Atezolizumab Dosing for Cancer
Recruiting in Palo Alto (17 mi)
Overseen byJames L Gulley, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Immunostimulatory agents, Immunosuppressive medications
Disqualifiers: Autoimmune disease, Severe allergies, others
No Placebo Group
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?Background:
A type of drug called monoclonal antibody immune checkpoint inhibitors are often used in cancer treatment. These drugs help the body s immune system fight cancer by blocking proteins that cause cancer cells to grow. One of these drugs (atezolizumab) is approved to treat certain cancers. Researchers want to find out if lower doses of this drug might provide the same benefit with fewer adverse effects.
Objective:
To test different doses and timing of atezolizumab for people with cancer.
Eligibility:
People aged 18 years and older with cancer that has spread locally or to other organs. They must be eligible for treatment with the study drug.
Design:
Participants will be screened. They will have blood tests and imaging scans. They will provide a sample of tissue from their tumor.
Atezolizumab is administered through a tube attached to a needle inserted into a vein in the arm. Participants will take this drug alone or combined with other drugs prescribed for their care.
The first 2 treatments will be done per the FDA recommended dose and schedule. Before administering the second dose of the study drug, researchers will check the level of the drug in the participant s blood. Depending on those results, their 3rd dose will be scheduled 2 to 6 weeks later.
For the 3rd dose of the study drug, participants will switch to the FDA minimum dosage. Dosages of any other drugs will not change.
Researchers will continue to test the levels of the drug in participants blood before each treatment for 16 weeks. After that, these levels will be tested every 3 months.
Study treatment may last up to 2 years.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, you cannot have taken certain investigational or immunostimulatory agents within a month before starting the study. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug Atezolizumab (Tecentriq) for cancer treatment?
Atezolizumab has shown effectiveness in treating advanced bladder cancer and non-small cell lung cancer, with studies indicating improved survival rates and tumor response compared to other treatments. It works by boosting the immune system's ability to fight cancer cells, and its effectiveness is particularly notable in patients with higher levels of a specific protein (PD-L1) on their cancer cells.
12345Is atezolizumab (Tecentriq) generally safe for humans?
Atezolizumab (Tecentriq) has been shown to have an acceptable safety profile in clinical trials for various cancers, including lung and bladder cancer. Common side effects include fatigue, decreased appetite, and nausea, while more serious side effects can include pneumonia and liver inflammation. Overall, it is considered to have a favorable toxicity profile.
34678What makes the drug atezolizumab unique for cancer treatment?
Atezolizumab is unique because it targets a specific protein called PD-L1, helping the immune system recognize and attack cancer cells. It is administered as an intravenous infusion and offers flexible dosing schedules, which can be extended beyond the standard regimen without compromising effectiveness.
3891011Eligibility Criteria
Adults aged 18+ with various advanced cancers (like lung, liver, melanoma) that have spread and are eligible for atezolizumab treatment can join. They must not be pregnant, breastfeeding (or willing to stop), and agree to use contraception. People with certain viral infections must have them under control. Those with a history of severe allergies or autoimmune diseases cannot participate.Inclusion Criteria
My organs and bone marrow are functioning well.
I had hepatitis C but now have no detectable virus.
I am 18 years old or older.
+11 more
Exclusion Criteria
You have taken a non-approved experimental drug for your condition within the last 28 days.
You have had a bone marrow or solid organ transplant in the past.
You are allergic to Chinese hamster ovary cell products or any part of the atezolizumab medicine.
+13 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Initial Treatment
Participants receive the FDA approved dose and frequency of atezolizumab for the first two doses
4-6 weeks
2 visits (in-person)
Therapeutic Drug Monitoring Treatment
Participants switch to 840 mg dose of atezolizumab with therapeutic drug monitoring to maintain target trough levels
16 weeks
8 visits (in-person)
Extended Monitoring
Participants continue to receive atezolizumab with dose adjustments every 3 months based on therapeutic drug monitoring
Up to 2 years
Every 3 months (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing if lower doses of atezolizumab, an immune system-boosting drug used in cancer treatment, are as effective as standard doses but cause fewer side effects. Participants will receive the FDA recommended dose initially then switch to the minimum dosage while researchers monitor drug levels in their blood over time.
