Functional Imaging of T-Cell Activation With [18F]F-AraG in Urothelial Carcinoma Patients Receiving Neoadjuvant Therapy or Patients With Cancer Receiving Standard of Care Anti-PD-1/L1

PRIMARY OBJECTIVES:

I. To assess the change in fluorine F 18 Ara-G (\[18F\]F-AraG) uptake in primary and/or metastatic tumor(s) on whole-body \[18F\]F-AraG PET/MR imaging associated with neoadjuvant atezolizumab and standard of care (SOC) anti-PD-1 or anti-PD-L1 treatment.

SECONDARY OBJECTIVES:

I. To correlate change in \[18F\]F-AraG uptake within the primary tumor with clinical and pathologic response in patients treated with neoadjuvant atezolizumab. (Cohort 1) II. To assess \[18F\]F-AraG uptake in lymphoid organs before and after anti-PD-1 or anti-PD-L1 treatment. (Cohort 1 and 2)

OUTLINE: Patients are assigned to 1 or 2 cohorts.

COHORT I (NEOADJUVANT COHORT): Patients receive fluorine F 18 Ara-G intravenously (IV) and undergo PET/MR imaging over 1.5-3 hours within 7 days of starting standard of care atezolizumab and within 7 days before surgery.

COHORT II (SOC COHORT): Patients receive fluorine F 18 Ara-G IV and undergo PET/MR imaging over 1.5-3 hours within 7 days of initiating course 1 of anti-PD-1 or anti-PD-L1 therapy and between day 15 of course 1 and day 7 of course 2 of anti-PD-1 or anti-PD-L1 treatment.

After completion of study, patients are followed up at days 2 and 8.

• Fluorine F 18 Ara-G (Drug), also known as 2'-deoxy-2'-fluoro-9-β-D-arabinofuranosylguanine, VisAcT: Given IV
• Positron Emission Tomography (Procedure), also known as PET, PET Scan: Undergo PET/MR imaging
• Magnetic Resonance Imaging (Procedure), also known as MRI: Undergo PET/MR imaging

Primary outcomes

• Change Between Pre-treatment and Post-treatment SUVmax (Standardized Uptake Values) in the Primary and/or Metastatic Tumor(s) on Whole-body [18F]F-AraG Positron Emission Tomography/Magnetic Resonance (PET/MR) Imaging by Study Cohort. [Up to 2 weeks]: The nonparametric paired Wilcoxon Signed-rank test will be used to assess differences in SUVmax before and after treatment. The log2 ratio of post-treatment versus baseline SUVmax within the tumor and lymphoid tissues will also be calculated

Secondary outcomes

• Compare Change in SUVmax of the Primary Tumor in Patients Who Achieve Pathologic Downstaging or Clinical Response and Those Without Pathologic or Clinical Response at Time of Surgery in Patients Receiving Neoadjuvant Atezolizumab (Cohort 1) [Up to 6 weeks]: To correlate change in SUVmax to clinical and/or pathologic response, patients will be divided into two groups: those who achieved clinical response and/or pathologic downs-staging, and those who did not. The median and interquartile range of change in SUVmax from baseline to pre-surgery in the different groups will be descriptively reported. For Cohort 1, clinical response will be determined by abdominal imaging performed <30 days after the last dose of atezolizumab prior to cystectomy compared to baseline pre-treatment imaging using RECIST v1.1 criteria, as specified in the companion treatment protocol. For Cohort 1, pathologic response will be determined by evidence of down-staging (e.g. from muscle invasive to non-muscle invasive, or complete pathologic response) at the time of cystectomy.
• Change Between Pre-treatment and Post-treatment SUVmax in Lymphoid Organs on Whole-body [18F]F-AraG PET/MR Imaging (Cohort 1 and 2) [Up to 8 days]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologically or cytologically documented cancer to which anti-PD1 or anti-PDL1 are approved therapies
* Eligible for with plan to undergo neoadjuvant treatment with atezolizumab followed by surgery as part of a companion study (NCT02451423), or planned to undergo treatment with anti-PD-1 or anti-PD-L1 per standard of care
* Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 regardless of disease stage (e.g. localized, locally advanced, or metastatic)
* In female patients, negative pregnancy test with no plans to become pregnant during the duration of the study
* Able to provide informed consent and follow the study guidelines
* Archival tumor tissue from biopsy or resection will be required for all patients; archival tissue should be of good quality based on total and viable tumor contents; fine needle aspiration, brushing, and cytologic cell pellets are not acceptable

Exclusion Criteria:

* History of prior treatment with immune checkpoint antibodies (e.g. anti-PD1, anti-PDL1, anti-CTLA4 antibody) or co-stimulatory agonist antibodies (e.g. anti-41BB, anti-OX40)

  * Prior intravesical treatment with Bacillus Calmette-Guerin (BCG) is allowed; however, the last dose must be at least 6 weeks from time of enrollment and patients must have documented progressive disease at least 6 weeks from completion of last BCG
* Diagnosis of immunodeficiency including history of human immunodeficiency virus (HIV)
* Receiving systemic steroid therapy or any form of immunosuppressive therapy within 7 days prior to first injection of \[18F\]F-AraG

  * Topical and inhaled corticosteroids are allowed
* Prior allogeneic stem cell or solid organ transplant
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
* Biopsy or resection of the primary tumor within 14 days the first injection of \[18F\]F-AraG
* Contraindication to magnetic resonance (MRI) imaging, as determined through review of the University of California, San Francisco (UCSF) MRI screening form by study investigator
* Evidence of active infection within 14 days of study enrollment
* Female patients who are pregnant or breastfeeding
* Inability to receive furosemide (Lasix) in the opinion of the treating investigator
* Patients that plan to receive off-label use of anti-PD1 or anti-PDL1

Participant flow

Outcome results

• Change Between Pre-treatment and Post-treatment SUVmax (Standardized Uptake Values) in the Primary and/or Metastatic Tumor(s) on Whole-body [18F]F-AraG Positron Emission Tomography/Magnetic Resonance (PET/MR) Imaging by Study Cohort. (Primary)
• Compare Change in SUVmax of the Primary Tumor in Patients Who Achieve Pathologic Downstaging or Clinical Response and Those Without Pathologic or Clinical Response at Time of Surgery in Patients Receiving Neoadjuvant Atezolizumab (Cohort 1) (Secondary)
• Change Between Pre-treatment and Post-treatment SUVmax in Lymphoid Organs on Whole-body [18F]F-AraG PET/MR Imaging (Cohort 1 and 2) (Secondary)

Adverse events

Time frame: Patients were evaluated one day and one week via telephone visit after each radiopharmaceutical injection for safety follow-up, up to 6 weeks.

Serious adverse events by term

Limitations and caveats: This study was terminated due to low accrual. Only four participants were accrued to Cohort 2 (SOC) for this protocol. No patients were enrolled for cohort 1.

• Informed Consent Form (PDF, 2018-11-13)
• Study Protocol and Statistical Analysis Plan (PDF, 2018-02-20)

• Lawrence Fong, MD, Principal investigator, University of California, San Francisco