PRO-MERIT (Prostate Cancer Messenger RNA Immunotherapy) RN5609C00
Research type
Research Study
Full 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
IRAS ID
264235
Contact name
Mark Linch
Contact email
Sponsor organisation
BioNTech RNA Pharmaceuticals GmbH
Eudract number
2018-004321-86
Clinicaltrials.gov Identifier
PRO-MERIT, Acronym
Duration of Study in the UK
4 years, 0 months, 30 days
Research summary
Research Summary:
Prostate cancer is the second most common malignant neoplasm in men and fifth cause of cancer-related death worldwide. Although multiple agents have been approved for metastatic castration-resistant prostate cancer (mCRPC) which prolong survival and provide palliative benefit, there is no curative treatment and the
need for novel agents is still present. The study drug W_pro1 is a vaccine based on messenger Ribonucleic Acid (mRNA). The vaccine is taken up by specific immune cells and then used as template to produce proteins which can be recognised by the immune system (so called antigens). These specific antigens are similar to proteins on the surface of the prostate tumour cell. The ultimate goal of this treatment is to enable the immune system to fight the tumour cells by recognising these antigens.This open-label, multicentre clinical trial will initially enrol a limited number of mCRPC patients in approximately 3 countries to identify a recommended dose (part 1 of the trial). In part 2, more patients will be treated with the recommended dose. The main goal of the study is to evaluate the safety and tolerability of W_pro1. In addition, the immune system response to the specific antigens and preliminary efficiency of W_pro1 will be assessed. The study consists of a screening period, treatment phase and follow-up period. Patients will be asked to provide archived tumour sample and blood samples and to attend all planned study visits. W_pro1 will be given by slow intravenous (into a vein) injections at each treatment visit. The dose will be gradually increased in 2 steps. Treatment then continues until a discontinuation criterion is met. All patients will be followed up for safety for 30 days and for preliminary efficacy at 6 months and 12 months after the last dose of W_pro1.
Lay Summary of Results:
Patient disposition The patient disposition for Part 1 and Part 2 of the study is presented below. Seventy-five male patients were enrolled in the study, 64 patients with mCRPC (Metastatic castration-resistant prostate cancer) and 11 patients with LPC (Localized prostate cancer). Of the 64 patients with mCRPC, 9 patients were treated with BNT112 monotherapy in Part 1, 28 patients received BNT112 in combination with cemiplimab, and 27 patients received BNT112 monotherapy in Part 2. Of the 11 patients with LPC, 5 patients received BNT112 in combination with cemiplimab and 6 patients received BNT112 monotherapy.
Demographics
Most patients were White, not Hispanic or Latino (both > 90% in total), and between 52 and 87 years of age for the group of patients with mCRPC and between 59 and 77 years of age for the group of patients with LPC. Mean body weight (80.4 to 90.5 kg), height (172.6 to 177.3 cm), and BMI (27.0 to 29.7 kg/m²) was similar in all treatment arms.
Efficacy
For patients with mCRPC, the ORR (Objective response rate) based on PCWG3 (Prostate Cancer Working Group 3) was 12% for those treated with BNT112 monotherapy, with all responses being PR (Partial response). The combination therapy with cemiplimab did not show an improvement in ORR. The clinical benefit rate (CBR), which includes CR (Complete response), PR, and SD (Stable disease), was around 40% for both treatment arms.
For patients with LPC, the ORR was high, with 80% in the combination therapy arm and 100% in the monotherapy arm. The CBR (Clinical benefit rate) for LPC patients was 100% in both treatment arms.
The evaluation of the prostate-specific antigen (PSA) decline and the prostate-specific antigen doubling time (PSADT) support the ORR results. While patients with mCRPC only showed a modest PSA decline and a short PSADT, patients with LPC showed a clinically meaningful PSA decline.
The ex vivo immunogenicity results also showed better de novo response in patients with LPC (50%; N = 8) as compared to patients with mCRPC (25%, N = 36) though the number of patients assessed in the LPC group was limited. The combination of cemiplimab did not show any enhancement in T-cell response against vaccine target antigens. In Part 2, higher frequency of patients with mCRPC treated with BNT112 monotherapy (33%) showed de novo induction and expansion of T cells ex vivo as compared to combination therapy (21%). The frequency of responding patients was similar between BNT112 monotherapy (50%) and combination therapy (50%) in the LPC group where all patients also received ADT (Androgen-deprivation therapy).
Overall, the study results suggest that BNT112 therapy shows some efficacy in patients with mCRPC and is substantially active in patients with LPC.
Safety and tolerability
The extent of exposure to BNT112 was as stipulated in the protocol (median relative dose intensity overall: 98.44%). Overall, there were 33.3% of patients with dose delays, 7.6% of patients with at least one dose modification, 1.5% of patients with dose interruptions, and 18.2% of patients with at least one skipped dose. The main reason for dose delays, modifications, interruptions, or modifications were due to TEAEs (Treatment emergent adverse event). Only 9.3% of patients from both Part 1 and Part 2 combined discontinued the study due to a TEAE.