1Treatment groups
Experimental Treatment
Group I: Arm 1Experimental Treatment1 Intervention
Atezolizumab treatment course
Atezolizumab is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Tecentriq for:
- Melanoma
- Hepatocellular carcinoma
- Small cell lung cancer
- Non-small cell lung cancer
- Urothelial carcinoma
🇪🇺 Approved in European Union as Tecentriq for:
- Melanoma
- Hepatocellular carcinoma
- Small cell lung cancer
- Non-small cell lung cancer
- Urothelial carcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients. [2020]To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
Atezolizumab: A Review in Previously Treated Advanced Non-Small Cell Lung Cancer. [2020]Atezolizumab (TECENTRIQ™), an immune checkpoint inhibitor, is an immunoglobulin G1 monoclonal antibody that binds to programmed death ligand 1 (PD-L1) and blocks its interactions with programmed death 1 and B7.1 receptors. Atezolizumab is approved as monotherapy in several countries worldwide for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have previously received chemotherapy. Approval was based on its clinical benefit in this setting in the phase II POPLAR and phase III OAK trials. In these studies, atezolizumab significantly prolonged overall survival (OS) relative to docetaxel, regardless of PD-L1 status. Increasing PD-L1 expression was associated with OS improvements. Atezolizumab also demonstrated efficacy in the phase II FIR and BIRCH trials, as assessed by objective response rates (ORRs) in patients with tumours expressing PD-L1. Higher ORRs were seen in patients with high PD-L1 expression. Atezolizumab had an acceptable, manageable tolerability profile, with a low incidence of immune-related adverse events. Therefore, atezolizumab is a valuable treatment option for patients with advanced NSCLC that has progressed during or after chemotherapy.
Atezolizumab: First Global Approval. [2019]Atezolizumab (Tecentriq™)-a monoclonal antibody targeting programmed death ligand 1 (PD-L1 or CD274 antigen)-is being developed by Genentech as treatment for a variety of haematological malignancies and solid tumours. It been approved in the US as a second-line therapy for urothelial carcinoma and is awaiting approval as a second-line therapy for non-small cell lung cancer. This article summarizes the milestones in the development of atezolizumab leading to this first approval for urothelial carcinoma.
Atezolizumab: A PD-L1-Blocking Antibody for Bladder Cancer. [2022]Atezolizumab (Tecentriq, MPDL3280A; Genentech/Roche) is an FcγR binding-deficient, fully humanized IgG1 mAb designed to interfere with the binding of PD-L1 ligand to its two receptors, PD-1 and B7.1. By blocking the PD-L1/PD-1 immune checkpoint, atezolizumab reduces immunosuppressive signals found within the tumor microenvironment and, consequently, increases T-cell-mediated immunity against the tumor. Atezolizumab has been FDA approved as second-line therapy for advanced bladder cancer. This accelerated approval was based on phase II trial data in patients with metastatic bladder cancer that showed unexpected and durable tumor responses. In subjects whose tumors progressed on first-line platinum-based chemotherapy, the objective response rate was 15%, the complete response rate was 5%, and 1-year overall survival was 36%. In subjects that were chemotherapy naïve and cisplatin ineligible, the objective response rate was 24%, the complete response rate was 7%, and 1-year overall survival was 57%. Better responses were associated with higher PD-L1 expression on the tumor-infiltrating leukocytes. These data suggest that patients with advanced bladder cancer treated with atezolizumab have significantly better response rates and survival than historical controls treated with other second-line regimens. The toxicity profile of atezolizumab is also favorable. Trials are currently assessing whether atezolizumab is effective in earlier bladder cancer stages and in the first-line metastatic setting. Clin Cancer Res; 23(8); 1886-90. ©2016 AACR.
[Atezolizumab (Tecentriq®): Activity, indication and modality of use in advanced or metastatic urinary bladder carcinoma]. [2019]Treatments for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin are currently limited. Atezolizumab (Tecentriq®) is a monoclonal antibody targeting PD-L1. The first of IMVIGOR 210 phase II trial (NCT02951767) investigated atezolizumab as front line treatment among 119 patients with metastatic urothelial cancer unfit for cisplatin. Response rate was 23% and median overall survival 15.9 months. The second cohort (NCT02108652) included 310 patients whose tumors were progressing after first line platinum-based chemotherapy. Response rate was 15% and median overall survival 7.9 months. Among patients with high PD-L1 expression on infiltrating immune cells (ICs), response rate was 26% and median overall survival 11 months. Atezolizumab was well-tolerated in both cohorts with 66% of treatment-related toxicities including 12% (cohort 1) and 7% (cohort 2) of grade 3-4 adverse events. These results led to an approval by the FDA in United States and the EMA in Europe. In France, atezolizumab was available through an early access agreement by the French National Agency for Medicines and Health Products (ANSM) for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin. So far, its avaibility in France within the EMA approval is pending its pricing.
Atezolizumab as the First Systemic Therapy Approved for Alveolar Soft Part Sarcoma. [2023]The objective was to review the pharmacology, efficacy, and safety of atezolizumab (Tecentriq) for the treatment of adult and pediatric patients aged 2 years and older with unresectable or metastatic alveolar soft part sarcoma (ASPS).
Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study. [2020]Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.
