Pembrolizumab in Intermediate Risk Recurrent Non-muscle Invasive Bladder Cancer (NMIBC)

NCT03167151 | Terminated Phase 1 Results

• 2 other identifiers: OCTO-0792016-002267-33
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 3

Brief Summary

A parallel group, open label, multi-centre, phase I/II marker-lesion study of intravesical or intravenous pembrolizumab in recurrent intermediate risk NMIBC. Thirty patients (fifteen in each of two arms) will be randomised 1:1 to treatment with either intravesical pembrolizumab (Arm A) or intravenous pembrolizumab (Arm B). The main study will be preceded by a single institution safety run-in phase involving intra-patient dose escalation in six patients to confirm the safety and tolerability of intravesical pembrolizumab and the dose to be used in the randomised phase.

Conditions

Non-muscle Invasive Bladder Cancer (NMIBC)

Keywords

Recurrent intermediate risk NMIBC; Intravesical Pembrolizumab; Intravenous Pembrolizumab; Phase I/II; Marker-lesion; Non-muscle invasive bladder cancer (NMIBC)

Outcome Measures

Primary Outcomes (1)

• Number of Dose Limiting Toxicities (DLTs) to Assess the Safety, Tolerability and Toxicities of Intravesical Pembrolizumab After Transurethral Resection of Bladder Tumour (TURBT).

  Adverse events are categorised according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Patients with intermediate risk Non-muscle Invasive Bladder Cancer (NMIBC) were assessed for dose limiting toxicity (DLT) and tolerability. Administration of at least 5 out of 6 treatments was required for the regime to be defined as tolerable.

  Adverse event monitoring starts on the day of the TURBT procedure (Day -14) until 90 days post treatment, or 30 days following administration of the last dose of study medication if the subject initiates a new anticancer therapy.

Other Outcomes (5)

• Correlation Between Expression of Programmed Death Ligand 1 (PD-L1) and Programmed Cell Death 1 (PD-1+) Infiltrating Lymphocytes and Efficacy of Pembrolizumab Therapy After TURBT.

  Day -14 TURBT, optional Day 50 TURBT, Day 85 TURBT and where applicable optional follow-up period ≤ 24 months

• Definition of Gene Expression Signatures and Genetic Profiles Capable of Predicting Efficacy of Pembrolizumab Treatment in NMIBC Patients.

  Day 1 pre-treatment

• Analysis of T-cell Receptor (TCR) Repertoire and Clonality of Infiltrating T-cells in Resected Tumour Specimens, Urine and Normal Bladder Tissue.

  Day 1 to 92

Study Arms (2)

Arm A Intravesical

EXPERIMENTAL

Intravesical Pembrolizumab (solution for infusion) 50-200 mg, given on D1, D8, D15, D22, D29, D36 \& D64. Dose to be decided after safety run-in.

Drug: Pembrolizumab

Arm B Intravenous

ACTIVE COMPARATOR

Intravenous Pembrolizumab (solution for infusion), 200mg, given on D1, D22, D43, D64

Drug: Pembrolizumab

Interventions

Pembrolizumab DRUG

Solution for Infusion (Intravesical and Intravenous) 100mg/ 4ml vial

Also known as: Keytruda

Arm A Intravesical; Arm B Intravenous

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible for participation in this trial, the subject must:
• Be willing and able to provide written informed consent for the trial and comply with the protocol scheduled follow-up visits and examinations for the duration of the study.
• Be ≥ 18 years of age on day of signing informed consent.
• Have recurrent NMIBC for which adjuvant treatment post TURBT would be a reasonable treatment option.
• Main study only: a. Have recurrent, multiple (minimum 2) tumours consistent with NMIBC.
• b. Have at least one lesion of between 5-10mm in size clinically that can be left un-resected at TURBT as the marker lesion.
• c. Have histologically confirmed low grade transitional cell NMIBC at original and any subsequent diagnosis.
• Have a normal upper urinary tract (as evidenced by ultrasound or CT urography within 2 years prior to randomisation) and no evidence of tumour in prostatic urethra at flexible cystoscopy.
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Have adequate organ function as defined below:
• Haemoglobin (Hb) ≥ 9 g/dL without transfusion or erythropoietin (EPO) dependency Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) or direct bilirubin \< ULN for subjects with total bilirubin levels \> 1.5 x ULN Serum alanine aminotransferase (ALT) and/or serum aspartate aminotransferase (AST) ≤ 2.5 x ULN Serum creatinine OR Measured or calculated creatinine clearance ≤ 1.5 x ULN OR
• ≥ 60ml/min for subject with creatinine levels \> 1.5 x institutional ULN Albumin ≥ 25g/L International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or APTT is within therapeutic range of intended use of anticoagulants a Creatinine clearance should be calculated as per institutional standard
• Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Both male and female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in section 5.1 for the course of the study and until 120 days after the last dose of the study medication.

You may not qualify if:

• The subject must be excluded from participating in the trial if the subject:
• Has received prior radiotherapy to the pelvis.
• Has significant urinary incontinence or known bladder instability.
• Main study only:
• Has more than 2 out of 3 of the following present at the current time: i. ≥8 tumours ii. Tumour ≥3cm in size iii. Frequent recurrence (\>1/year)
• Has a previous history of any of the following: T1 tumour, high grade/G3 tumour, carcinoma in situ, multiple recurrent large (\>3cm) Ta, G1 or G2 tumours.
• Had a primary tumour of unknown pathological stage or grade.
• Has disease for which resection of all visible tumours is not possible.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 28 days of the first dose of trial treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Subjects requiring use of inhaled or intranasal corticosteroids or local steroid injections would not be excluded.
• Has a known history of active tuberculosis (TB).
• Has received intravesical Bacillus Calmette-Guerin (BCG) treatment within 30 days prior to the first dose of trial treatment.
• Has hypersensitivity to pembrolizumab or any of its excipients.
• Has had treatment with any other anti-cancer monoclonal antibody within 28 days prior to enrolment or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had treatment with prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of administration of study drug or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

Sponsors & Collaborators

• University of Oxford: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (3)

University Hospital Southampton NHS Foundation Trust

Southampton, Hampshire, SO16 6YD, United Kingdom

Location

Oxford University Hospitals NHS Foundation Trust

Oxford, Oxfordshire, OX3 9DU, United Kingdom

Location

Royal Surrey County Hospital NHS Foundation Trust

Guildford, Surrey, GU2 7XX, United Kingdom

Location

MeSH Terms

Conditions

Non-Muscle Invasive Bladder Neoplasms

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urinary Bladder Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Limitations and Caveats

Due to the issues with slow recruitment, the decision was taken to end the trial after the safety run in phase, before the randomised phase began. This meant only a very small number of patients could be analysed.

Results Point of Contact

• Title: Dr Andrew S Protheroe
• Organization: Oxford University Hospitals NHS Foundation Trust

andrew.protheroe@oncology.ox.ac.uk

01865 253275

Study Officials

• Andrew S Protheroe, MRCP, FRCP

  Oxford University Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 2, 2017
• First Posted: May 25, 2017
• Study Start: March 2, 2018
• Primary Completion: March 26, 2019
• Study Completion: June 26, 2019
• Last Updated: July 31, 2020
• Results First Posted: July 31, 2020

Record last verified: 2019-12

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)