Clinical trial NCT04382898: PRO-MERIT (Prostate Cancer Messenger RNA Immunotherapy)
Official title: First-in-human, Dose Titration and Expansion Trial to Evaluate Safety, Immunogenicity and Preliminary Efficacy of W_pro1 (BNT112) Monotherapy and in Combination With Cemiplimab in Patients With Prostate Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Prostate Cancer
Keywords: Prostate cancer
PRO-MERIT
Cancer vaccine
W_pro1
BioNTech SE
RNA
mCRPC
LPC
Cemiplimab
BNT112
Lead sponsor: BioNTech SE
Sponsor class: INDUSTRY
First posted: 2020-05-11
Enrollment: 75
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: * 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.

Primary outcomes:
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (21 days)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Related to Trial Procedure
timeFrame: From Baseline up to 30 days after the last dose of BNT112 (for Part 1 and Part 2 Arms 1b and 3) or up to 90 days after the last dose of cemiplimab (for Part 2, Arm 1a and Arm 2) (up to 4 years and 1 month)
measure: Part 2 Arm 1a: Objective Response Rate (ORR)
timeFrame: From start of treatment up to 46 weeks
measure: Part 2 Arm 1b: Objective Response Rate (ORR)
timeFrame: From start of treatment up to 104 weeks
Secondary outcomes:
measure: Number of Participants Reporting Change From Baseline in Prostate-specific Antigen (PSA) Levels
timeFrame: Day8 (Cycles1&2 only), Day1 Cycle 2 & Day 15 (Cycles1,2 & 8 only) (each cycle of 21-days), & EOT (30 days after last dose of BNT112 [Part 1 & Part 2 Arms 1b & 3] or 90 days after last dose of cemiplimab [Part 2, Arm 1a & Arm 2] [up to 4 years & 1 months])
measure: Number of Participants Reporting Change From Baseline in PSA Doubling Time (PSADT)
timeFrame: Cycle 4 Day 1, Cycle 8 Day 1, Cycle 12 Day 1 (each cycle duration=21 days)
measure: Number of Participants With PSA Decline of >=50%
timeFrame: Day8 (Cycles1&2 only), Day1 Cycle 2 & Day 15 (Cycles1,2 & 8 only) (each cycle of 21-days), & EOT (30 days after last dose of BNT112 [Part 1 & Part 2 Arms 1b & 3] or 90 days after last dose of cemiplimab [Part 2, Arm 1a & Arm 2] [up to 4 years & 1 months])
measure: Part 1: Objective Response Rate (ORR)
timeFrame: From start of treatment up to 27 weeks
measure: Part 2: Arms 2 and 3: Number of Participants With Tumor Response Post-Treatment
timeFrame: From start of treatment up to 25 weeks (Arm 2) and up to 26 weeks (Arm 3)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center
state: Arizona
city: Miami
country: United States
facility: University of Miami Hospital & Clinics /Sylvester Comprehensive Cancer Center
state: Florida
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Inst.
state: Pennsylvania
city: San Antonio
country: United States
facility: Urology San Antonio P.A.
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universität
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nürtingen
country: Germany
facility: Studienpraxis Urologie
city: Planegg
country: Germany
facility: Urologische Klinik Planegg
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Budapest
country: Hungary
facility: Magyar Honvédség Egészségügyi Központ (MH EK Honvédkórház)
city: Budapest
country: Hungary
facility: Semmelweis Egyetem, Belgyógyászati Klinika
city: Debrecen
country: Hungary
facility: Onkológiai Klinika
city: Nyíregyháza
country: Hungary
facility: Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház
city: Tatabánya
country: Hungary
facility: Szent Borbála Kórház
city: Cambridge
country: United Kingdom
facility: Cancer Research UK Cambridge Centre
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre (VCC)
city: Glasgow
country: United Kingdom
facility: University of Glasgow, Beatson WoS Cancer Centre
city: London
country: United Kingdom
facility: University College London Hospitals
city: London
country: United Kingdom
facility: The Royal Marsden Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton - Southampton General Hospital
Study officials:
affiliation: BioNTech SE
name: BioNTech Responsible Person
role: STUDY_DIRECTOR
References: