PRO-MERIT (Prostate Cancer Messenger RNA Immunotherapy)

Open-label, multicenter, dose titration and four-arm expansion trial to evaluate the safety, tolerability, immunogenicity, and preliminary efficacy of BNT112 cancer vaccine (BNT112) monotherapy or in combination with cemiplimab in patients with metastatic castration resistant prostate cancer (mCRPC: Part 1 and Part 2 Arms 1A and 1B) and in patients with high-risk, localized prostate cancer (LPC).

As of February 2023, the trial only recruited LPC patients and no longer mCRPC patients.

* BNT112 consisted of messenger ribonucleic acid (mRNA \[or RNA\]) targeting 5 antigens expressed in de novo and metastatic prostate cancer that were separately complexed with liposomes to form serum-stable RNA lipoplexes (RNA-LPX).
* The RNA molecules were immune-pharmacologically optimized for high stability, translational efficiency and presentation on major histocompatibility complex (MHC) class I and II molecules. The vaccine was intended for intravenous (IV) bolus injection.
* The RNA-LPX cancer vaccine induced activation of both the adaptive immune system (vaccine antigen-specific CD8+/CD4+ T cell) as well as the innate immune system (TLR7 agonism of single-stranded RNA). The physiology of efficient induction, expansion and differentiation of antigen-specific T cells was associated with programmed death receptor-1 (PD-1) upregulation on these T cells. Thus, the cancer vaccine was expected to have a synergistic mechanism of action with anti-PD-1.
* The step-up dose titration approach allowed for optimal dose management on an individual basis and accounted for inter- and intra-individual variability of the immune system.
* In summary, the mechanism of action of BNT112 both in monotherapy and in combination with anti-PD-1 immune checkpoint inhibitor cemiplimab, together with carefully selected and refined clinical setting presented a unique opportunity for patients with different stages of prostate cancer.

Eligibility Criteria:
Inclusion criteria:

* Patients were male and aged \>=18 years.
* Patients had histologically confirmed prostate adenocarcinoma.
* Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.

Specific key inclusion criteria for mCRPC patients (Part 1 and Part 2 Arms 1A and 1B) - Recruitment of mCRPC patients now completed:

* Patients had histologically confirmed mCRPC and had progressed after at least 2 but no more than 3 lines of life-prolonging systemic therapy (e.g., abiraterone or enzalutamide, docetaxel, cabazitaxel) or cannot tolerate or refused any of these therapies. These lines of therapy included life-prolonging therapies administered in the metastatic hormone-sensitive setting.
* Prior surgical or chemical castration with a serum testosterone \<1.7 nmol/L (50 ng/dL). If the method of castration was luteinizing hormone-releasing hormone analogue (LHRHa), there was a plan to maintain effective LHRHa therapy for the duration of the trial.
* Patients had documented mCRPC progression within 6 months prior to screening (assuming no subsequent change in treatments), as determined by the investigator.
* Patients agreed to provide an archival pre-treatment formalin-fixed, paraffin-embedded tumor sample if available.

Specific key inclusion criteria for newly diagnosed LPC patients (Part 2 Arms 2 and 3):

* Treatment-naïve patients with LPC (i.e., N0, M0). According to risk levels of the European Association of Urology Guidelines on Prostate Cancer (2018), and in line with the U.S. National Comprehensive Cancer Network (NCCN 2020), patients had at least 1 of the following:

  1. PSA \>20 ng/mL or
  2. Gleason Score \>7 or
  3. Localized stage \>=cT2c, N0, M0 according to tumor, node, metastasis classification.
* Patients who intend to have and were suitable for a radical prostatectomy.
* Patients agreed to provide tumor sample(s) from pre-treatment diagnostic biopsy and planned post-treatment surgery.

