Combination of pembrolizumab and BCG treatment after endoscopic ablation of high-risk superficial upper urinary tract urothelial carcinoma in patients not candidates for radical nephroureterectomy: protocol for phase-II study

Abstract

Introduction: The treatment standard for high-risk upper urinary tract urothelial carcinoma (UUTUC) is radical nephroureterectomy. However, some patients may be unfit or unwilling, and in such patients the available alternatives are suboptimal. Therapies targeting the programmed death (PD) pathway have shown promise in urothelial carcinom (UC). We designed the current study to determine the safety and efficacy of administering MK-3475 (a monoclonal antibody targeting interaction between PD-1 and its ligand) in combination with bacillus Calmette-Guerin (BCG) in high-risk non-muscle invasive UUTUC patients.

Methods: This represents a single-centre phase-II efficacy study of MK-3475 therapy in combination with BCG for subjects, 18 years of age or older, with pathologically documented non-muscle invasive high-risk UUTUC unfit or unwilling to be treated with radical nephroureterectomy. Twenty subjects will be enrolled; patients will receive treatment with 200 mg of MK-3475 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 and efficacy of administering MK-3475 at a fixed dose of 200 mg every 3 weeks in conjunction with intrapelvic BCG. Secondary objectives include 19 week and the 3, 12 and 24-month post-treatment completion complete response and progression-free rate assessments.

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: NCT03345134.

Keywords: bacillus Calmette-Guerin; pembrolizumab; radical nephroureterectomy; upper urinary tract; urothelial carcinoma.

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

aAblation may be performed in an antegrade or retrograde fashion. bSix weekly doses of BCG in total. cPatients with suspicious lesions, or positive cytology, will be evaluated with renal pelvis biopsy under general anaesthesia. BCG, bacillus Calmette-Guerin; UUTUC, upperurinary tract urothelial carcinoma.

Figure 2

aMain study screen visit: subjects who appear eligible will be consented with a main study consent allowing for all study screening and treatment procedures. Screening visit laboratory procedures may be used for day 1 cycle 1 if completed within 10 days of day 1 cycle 1. bDiscontinuation 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 follow-up visit procedures listed in the flow chart. cFollow-up visits should occur at approximately 3, 6, 9, 12, 18 and 24 months from week 19 ureteroscopy. A 2-week window before and after the specified date is allowable to meet the timelines listed. Subject will complete final set of Questionnaires at the 3-month visit. Complete response 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.dSubject Identification card may be given at any time after main study informed consent has occurred and prior to treatment on day 1 cycle 1. ePrior and concomitant medications will include any medications taken within the 28 days prior to main study consent and through the safety visit and will include prescribed, over-the-counter and herbal/alternative remedies. fPost-study treatment anticancer therapy and recurrence status may be collected through follow-up chart review. gTo monitor for systemicdissemination of BCG infection, daily phone calls of days 2–4 of each cycle of BCG treatment (weeks 7–12) will occur to monitor for fever and symptoms of systemic infection. Subjects will each be given anoral thermometer and a diary to record oral temperature twice daily (morning and evening) and to record any symptoms they may be having.The diary will be utilised days 1–7 for each of the six BCG cycles (weeks 7–12). hTransurethral resections: all TUBR will occur as part of SOC and as clinically indicated. For the purposes of entry into this study, the screening window for endoscopic ablation with repeat biopsy will be within 90 days of day 1. iAdverse events will be collected from the time of main study informed consent through 30 days post last study drug infusion/treatment. jPhysical exam: full physical exams are required at screening and at the 30-day follow-up. All other exams may be symptom directed. kPerformance status: ECOG performance status scale should be used. lECG, chest X-ray and pulmonary function tests will be completed prior to day 1 cycle 1 and will only be repeated as clinically indicated. mPT/INR and aPTT will be completed prior to all resections/possibly biopsies as standard of care. All other monitoring of PT/INR and aPTT will be completed as clinically indicated (ie, if on Coumadin).nUreteroscopy will be performed as standard of care but will be considered measuresfor efficacy. Biopsy will be performed as clinically indicated.oSpecimen collection/correlative studies: whole blood,serum and urine will be collected at the time of screening consent/main study consent (only one collection at either time point) as well as each visit through week 19 repeat ureteroscopy (12 visits). Saliva will be collected only at baseline. Tumour tissue will only be collected at baseline and at week 19 biopsy if a biopsy is clinically indicated at the time of ureteroscopy. Specimen collection is requested at the 3, 6, 9, 12, 18, and 24-month follow-up visits if the subject is being treated locally at the site. Tissue will only be collected if a biopsy is clinically indicated at the time of ureteroscopy. pChest X-rays performed in the 90 days’ window prior to the screening visit are acceptable. qCBC,CMP and correlative labs do not need to be repeated on day 1 cycle 1 if they were completed within 10 days prior to day 1 cycle 1 during screening. aPTT, activated partial thrombin time; BCG, bacillus Calmette-Guerin; CB, complete blood count; CMP, comprehensive metabloic panel; ECOG, Eastern Cooperative oncology Group; HCG, Human chorionic gonadotrophin; INR, International Normalization Ratio; PT, Prothrombin time; SOC, standard of care; TURBT, Transurethral resection of bladder tumor; TSH, Thyroid stimulating hormone; UUTUC, upperurinary tracturothelial carcinoma.