U.S. Food and Drug Administration Approval Summary: Atezolizumab for Metastatic Non-Small Cell Lung Cancer. [2022]On October 18, 2016, the FDA approved atezolizumab (TECENTRIQ; Genentech, Inc.) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose disease progressed during or following platinum-containing chemotherapy. Approval was based on demonstration of clinically meaningful improvements in overall survival (OS) and an acceptable safety profile in two randomized clinical trials (OAK and POPLAR). Median OS in OAK, a phase III trial, was 13.8 months [95% confidence interval (CI), 11.8-15.7] in the atezolizumab arm compared with 9.6 months (95% CI, 8.6-11.2) in the docetaxel arm [hazard ratio (HR) = 0.74; 95% CI, 0.63-0.87; P = 0.0004]. Median OS in POPLAR, a phase II trial, was 12.6 months (95% CI, 9.7-16.0) and 9.7 months (95% CI, 8.6-12.0; HR = 0.69; 95% CI, 0.52-0.92) for the atezolizumab and docetaxel arms, respectively. In patients treated with atezolizumab, the most common (≥20%) adverse reactions were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation; the most common (≥2%) grade 3 to 4 adverse events were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included 1.4% incidence each of grade 3 to 4 pneumonitis, hepatitis, colitis, and thyroid disease. Clin Cancer Res; 23(16); 4534-9. ©2017 AACR.
Killing a fly with a sledgehammer: Atezolizumab exposure in real-world lung cancer patients. [2023]Atezolizumab is an anti-PDL1 approved for treating lung cancer. A threshold of 6 μg/mL in plasma has been associated with target engagement. The extent to which patients could be overexposed with the standard 1200 mg q3w dosing remains unknown. Here, we monitored atezolizumab peak and trough levels in 27 real-world patients with lung cancer as part of routine therapeutic drug monitoring. Individual pharmacokinetic (PK) parameters were calculated using a population approach and optimal dosing-intervals were simulated with respect to the target trough levels. No patient had plasma levels below 6 μg/mL. The results showed that the mean trough level after the first treatment was 78.3 ± 17 μg/mL, that is, 13 times above the target concentration. The overall response rate was 55.5%. Low-grade immune-related adverse events was observed in 37% of patients. No relationship was found between exposure metrics of atezolizumab (i.e., minimum plasma concentration, maximum plasma concentration, and area under the curve) and pharmacodynamic end points (i.e., efficacy and toxicity). Further simulations suggest that the dosing interval could be extended from 21 days to 49 up to 136 days (mean: 85.7 days, i.e., q12w), while ensuring plasma levels still above the 6 μg/mL target threshold. This observational, real-world study suggests that the standard 1200 mg q3w fixed-dose regimen of atezolizumab results in significant overexposure in all the patients. This was not associated with increased side effects. As plasma levels largely exceed pharmacologically active concentrations, interindividual variability in PK parameters did not impact efficacy. Our data suggest that dosing intervals could be markedly extended with respect to the target threshold associated with efficacy.
Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation. [2022]Atezolizumab is approved as an intravenous (IV) infusion for use as a single agent and in combination with other therapies in a number of indications. The objectives of this publication are to characterize atezolizumab pharmacokinetics (PK) across indications with the available clinical data from one phase I and eight phase III studies, to determine the exposure-response (ER) relationships in combination settings across a variety of tumor types, and to provide the clinical safety to support the extension of the 840 mg q2w, 1200 mg q3w, and 1680 mg q4w IV dosing regimens across various indications in combination settings. Across all clinical studies, atezolizumab PK remained in the dose-linear range and were similar across tumor types when used in combination therapy or as a monotherapy. In the combination studies, efficacy was independent of the exposures tested and there was no significant increase in adverse events with increasing atezolizumab exposure (flat ER). The safety profile of atezolizumab in the individual combination studies was generally consistent with the established safety profile of atezolizumab, the combination partners, and the disease under study. The similar atezolizumab PK across monotherapy and combination therapy settings as well as the flat ER in new tumor types and combination therapies support the use of the 3 interchangeable atezolizumab dosing regimens in the combination setting. Atezolizumab is now approved with 3 interchangeable IV dosing regimens of 840 mg q2w, 1200 mg q3w, and 1680 mg q4w for single-agent and combination therapy use in the USA and EU.
Model-based simulation to support the extended dosing regimens of atezolizumab. [2021]The currently recommended dosages of atezolizumab for patients with non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) is 840 mg every 2 weeks, 1200 mg every 3 weeks (q3w), and 1680 mg every 4 weeks (q4w). However, it has been argued that these dosages may not be optimal. This study aimed to explore the feasibility of extended dosing regimens by population pharmacokinetics (PK) simulations and exposure-response (E-R) relationships.