Main exclusion criteria for all patients:

Medical conditions

* Patients with uncontrolled intercurrent illness.
* Patients with a known history or current malignancy other than the inclusion diagnosis. Note: Exceptions were patients with malignancies with a negligible risk of metastasis or death, that had been adequately treated, such as non-invasive basal cell or non-invasive squamous cell skin carcinoma, non-invasive, superficial bladder cancer, and any cancer with a complete response (CR) that lasted more than 2 years might be included.
* Patients who had major surgery (e.g., requiring general anesthesia) within 4 weeks before screening, or have not fully recovered from surgery, or had a surgery planned during the time of trial participation, except for the radical prostatectomy planned for patients in Part 2 Arms 2 and 3.
* Patients who had a known history of any of the following:

  1. Human immunodeficiency virus (HIV) 1 or 2
  2. Hepatitis B (carrier or active infection)
  3. Hepatitis C (unless considered cured 5 years post curative anti-viral therapy)
* Patients who have received or currently receive the following therapy/treatment:

  1. Chronic systemic immunosuppressive corticosteroid treatment (prednisone \>5 mg daily orally \[PO\] or IV, or equivalent) during the trial. Note: Replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted.
  2. Prior treatment with other immune modulating agents that was (a) within fewer than 4 weeks (28 days) or 5 half-lives (whichever is longer) prior to the first dose of cemiplimab, or (b) associated with immune-mediated AEs that were Grade \>=1 within 90 days prior to the first dose of cemiplimab, or (c) associated with toxicity that resulted in discontinuation of the immune-modulating agent.
  3. Prior treatment with other immune modulating agents for any non-cancer disease within 4 weeks or 5 half-lives of the agent (whichever is longer) before the first dose of IMP.
  4. Prior treatment with live-attenuated vaccines within 4 weeks before the first dose of IMP and during treatment with IMP.
  5. Prior treatment with an investigational drug (including investigational vaccines) within 4 weeks or 5 half-lives of the agent (whichever is longer) before the planned first dose of IMP.
  6. Therapeutic PO or IV antibiotics within 14 days prior to enrollment. Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) might be enrolled.
  7. Concurrent use of herbal products that might decrease PSA levels (e.g., saw palmetto).

Specific key exclusion criteria for mCRPC Patients (Part 1 and Part 2 Arms 1A and 1B) - Recruitment of mCRPC patients now completed:

Excluded medical conditions

* Patients with toxicities from previous anti-cancer therapies that have not resolved to baseline levels or to Grade \<=1 according to National Cancer Institute (NCI) CTCAE v5.0 with the exception of alopecia, anorexia, vitiligo, fatigue, hyperthyroidism, hypothyroidism, and peripheral neuropathy. Anorexia, hyperthyroidism, hypothyroidism, and peripheral neuropathy must have recovered to Grade \<=2.
* Patients with clinically active brain metastases.

  1. Patients with a history of symptomatic metastatic brain or meningeal tumors might be included, if the end of definitive therapy was \>3 months before the first dose of BNT112 and the patients had no clinical or radiological evidence of tumor growth.
  2. Patients with brain metastases must not be undergoing acute or chronic corticosteroid therapy or steroid taper.
  3. Patients with central nervous system symptoms should undergo a computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain to exclude new or progressive brain metastases. Spinal cord metastasis is acceptable. However, patients with spinal cord compression should be excluded.

Excluded prior or concomitant anti-cancer therapies

* Patients who received or currently receive the following anti-cancer therapy/agent:

  1. Prior radiation therapy with curative intent within 14 days before the first dose of IMP. Note: Palliative radiotherapy is allowed.
  2. Prior treatment with an anti-cancer agent (within 4 weeks or for systemic therapies after at least 5 half-lives of the drug \[whichever is longer\] before the first dose of IMP). Note: Prior treatment with bone resorptive therapy, such as bisphosphonates (e.g., pamidronate, zoledronic acid, etc.) and denosumab, is allowed assuming that the patients have been on stable doses for \>=4 weeks prior to first dose of trial treatment.
  3. Prior treatment with anti-cancer immunomodulating agents, such as blockers of programmed death receptor-1 PD-1, programmed cell death 1 ligand 1 (PD-L1), tumor necrosis factor receptor superfamily member 9 (TNRSF9, 4-1BB, CD137), OX-40, therapeutic vaccines, cytokine treatments, or any investigational agent within 4 weeks or 5 half-lives (whichever was longer) before the first dose of IMP.