Phase I Trial of Radiotherapy in Combination With Atezolizumab in Borderline Resectable and Unresectable Cutaneous Squamous Cell Carcinoma(cSCC)
Overview
- Phase
- Phase 1
- Intervention
- Atezolizumab
- Conditions
- Locally Advanced Skin Squamous Cell Carcinoma
- Sponsor
- City of Hope Medical Center
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Dose limiting toxicity
- Status
- Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
This phase I trial tests the safety and side effects radiotherapy in combination with atezolizumab in treating patients with cutaneous squamous cell cancer that has spread to nearby tissue or lymph nodes (locally advanced) and can be removed from surgery (resectable) or cannot be remove by surgery (unresectable). Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving radiotherapy in combination with atezolizumab may help improve outcomes for remission (cancer that is under control) than taking either treatment separately.
Detailed Description
PRIMARY OBJECTIVE: I. To determine the safety profile of combination of atezolizumab + radiation therapy (RT) in borderline resectable or unresectable cutaneous squamous cell carcinoma (cSCC). SECONDARY OBJECTIVES: I. Determine pathologic response after neoadjuvant atezolizumab + RT. II. Determine clinical response (via imaging and clinical exam) postoperatively (if surgically resectable) or at post-treatment biopsy (if not surgically resectable), and 3 months following the completion of surgery or RT (if not surgically resectable). III. Define the toxicity profile associated with the treatment protocol. IV. Assess short-term quality-of-life associated with the treatment protocol. EXPLORATORY OBJECTIVES: I. To compare immune checkpoint molecule (e.g. PD1, PD-L1, TIM3, TIGIT, etc.) expression intensity within tumor cells and immune cells in the tumor microenvironment, as well as immune cell subset infiltration patterns including T cells before and after atezolizumab + stereotactic body radiation therapy (SBRT) by multiplex immunohistochemistry (or immunofluorescence). II. To evaluate the impact of tumor molecular features on immune response and treatment outcome using next generation targeted deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequencing of pre-treatment tumor tissue. III. To compare changes in circulating immune cell subsets in peripheral blood by RNA-based T-cell receptor (TCR)-sequencing and immunophenotyping by flow cytometry (or immunophenotyping by single-cell RNA sequencing), and correlate changes with response, clinical outcomes, and toxicity. IV. To evaluate circulating tumor DNA (ctDNA) levels before start of treatment and immediately prior to surgery/repeat biopsy. OUTLINE: Patients undergo SBRT on days 1, 3, 5, 7, and 9 of cycle 1. Beginning 1-2 days after SBRT, patients also receive atezolizumab intravenously (IV) on day 1. Treatment repeats every 3 weeks for 3 cycles in the absence of disease progression or unacceptable toxicity. After completion of study, patients are followed up every 12 weeks for 24 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed locally advanced borderline resectable or unresectable cSCC and oligometastatic (1-3 sites of metastatic disease) cSCC receiving therapy to the primary
- •Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 10 mm with computed tomography (CT) scan or \> 10 mm with calipers by clinical exam by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act \[HIPAA\] in the United States of America \[USA\], European Union \[EU\] Data Privacy Directive in the EU) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
- •Age \>= 18 years at time of study entry
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 1
- •Life expectancy \>= 24 weeks
- •Body weight \> 30 kg
- •Hemoglobin \>= 9.0 g/dL
- •Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L (\>= 1000 per mm\^3)
- •Platelet count \>= 75 x 10\^9/L (\>= 75,000 per mm\^3)
Exclusion Criteria
- •Participation in another clinical study with an investigational product during the last 3 months
- •Patients with active interstitial lung disease (ILD)/pneumonitis or with a history of ILD/pneumonitis requiring steroids
- •Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
- •Any previous treatment with a PD1 or PD-L1 inhibitor, including atezolizumab, 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)
- •Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
- •Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 30 days prior to the first dose of study drug for patients who have received prior tyrosine kinase inhibitors (TKIs) \[e.g., erlotinib, gefitinib and crizotinib\] and within 6 weeks for nitrosourea or mitomycin C. (If sufficient wash-out time has not occurred due to the schedule or pharmacokinetics (PK) properties of an agent, a longer wash-out period may be required.)
- •Patients with corrected QT (QTc) interval \> 470 msec during screening
- •Current or prior use of immunosuppressive medication within 14 days (use 28 days if combining atezolizumab with a novel agent) before the first dose of atezolizumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion:
- •Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- •Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
Arms & Interventions
Treatment (SBRT, atezolizumab)
Patients undergo SBRT on days 1, 3, 5, 7, and 9 of cycle 1. Beginning 1-2 days after SBRT, patients also receive atezolizumab IV on day 1. Treatment repeats every 3 weeks for 3 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Treatment (SBRT, atezolizumab)
Patients undergo SBRT on days 1, 3, 5, 7, and 9 of cycle 1. Beginning 1-2 days after SBRT, patients also receive atezolizumab IV on day 1. Treatment repeats every 3 weeks for 3 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Stereotactic Body Radiation Therapy
Outcomes
Primary Outcomes
Dose limiting toxicity
Time Frame: Up to 3 weeks
Incidence of adverse events
Time Frame: Up to 90 days
Toxicity will be assessed by Common Terminology Criteria for Adverse Events version 5 criteria.
Secondary Outcomes
- Progression free survival (PFS)(From the date of diagnosis to the date of progression, assessed up to 24 months)
- Overall survival (OS)(From the date of diagnosis to the date of death, assessed up to 24 months)
- Treatment response rate(After completion of cycle 3 (each cycle is 21 days))