The incidences of dose delays and skipped doses were slightly higher in patients who received BNT112 and cemiplimab combination than in those who received BNT112 monotherapy from the mCRPC group. No difference could be observed in the combination versus the monotherapy in the LPC group.
Overall, two patients in Part 1 experienced hypertension that was classified as non-serious DLT (Dose-limiting toxicity) and related to study drug by both the sponsor and the investigator.
Almost all patients experienced at least one TEAE (73 patients; 97.3%) and 68 patients (90.7%) experienced at least one TEAE that was considered related to study treatment.
Overall, there were 3 patients (4.0%) who had Grade 5 TEAE and 42 patients (56.0%) that had an TEAE of CTCAE (Common Terminology Criteria for Adverse Events) Grade ≥3.
In the mCRPC group, the most frequent TEAEs were pyrexia (60%), chills (40%), fatigue (29.1%), anaemia (23.6%), and nausea (21.8%) irrespective of treatment, i.e., with similar frequencies for patients in the monotherapy subgroup as for patients in the BNT112+cemiplimab group. Similarly, in the LPC group, the most frequent TEAEs were chills and influenza like illness (each 45.5%), headache and hypertension (each 36.4%), and pyrexia, dizziness, hot flush, fatigue, pollakiuria (each 27.3%), irrespective of treatment. These TEAEs were managed with simple measures and widely available medications such as analgesics and antipyretics (e.g., paracetamol). There were no notable differences between the treatment arms in terms of the frequency of TEAEs. Generally, BNT112 was well tolerated, demonstrated by the absence of any IMP-related (Investigational medicinal product) deaths during the clinical study.
More than 90% of patients in this study (68/75 patients) experienced at least one TEAE that was assessed as related to either IMP. No difference was observed between the total monotherapy and the combination therapy groups for both indications (each 30/33 patients; 90.9%).
In total, 38 deaths occurred during the study. None of the deaths were considered related to BNT112 or cemiplimab. Most of the patients died due to disease progression and general health deterioration (i.e., study condition) and four patients died due to unknown causes.
In the mCRPC group, a quarter of all patients (25.5%) experienced at least one treatment emergent serious adverse event (TESAE). The frequency of serious TEAEs was slightly lower in the BNT112+cemiplimab combination therapy when compared to BNT112 monotherapy (5/28 patients; 17.9% vs 9/37 patients; 33.3%). Similarly, in the LPC group, four patients (36.4%) experienced at least one serious TEAE. However, no significant difference could be observed between the BNT112+cemiplimab combination therapy and the BNT112 monotherapy.
No relevant change in routine clinical laboratory values occurred after IMP dosing. There were some transient reductions of hemoglobin and blood lymphocyte counts. Based on previous clinical experience with RNA (Ribonucleic acid) vaccines, the transient decrease in lymphocytes is likely attributable to innate immune stimulation-related redistribution of lymphocytes into lymphoid tissues (Kamphuis et al. 2006). Decrease in lymphocyte count is considered a pharmacodynamics marker for the mode of action of RNA vaccines. Body temperature and heart rate increase was common following vaccination.
None of the other safety parameters, including laboratory evaluations (blood chemistry, urinalysis, cytokines), vital signs, physical examinations, and electrocardiogram (ECG) examinations gave rise to safety concerns.
Overall, the safety profile was comparable between LPC and mCRPC patients. The safety profile of BNT112 given as monotherapy or in combination with cemiplimab observed in this study is consistent with its mode of action.
Conclusion
The PRO-MERIT study was the first-in-human (FIH), dose titration and expansion study to evaluate safety, immunogenicity and preliminary efficacy of BNT112 monotherapy and in combination with cemiplimab in patients with prostate cancer. There were no changes in the conduct of the study considered by the sponsor to either impact the study objectives or to have compromised patient safety. There were also no protocol deviations considered by the sponsor to have impacted either GCP compliance, or patient safety.
For patients with mCRPC, the ORR based on PCWG3 was 12% in comparison with LPC where the ORR was much higher, with 80% in the combination therapy arm and 100% in the monotherapy arm, albeit with much less patients available for analysis. The CBR, which includes CR, PR, and SD, was around 40% for both treatment arms in the mCRPC group. The CBR for LPC patients was 100% in both treatment arms indicating a more favorable response in this group.
Similarly, the immunogenicity results also showed better de novo response ex vivo in LPC patients as compared to mCRPC patients, although the number of patients assessed in LPC group was limited.
Overall, the data presented in this report demonstrates that both BNT112 monotherapy and BNT112 combined with cemiplimab have an acceptable safety and tolerability profile, with manageable TEAEs.REC name
North East - York Research Ethics Committee
REC reference
19/NE/0174
Date of REC Opinion
24 Jul 2019
REC opinion
Further Information Favourable Opinion