Mesothelin Positive, Stage IIIA Non-Small Cell Lung Cancer AJCC v7, Stage IIIB Non-Small Cell Lung Cancer AJCC v7, Stage III Non-Small Cell Lung Cancer AJCC v7, Stage IV Non-Small Cell Lung Cancer AJCC v7
Conditions
Brief summary
This phase I/II trial studies the best dose and side effects of anetumab ravtansine when given together with atezolizumab and how well they work in treating participants with non-small cell lung cancer that has spread to other places in the body. Monoclonal antibodies, such as anetumab ravtansine and atezolizumab, may interfere with the ability of tumor cells to grow and spread.
Detailed description
PRIMARY OBJECTIVES: I. To identify the recommended phase II dose of anetumab ravtansine combined with atezolizumab in advanced MSLN+ non-small cell lung cancer (NSCLC). (Phase I) II. To determine the confirmed response rate for the combination of anetumab ravtansine and atezolizumab in MSLN+ 2nd line NSCLC. (Phase II) SECONDARY OBJECTIVES: I. To describe adverse events and toxicities of the combination treatment of anetumab ravtansine and atezolizumab. (Phase I) II. To identify preliminary evidence of clinical activity (i.e. response, timed endpoints, etc.) (Phase I) III. To determine the progression-free survival (PFS) and the 1-year PFS rate for the combination of anetumab ravtansine and atezolizumab in 2nd-line NSCLC. (Phase II) IV. To determine the overall survival of anetumab ravtansine combined with atezolizumab in second-line therapy of NSCLC. (Phase II) V. Adverse events will also be summarized as well. (Phase II) CORRELATIVE OBJECTIVES: I. To determine using flow cytometry the levels of Bcl-2 interacting mediator of cell death (BIM) in circulating CD8+ CD11a+ PD-1+ T-cells, in peripheral blood samples collected from patients prior to initiation of therapy (baseline) and correlating these with confirmed response rate during and following treatment with the combination regimen. II. To determine tissue MSLN and PD-L1 expression and correlate with response to combination therapy with atezolizumab and anetumab ravtansine. III. To correlate baseline serum soluble PDL-1 (sPDL-1) with response to therapy. OUTLINE: This is a phase I, dose-escalation study of anetumab ravtansine followed by a phase II study. Participants receive anetumab ravtansine intravenously (IV) over 60 minutes and atezolizumab IV over 30-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up every 3 months for up to 2 years.
Interventions
BIOLOGICALAnetumab Ravtansine
Given IV
BIOLOGICALAtezolizumab
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PRE REGISTRATION ? INCLUSION CRITERIA: Ability to understand and the willingness to sign a written informed consent document * PRE REGISTRATION ? INCLUSION CRITERIA: Patient has disease amenable to biopsy if the archival tissue sample is unavailable; note: Archive sample must not be older than 12 months * REGISTRATION ? INCLUSION CRITERIA * Phase I only: Diagnosis of advanced/metastatic NSCLC for which no standard treatment option; Phase II only: Advanced NSCLC patients who have received at least 1 platinum-based systemic chemotherapy regimen * Patients with tumors having actionable genomic alterations should have received prior therapy with Food and Drug Administration (FDA) approved agents targeting these aberrations (ie EGFR, ALK, ROS1, BRAF V600E) * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Phase II only: Must have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria * Ability to understand and the willingness to sign a written informed consent document * Histological or cytologically confirmed NSCLC that shows moderate or stronger mesothelin expression in 30% of tumor cells by a companion assay; MSLN expression score using Ventana immunohistochemistry (IHC) SP74 assay; Phase I only: In addition 5- 30% tumor cells and 1, 2, or 3+ MSLN score; Phase II only: 30% tumor cells and either 2+/3+ * Life expectancy of \>= 12 weeks * Absolute neutrophil count \>= 1.5 ? 10\^9/L =\< 14 days prior to registration * Platelets \>= 100 ? 10\^9/L =\< 14 days prior to registration * Hemoglobin \>= 9 g/dL =\< 14 days prior to registration * Potassium \>= lower limit of normal (LLN) range for the institution =\< 14 days prior to registration * NOTE: Supplementation may be given before the first dose of study medication * Calcium \>= LLN (corrected for serum albumin, if albumin abnormal) =\< 14 days prior to registration * NOTE: Supplementation may be given before the first dose of study medication * Magnesium \>= LLN =\< 14 days prior to registration * NOTE: Supplementation may be given before the first dose of study medication * Sodium \>= LLN =\< 14 days prior to registration * NOTE: Supplementation may be given before the first dose of study medication * Phosphorus \>= LLN =\< 14 days prior to registration * NOTE: Supplementation may be given before the first dose of study medication * International normalized ratio (INR) =\< 1.5 =\< 14 days prior to registration * Serum creatinine =\< 1.5 mg/dL or creatinine clearance \>= 50 mL/min (calculated by Cockcroft Gault equation) =\< 14 days prior to registration * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN or =\< 5 x upper limits of normal (ULN) if liver metastases are present =\< 14 days prior to registration * Total bilirubin =\< 1.5 x ULN =\< 14 days prior to registration * Standard 12-lead electrocardiogram (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs): * QT corrected by Fridericia's formula (QTcF) interval at screening \< 450msec (using Fridericia?s correction) * Negative pregnancy test performed =\< 7 days prior to registration (women of childbearing potential only) * Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) * Willing to provide blood samples for correlative research purposes
Exclusion criteria
* REGISTRATION ?