Figure 3

aAll pathology specimens used for enrolment are required to be trad by the research site pathology laboratory. bPatients are to have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumour lesion. tissue must be obtained from the most recent upper urinary tract biopsy. However, in patients with small tumours or carcinoma in situ of the upper urinary tract, and considering the difficulty of obtaining sufficient tissue for testing beyond pathologic diagnosis, not providing this tissue is not going to exclude the patient from the study. cIf the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. dSubjects of childbearing potential are those who have not been surgically sterilised or have not been free from menses for >1 year. CIS, carcinoma in situ; ECOG, Eastern Cooperative Oncology Group; UUTUC, upperurinary tract urothelial carcinoma.

Figure 4

aChest 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. bExceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localised prostate cancer with no recurrence after curative surgery or radiation, or in situ cervical cancer that has undergone potentially curative therapy. lower urinary tract transitional cell carcinoma is also allowable on study as high-risk transitional cell carcinoma is commonly multifocal, and intraluminal BCG therapy is also used for treatment of lower urinary tract lesions in a manner similar to that of UUTUC. cUse of disease modifying agents, corticosteroids or immunosuppressive drugs. replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency and so on) is not considered a form of systemic treatment. dThis includes anything that may confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. eSubjects will not be specifically tested for the study; however, subjects that are tested within 28 days of beginning study or while on study and test positive with the PPD test before treatment should have active tuberculosis ruled out before therapy begins for their superficial renal pelvis cancer. BCG, bacillus Calmette-Guerin; PPD, purified protein derviative; TCC, transitional cell carcinoma; TUR, transurethral resection; UUTUC; upperurinary tract urothelial carcinoma.

Figure 5

aMK-3475 dosing interval may be increased due to toxicity as is described in the dose modification and adverse effects section. BCG treatment may be interrupted or delayed as per the dose modification and adverse effects section. bBCG: one vial of TICE BCG suspended in 50 mL preservative-free saline. BCG is to be given through a urinary catheter into the renal pelvis either retrograde or antegrade through a nephrostomy tube. BCG treatment will occur once per week for 6 weeks. BCG treatment will commence on the third cycle of treatment with MK-3475, week 7. BCG is an FDA-approved treatment and will be supplied commercially through the study site pharmacy. The preparation of the BCG suspension will be completed using aseptic technique and according to FDA-approved labelling and use information. Patients may have treatment with more than one vial to ensure treatment of all tumour sites. additional lesions in patients with multi-focal disease will be treated per intuitional standard and directed by the treating urologist. BCG, bacillus Calmette-Guerin; FDA, Food and Drug Administration.