Phase I Study of Hypofractionated Radiotherapy and Anti-PD1 Antibody (Pembrolizumab) in the Treatment of Advanced Bladder Cancer

Condition: Invasive Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02560636

Sponsor: Royal Marsden NHS Foundation Trust

Phase: Phase 1


  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  1. Histologically confirmed invasive bladder.carcinoma (T2-4,N0-3,M0-1).
  2. Be willing and able to provide written informed consent for the trial.
  3. Be ≥ 18 years of age on day of signing informed consent.
  4. Have measurable disease based on RECIST 1.
  5. , or, in group A, disease assessable by cystoscopic assessment.
  6. Have consented to analysis of tissue from an archival tissue sample
  7. Have a performance status of 0-1 on the ECOG Performance Scale.
  8. Planned for hypofractionated radiotherapy
  9. Demonstrate adequate organ function as defined in table 2 (please see protocol) all screening blood tests should be performed within 10 days of confirmation of eligibility.
  10. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to confirmation of study eligibility. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  11. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  12. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy if their partner has childbearing potential (as defined by not being surgically sterilized or have not been free from menses for > 1 year).

Exclusion Criteria:

  • The subject must be excluded from participating in the trial if the subject: 1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment. 2. Previous pelvic radiotherapy, history of inflammatory bowel disease or other conditions that would in the opinion of the investigator would preclude the safe administration of pelvic radiotherapy. 3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (>dose equivalent to 10mg of Prednisolone/day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 4. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent or therapy.
  • Note: Subjects with ≤ Grade 2 neuropathy or chemotherapy induced alopecia/nail changes are an exception to this criterion and may qualify for the study.
  • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 6. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localized prostate cancer (≤T2 ≤ Gl3+4) or in situ cervical cancer that has undergone potentially curative therapy. Patients may have received treatment for previous urothelial malignancy. 7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. 8. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. 9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 10. Has an active infection requiring systemic therapy. 11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 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. 12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 15. Has a known history of Human Immunodeficiency Virus (HIV). 16. Has known clinical history of Hepatitis B or Hepatitis C . 17. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

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