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) (Phase I) | Up to 21 days | Maximum tolerated dose (MTD) of anetumab ravtansine combined with atezolizumab defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I) |
| Rate of Confirmed Response (Phase II) | 6 months | Defined as a patient who has achieved a partial response (PR) or complete response (CR) on two consecutive evaluations at least 4 weeks apart. Will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Activity (Phase I) | Up to 6 months | Will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population. |
| Incidence of Adverse Events According to Common Terminology Criteria for Adverse Events Version 4.0 (Phase I) | Up to 21 days after last dose | The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population. |
| Overall Survival (Phase II) | Up to 2 years | Defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier. |
| Progression-free Survival (Phase II) | 1 year and up to 2 years | Defined as the time from registration to the earliest date of documentation of disease progression or death due to any cause. The distribution of progression-free survival will be estimated using the method of Kaplan Meier. Will also report the 1-year progression free survival (PFS) rate for the combination of anetumab ravtansine and atezolizumab in 2nd-line non-small cell lung cancer (NSCLC). |
Countries
United States
Participant flow
Recruitment details
One (1) patient was recruited from August 2018 to September 2019 at Mayo Clinic. This trial was permanently closed on September 11, 2019. Since only one patient was accrued, patient confidentiality prevents the reporting of this patient.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Anetumab Ravtansine, Atezolizumab) Participants receive 5.5 mg/kg anetumab ravtansine IV over 60 minutes and 1200 mg atezolizumab IV over 30-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | 0 |
| Total | 0 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 0 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) (Phase I)
Maximum tolerated dose (MTD) of anetumab ravtansine combined with atezolizumab defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I)
Time frame: Up to 21 days
Population: Since only one patient was accrued, patient confidentiality prevents the reporting of this patient.
Primary
Rate of Confirmed Response (Phase II)
Defined as a patient who has achieved a partial response (PR) or complete response (CR) on two consecutive evaluations at least 4 weeks apart. Will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.
Time frame: 6 months
Population: Since only one patient was accrued, patient confidentiality prevents the reporting of this patient.
Secondary
Clinical Activity (Phase I)
Will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population.
Time frame: Up to 6 months
Population: Since only one patient was accrued, patient confidentiality prevents the reporting of this patient.
Secondary
Incidence of Adverse Events According to Common Terminology Criteria for Adverse Events Version 4.0 (Phase I)
The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population.
Time frame: Up to 21 days after last dose
Population: Since only one patient was accrued, patient confidentiality prevents the reporting of this patient.
Secondary
Overall Survival (Phase II)
Defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Time frame: Up to 2 years
Population: Since only one patient was accrued, patient confidentiality prevents the reporting of this patient.
Secondary
Progression-free Survival (Phase II)
Defined as the time from registration to the earliest date of documentation of disease progression or death due to any cause. The distribution of progression-free survival will be estimated using the method of Kaplan Meier. Will also report the 1-year progression free survival (PFS) rate for the combination of anetumab ravtansine and atezolizumab in 2nd-line non-small cell lung cancer (NSCLC).
Time frame: 1 year and up to 2 years
Population: Since only one patient was accrued, patient confidentiality prevents the reporting of this patient.