Protocol for phase I study of pembrolizumab in combination with Bacillus Calmette-Guérin for patients with high-risk non-muscle invasive bladder cancer

Abstract

Introduction: The initial treatment for high-risk non-muscle invasive bladder cancer (NMIBC) is endoscopic resection of the tumour followed by BCG therapy. In those who develop recurrence, the standard treatment is radical cystectomy. Despite the advancement in surgical technique and postoperative care, the degree of morbidity associated with radical cystectomy remains high, therefore less invasive treatment modalities are desirable. Therapies targeting the programmed death (PD) pathway have shown promise in urothelial carcinoma. We undertook the current study to determine the safety and efficacy of administering pembrolizumab (a monoclonal antibody targeting the interaction between PD-1 and its ligand) in combination with BCG in high-risk NMIBC.

Methods: This is a single-centre phase I safety and efficacy study of pembrolizumab used in combination with intravesicular BCG treatment for subjects with pathologically documented high-risk NMIBC despite having received two courses of induction therapy or BCG treatment followed by maintenance BCG. Fifteen subjects will be enrolled, patients will receive treatment with 200 mg of pembrolizumab every 21 days, starting 2 weeks from the initial endoscopic resection and continuing for 6 weeks after the final dose of BCG. The primary objective is to determine the safety of administering pembrolizumab at a fixed dose of 200 mg every 3 weeks in conjunction with intravesicular BCG treatment in patients with high-risk NMIBC who have failed previous treatment. Secondary objectives are to determine the 19 weeks and the 3, 12 and 24 months post-treatment completion complete response rate with combined pembrolizumab and intravesicular BCG therapy in the aforementioned patients.

Ethics and dissemination: The study has been approved by the Institutional Review Board of the Henry Ford Hospital. The results of this study will be published in a peer-reviewed journal and presented at a scientific conference.

Trial registration number: NCT02324582.

Keywords: bacillus calmette-guerin; bladder cancer; cystectomy; non-muscle invasive; pembrolizumab.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Trial design for phase I study of pembrolizumab in combination with Bacillus Calmette-Guérin for patients with high risk non-muscle invasive bladder cancer. CIS, carcinoma in situ; IFN, interferon.

Figure 2

Trial schedule for phase I study of pembrolizumab in combination with Bacillus Calmette-Guérin for patients with high risk non-muscle invasive bladder cancer. *Screening visit: No study required procedures should be conducted (unless part of routine care) prior to the signing of the informed consent document. Screening visit laboratory procedures may be used for day 1 of cycle 1 if completed within 10 days of day 1 of cycle 1. †Early discontinuation visit: all subjects who discontinue treatment early for any reason should undergo all procedures listed in the flow chart for discontinuation visit. ‡If a subject has completed all study treatment, the subject should complete the 30-day safety follow-up visit procedures listed in the flow chart. §Follow-up visits should occur at approximately 3, 6, 9, 12, 18 and 24 months from week 19 cystoscopy. It is expected that follow-up data will be collected from routine office visits, which generally occur every 3 months in this population. There may be a shift in schedules if the participant has been given maintenance therapy or was found to have a recurrence. Subject will complete a final set of questionnaires at the 3 month visit. Follow-up information may be collected via medical record and document review only. However, patient contact via phone or in person may occur if information is not available via chart review. **Subject identification card may be given at any time after consent process has occurred and prior to treatment on day 1 of cycle 1. ††Prior and concomitant medications will include any medications taken within the 28 days prior to consent and through the safety visit and will include prescribed, over-the-counter and herbal/alternative remedies. ‡‡Poststudy treatment anticancer therapy and recurrence status may be collected through follow-up chart review. §§Questionnaires: American Urologic Association Symptoms Index, International prostate symptom score (IPSS) and Quality of Life will be completed prior to any treatment or procedures scheduled for that visit. ***Transurethral resections: all TUBR will occur as part of SOC and as clinically indicated. †††Adverse events will be collected from time of main study informed consent through 30 days post last study drug infusion/treatment. ‡‡‡Physical exam: full physical exams are required at screening and at the 30-day follow-up. All other exams may be symptom directed. §§§Performance status: Eastern cooperative group (ECOG) performance status scale should be used to measure performance status. ****ECG, chest X-ray and pulmonary function tests will be completed prior to day 1 of cycle 1 and will only be repeated as clinically indicated. ††††Prothromin time (PT)/International normalization ratio (INR) and Acticatved prothrombin time (aPTT) will be completed prior to all resections/possibly biopsies as standard of care. All other monitoring of PT/INR and aPTT will only be completed as clinically indicated (ie, if on coumadin). ‡‡‡‡Cystoscopy will be performed as standard of care but will be considered measures for efficacy. Biopsy will be performed as clinically indicated. §§§§Specimen collection/correlative studies: whole blood, serum and urine will be collected at time of consent or may be collected at any time prior to treatment on day 1 of cycle 1. Specimens for correlative study will also occur at each visit through week 19, repeat cystoscopy (12 visits). Saliva will be collected only at baseline. Tumour tissue will only be collected at week 19 biopsy if a biopsy is clinically indicated at the time of cystoscopy. Specimen collection is requested at 3, 6, 9, 12, 18 and 24 months follow-up visits if subject is being treated locally at the site, although not required. Tissue will only be collected if a biopsy is clinically indicated at time of cystoscopy.

Figure 3

Subject inclusion criteria for phase I study of pembrolizumab in combination with Bacillus Calmette-Guérin for patients with high risk non-muscle invasive bladder cancer. CIS, carcinoma in situ.

Figure 4

Subject exclusion criteria for phase I study of pembrolizumab in combination with Bacillus Calmette-Guérin for patients with high risk non-muscle invasive bladder cancer. *Chest X-ray, CT urogram or MRI and urogram are allowed to ascertain the superficial nature of the disease when indicated, but not required. If urogram protocol is not available or contrast allergy/poor renal function precludes such imaging, then non-contrast CT or MRI of the abdomen/pelvis within 90 days of study entry will suffice. †Exceptions include upper urinary tract transitional cell cracinoma (TCC), basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer that has undergone potentially curative therapy. ‡Use of disease-modifying agents, corticosteroids or immunosuppressive drugs. Replacement therapy (eg, thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment. PD, programmed death.

Figure 5

Trial treatment for phase I study of pembrolizumab in combination with Bacillus Calmette-Guérin for patients with high risk non-muscle invasive bladder cancer. *The first three subjects will be dosed at 100 mg. If the Data Safety Review Team approves, the dose will be escalated to 200 mg when the fourth subject is enrolled. †The MK-3475 dosing interval may be increased due to toxicity. BCG treatment may be interrupted or delayed as per the instructions for use supplied with BCG. ‡BCG: one phial of BCG suspended in 50 mL preservative-free saline.