Anti-Mesothelin Immunotoxin LMB-100 Followed by Pembrolizumab in Malignant Mesothelioma
- Registration Number
- NCT03644550
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Treatment outcomes for people with pleural or peritoneal mesothelioma are often poor. The drug LMB-100 can attack and kill cancer cells. The drug pembrolizumab helps the immune system fight cancer. Together, these drugs might help people with these cancers.
Objective:
To test if pembrolizumab given after LMB-100 shrinks tumors in people with pleural or peritoneal mesothelioma.
Eligibility:
People ages 18 and older with pleural or peritoneal mesothelioma that has not responded to platinum-based therapy
Design:
Participants will be screened with:
Tumor sample. Participants will have a biopsy if one is needed.
Medical history
Physical exam
Blood, heart, and urine tests
X-rays and scans: Participants will lie on a table. A machine will take pictures of the body.
Participants will receive LMB-100 by intravenous (IV) on days 1, 3, and 5 of two 21-day cycles. They will be observed for up to 2 hours after each infusion. They will receive drugs like Benadryl, Tylenol, and Zantac to help with side effects.
Starting with the 3rd cycle, participants will receive pembrolizumab by IV on day 1 of each 21-day cycle for up to 2 years.
Participants will have blood and urine tests, heart tests, and chest x-rays at least once per cycle. They will have scans every 6 weeks.
Participants may opt to provide tumor biopsies before starting the first cycle, after 2 cycles of LMB-100, and after 2 cycles of pembrolizumab.
Participants will a follow-up visit 4-6 weeks after their last drug dose of the study drug. This includes blood and heart tests and scans. They may then have scans every 6 weeks.
Participants will be contacted once a year for follow-up.
- Detailed Description
Background:
* LMB-100, and a closely related immunotoxin, SS1P, also targeting mesothelin, have been studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.
* LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing tumor models including mesothelioma patient-derived xenografts (PDX) models
* Programmed cell death protein 1 (PD-1) (encoded by the gene Pdcd1) is an Ig superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands
* The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions.
* In immune-competent mice bearing human mesothelin expressing tumors local administration of LMB-100 with CTLA-4 blockade eradicates murine tumors by promoting anti-cancer immunity.
* LMB-100 treatment increase cluster of differentiation 8 (CD8)+ T cell infiltration in murine lung adenocarcinoma tumors that express human mesothelin.
* Combination treatment with LMB-100 plus anti-PD1 results in greater anti-tumor efficacy in murine lung cancer model
* Pembrolizumab is an anti PD-1 antibody that has demonstrated responses of long duration in clinical trials and has generally been well-tolerated
* It is hypothesized that the anti-mesothelin immunotoxin LMB-100 followed by pembrolizumab will result in greater anti-tumor efficacy in patients with mesothelioma.
Objectives:
- To determine the objective response rate of sequential therapy with LMB-100 followed by pembrolizumab in subjects with pleural and peritoneal mesothelioma.
Eligibility:
* Histologically confirmed epithelial or biphasic pleural or peritoneal mesothelioma (with \<50% sarcomatoid component) not amenable to potentially curative surgical resection.
* Subjects must have at least one prior chemotherapy regimen that includes pemetrexed and cisplatin or carboplatin.
* Age greater than or equal to 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate organ and bone marrow function
* Prior PD1/Programmed death-ligand 1 (PD-L1) inhibitor treatment is prohibited
* Chemotherapy within 4 weeks or radiotherapy within 2 weeks prior to start of study therapy is prohibited.
* Subjects with active central nervous system (CNS) metastasis are excluded
* Subjects with active autoimmune disease for which they had received systemic treatment during the previous 2 years receiving systemic glucocorticoids (excluding daily glucocorticoid-replacement therapy for conditions such as adrenal or pituitary insufficiency) are excluded
* Subjects with active interstitial lung disease, or a history of pneumonitis for which they had received glucocorticoids are excluded
Design:
* This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab in subjects with advanced pleural or peritoneal mesothelioma who have progressed on standard therapies.
* Subjects will receive LMB-100 at the single agent maximum tolerated dose (MTD) on days 1, 3 and 5 of a 21-day cycle for 2 cycles and pembrolizumab 200 mg on day 1 of each subsequent 21-day cycle until disease progression (on or after pembrolizumab) or intolerable toxicity for a maximum of 2 years (unless second course initiated).
* Tumor biopsies will be performed at baseline, at the end of cycle 2 and at the end of cycle 4 to evaluate changes in the tumor immune microenvironment following treatment with LMB-100 and pembrolizumab.
* Up to 35 evaluable subjects will be enrolled
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 18
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 1/LMB- 100+pembrolizumab Pembrolizumab LMB-100 administered in cycles 1 and 2 + pembrolizumab administered in subsequent cycles. LMB-100 140mcg/kg Intravenous infusion (IVI), Days 1, 3, 5 in cycles 1, 2. Pembrolizumab 200mg IVI, every (Q) subsequent cycle on Day 1. 1/LMB- 100+pembrolizumab LMB-100 LMB-100 administered in cycles 1 and 2 + pembrolizumab administered in subsequent cycles. LMB-100 140mcg/kg Intravenous infusion (IVI), Days 1, 3, 5 in cycles 1, 2. Pembrolizumab 200mg IVI, every (Q) subsequent cycle on Day 1.
- Primary Outcome Measures
Name Time Method Number of Participants With an Objective Response (Partial Response + Complete Response) Every 6 weeks until disease progression, an average of 3.1 months Number of participants who received at least 1 cycle of study therapy and who had their disease reevaluated that experienced a partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or modified RECIST criteria. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
- Secondary Outcome Measures
Name Time Method Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Date treatment consent signed to date off study, approximately 22 months and 29 days. Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Progression Free Survival (PFS) Time from start of treatment to time of progression (on or after pembrolizumab) or death, whichever occurs first, an average of 6.5 months Progression free survival (PFS) is defined as the duration of time from start of treatment to time of progression (on or after pembrolizumab) or death, whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 20% increase in the sum of the diameters of target lesions,taking as reference the smallest sum on study.
Overall Survival (OS) Time between the first day of treatment to the day of death, an average of 17 months Overall survival is the time between the first day of treatment to the day of death.
Duration of Overall Response (DOR) Time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, an average of 3.1 months The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is defined as disappearance of all target lesions with no evidence of tumor elsewhere. Partial Response (PR) is defined as at least a 30% decrease in the total tumor measurement.
Percentage of Participants With an Overall Response An average of 3.1 months. Percentage of participants who received at least 1 cycle of study therapy and who had their disease reevaluated that experienced a partial or complete response per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or modified RECIST criteria. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States