients with positive RCL sample	Through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prostate-specific antigen (PSA) response rate - PSA50	PSA50 response rate is defined as the proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later.	Through study completion, an average of 2 years
PSA response rate - PSA90	PSA90 response rate is defined as the proportion of participants achieving a ≥ 90% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later.	Through study completion, an average of 2 years
Duration of PSA Response (DoPSA50, DoPSA90)	Time from the date of first documented PSA50 and PSA90 until the date of documented PSA progression or death due to any cause in the absence of PSA progression.	Through study completion, an average of 2 years
Durable PSA Response Rate (DRRPSA50, DRRPSA90)	Percentage of participants who have a confirmed PSA50 and PSA90 response with a duration of at least 6 months.	Through study completion, an average of 2 years
Time to PSA Response (TTPSA50, TTPSA90)	Time from AZD0754 infusion date until the date of the first documented PSA50 and PSA90 response.	Through study completion, an average of 2 years
Time to PSA Progression (TTPSAP50, TTPSAP90)	Time from the date of first documented PSA50 and PSA90 response until the date of documented PSA progression.	Through study completion, an average of 2 years
Best Overall Response (BOR)	Best overall radiological visit response the participant achieves per RECIST V1.1 and PCWG3.	Through study completion, an average of 2 years
Objective Response Rate (ORR)	Percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR).	Through study completion, an average of 2 years
Time to Response (TTR)	Time from AZD0754 infusion date until date of first documented evidence of CR or PR.	Through study completion, an average of 2 years
Duration of Response (DoR)	Time from the date of first documented evidence of CR or PR until date of first documented disease progression or death.	Through study completion, an average of 2 years
Durable Response Rate (DRR)	Percentage of participants who have a confirmed response (CR/PR) with a duration of at least 6 months.	Through study completion, an average of 2 years
Disease Control Rate (DCR)	Percentage of participants who have a confirmed CR, PR, or Stable Disease (SD) for at least 11 and 23 weeks after AZD0754 infusion.	12 and 24 weeks after AZD0754 infusion
Percentage change in tumor size	Percentage change in tumor size from baseline per RECIST V1.1 and PCWG3.	Through study completion, an average of 2 years
Radiographic Progression-free Survival (rPFS)	Time from AZD0754 infusion until date of objective disease progression according to RECIST V1.1 and PCWG3 criteria.	Through study completion, an average of 2 years
Overall Survival (OS)	Time from AZD0754 infusion until death due to any cause	Through study completion, an average of 2 years
Time from AZD0754 Infusion to the first Symptomatic Skeletal-related Events (SSRE)	Time from AZD0754 Infusion to the first Symptomatic Skeletal-related Event (SSRE).	Through study completion, an average of 2 years
Pharmacokinetics - maximum observed serum concentration (Cmax) of AZD0754	Maximum observed serum concentration	Through study completion, an average of 2 years
Pharmacokinetics - time taken to reach maximum serum concentration (Tmax) of AZD0754	Time taken to reach maximum serum concentration	Through study completion, an average of 2 years
Pharmacokinetics - Last measurable serum concentration (Clast) of AZD0754	Last measurable serum concentration	Through study completion, an average of 2 years
Pharmacokinetics - time of last measurable serum concentration (Tlast) of AZD0754	Time of last measurable serum concentration	Through study completion, an average of 2 years
Pharmacokinetics - Exposure of AZD0754	Area Under the concentration time curve	Through study completion, an average of 2 years
Biomarker - STEAP2 expression in Tumor	Investigate STEAP2 expression in tumor as measured by IHC.	Through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2024
• Primary Completion (Estimated): May 24, 2027
• Study Completion (Estimated): May 24, 2027

Study Registration Dates

• First Submitted: January 5, 2024
• First Submitted That Met QC Criteria: February 19, 2024
• First Posted (Actual): February 20, 2024

Study Record Updates

• Last Update Posted (Actual): April 29, 2024
• Last Update Submitted That Met QC Criteria: April 26, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: CAR-T; Prostate Cancer; mCRPC; Metastatic Prostate Cancer; CART; Metastatic castration-resistant prostate cancer; AZD0754
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: D9660C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. "Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No