Gemcitabine and Avelumab in Treating Patients with Advanced Kidney Cancer
- Histologic evidence of metastatic RCC with sarcomatoid features (>= 10% sarcomatoid component) or poor-risk RCC prognostic features (as defined by International Metastatic Renal Cell Carcinoma Database [IMDC] criteria). An outside pathology report is sufficient for study eligibility. However, pathology should still be obtained as possible for internal institutional pathology review
- Phase I dose-escalation portion only: * Patients must have =< 3 prior systemic treatment regimens with recent evidence of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Previous treatment with immune-checkpoint inhibitor therapy is allowable as a line of systemic therapy for the phase I portion. Prior systemic therapy in the adjuvant treatment setting is allowable as a prior line of therapy
- Phase Ib dose-expansion portion only: * Patients must have been treated with 0 or 1 prior lines of systemic therapy. Previous treatment with immune-checkpoint inhibitor therapy is allowable as a line of systemic therapy for the phase Ib expansion portion
- No prior therapy with gemcitabine chemotherapy
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Patients must have primary or metastatic formalin-fixed paraffin-embedded (FFPE) tissue available for histologic confirmation and possible determination of percent sarcomatoid component (if applicable). Outside pathology report is sufficient for study eligibility. However, pathology should still be obtained as possible for internal institutional pathology review
- Patients with history of treated brain metastases are eligible if off systemic corticosteroids for at least 2 weeks
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained =< 14 days prior to the first day of study therapy)
- Platelet count >= 100 x 10^9/L (obtained =< 14 days prior to the first day of study therapy)
- Hemoglobin >= 9 g/dL (may have been transfused) (obtained =< 14 days prior to the first day of study therapy)
- Total bilirubin level =< 1.5 x the upper limit of normal (ULN) range (obtained =< 14 days prior to the first day of study therapy)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 2.5 x ULN or AST and ALT levels =< 5 x ULN (for subjects with documented metastatic disease to the liver) (obtained =< 14 days prior to the first day of study therapy)
- Estimated creatinine clearance >= 45 mL/min using Cockcroft Gault formula (obtained =< 14 days prior to the first day of study therapy)
- Patients must have a projected life expectancy of at least 3 months
- Pregnancy test: negative serum or urine pregnancy test at screening for women of childbearing potential * Contraception: highly effective contraception for both male and female subjects throughout the study and for at least 30 days after last avelumab treatment administration if the risk of conception exists * In addition, women must not breastfeed while on this study as study drugs may also affect a breast-feeding child. Pregnant women and women who are breastfeeding are not allowed to participate in this study
- Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
- Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
- Prior organ transplantation including allogenic stem-cell transplantation
- Active infection requiring systemic therapy
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome, or positive HIV test result at screening
- Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test positive)
- Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines
- Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.03 grade >= 3)
- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication
- Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 grade > 1); however, alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator’s judgment are acceptable
- Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
I. To determine the feasibility and safety of avelumab and gemcitabine combination therapy in patients with metastatic renal cell carcinoma with sarcomatoid differentiation (sRCC) or poor-risk renal cell carcinoma (RCC).
II. To determine the maximum tolerated dose (MTD) of avelumab and gemcitabine combination therapy in patients with metastatic sRCC or poor-risk RCC.
I. To evaluate efficacy by assessment of the objective response rate (ORR) of patients with metastatic sRCC or poor-risk RCC with measurable disease receiving combination therapy.
II. To assess the clinical benefit rate (CBR) of patients with metastatic sRCC or poor-risk RCC receiving combination therapy.
III. To estimate the progression free survival (PFS) and overall survival (OS) of patients with metastatic sRCC or poor-risk RCC receiving combination therapy.
I. To assess changes in markers of T cell exhaustion and re-invigoration using peripheral blood multiparameter flow cytometry in patients with metastatic sRCC receiving combination therapy.
II. To assess changes in systemic plasma levels of inflammatory cytokines and chemokines, and potential links between kinetics and changes in T cell re-invigoration in patients with metastatic sRCC receiving combination therapy.
III. To evaluate the relationship between markers of T cell exhaustion and re-invigoration and the pre-treatment tumor burden for predicting clinical response in patients with metastatic sRCC and measurable disease receiving combination therapy.
OUTLINE: This is a phase I, dose-escalation study of gemcitabine followed by a phase Ib study.
Patients receive gemcitabine intravenously (IV) over 30 minutes on day 1. Beginning course 2, patients also receive avelumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 6 courses of gemcitabine and 5 courses of avelumab in the absence of disease progression or unacceptable toxicity. Patients may then continue to receive avelumab IV every 2 weeks for 12 months, per investigator discretion, in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 28 days, 90 days, and then every 12 weeks thereafter.
Trial Phase Phase I
Trial Type Treatment
University of Pennsylvania / Abramson Cancer Center
Vivek K. Narayan
- Primary ID UPCC 02818
- Secondary IDs NCI-2018-02400
- Clinicaltrials.gov ID NCT03483883