Avelumab Plus Bacille Calmette-Guerin (BCG) in Patients With Non-muscle Invasive Bladder Cancer

Phase Ib Study of Avelumab Plus Bacille Calmette-Guerin (BCG) in Patients With Non-muscle Invasive Bladder Cancer (ABC Trial)

The purpose of this study is to test the safety of avelumab and Bacille Calmette-Guerin (BCG) and see what effects (good and bad) that this combination treatment has on subjects with recurrent bladder cancer.

There will be exams, tests and procedures to see if the patient is eligible for the study. Some are part of regular cancer care and others are part of the study. Subjects will also need to complete a research questionnaire at certain points in the study.

Subjects will receive treatment of avelumab and intravesical BCG until unacceptable toxicity or tumor progression.

Study participation is up to three years.

Inclusion Criteria:

1. Histologically or cytologically documented Non-muscle Invasive Bladder Cancer (NMIBC)
2. Patient with BCG-treated but unresponsive NMIBC (persistent or recurrent defined as tumor lesion present after prior response).
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 2.
4. Patients who are able to understand and sign the informed consent form.
5. Age ≥ 18 years old
6. Ability to comply with protocol
7. Life expectancy >/=12 weeks
8. Adequate hematologic and end-organ function per protocol
9. For women of childbearing potential: Negative serum or urine pregnancy test at screening.
10. For both male and female subjects: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 30 days after the last dose of study drug.

Exclusion Criteria:

1. Evidence of locally advanced or metastatic bladder cancer (including current disease involving renal pelvis, ureter, or prostatic urethra).

2. Evidence of muscle-invasive bladder cancer

3. Evidence of extravesical bladder cancer

4. Active central nervous system (CNS) metastases.

5. Prior treatment with PD-L1 or PD-1 inhibitor.

6. Prior radiation to bladder

7. Known additional malignancy that required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin.

8. Patient is considered a poor medical risk that would interfere with cooperation with the requirements of the study.

9. Patient has a condition or laboratory abnormality that might confound the study results, or interfere with the patient's participation for the full duration of the study treatment.

10. Patient has not recovered (i.e, to ≤Grade 1 or to baseline) from previous intravesical BCG or other anti-cancer therapy induced AEs.

11. Treatment with any approved anti-cancer therapy, including chemotherapy (systemic or intravesical), radiation therapy, or hormonal therapy within 3 weeks prior to the first dose of study treatment

12. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 4 weeks prior to the first dose of study treatment

13. Pregnant or lactating, or intending to become pregnant during the study

    a. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to the first dose of study treatment.

14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

15. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells

16. Allergy or hypersensitivity to components of the avelumab formulation

17. History of autoimmune disease defined per protocol

18. Prior allogeneic stem cell or solid organ transplantation

19. Current use of immunosuppressive medication defined per protocol

20. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

    a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

21. Positive test for HIV

22. Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test at screening);

    a. Patients with past or resolved hepatitis B (HBV) infection (positive anti-hepatitis B core antigen [anti-HBc] antibody test) are eligible. HBV DNA must be obtained in these patients prior to the first dose of study treatment.

23. Active hepatitis C

    a. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction assay is negative for HCV RNA.

24. Active infection requiring systemic therapy

25. Severe infections within 4 weeks prior to the first dose of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia

26. Significant cardiovascular disease, such as cerebral vascular accident/stroke (< 6 months prior to enrollment), New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina

27. Administration of a live/attenuated vaccine within 4 weeks prior to the first dose of study treatment, within 5 months following the administration of the last dose of study drug, or anticipation that such a live/attenuated vaccine will be required during the study

28. Other severe acute or chronic medical conditions defined per protocol