Neoplasms Clinical Trial
Official title:
A Phase Ib/II Study of Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in Participants With Previously Treated Metastatic and/ or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors
Verified date | February 2022 |
Source | National Institutes of Health Clinical Center (CC) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
Background: LMB-100 is a man-made protein designed to kill cancer cells. LMB-100 targets a cancer marker called mesothelin. Mesothelin is found on the surface of many different tumors, including pancreatic cancer, but is made by a very small number of normal tissues. Other cancers that make mesothelin include mesothelioma, cholangiocarcinoma, thymic carcinoma, ovarian, lung, gastric, endometrial, cervical, and ampullary cancers. After binding to the mesothelin on tumors, LMB-100 can attack and kill cancer cells. Researchers want to see how well it works when given with and without nab-paclitaxel, a drug which treats pancreatic cancer. Objectives: Arm A- To find a safe dose of LMB-100 with a fixed standard dose of nab-paclitaxel in people with advanced pancreatic cancer. To see how well the combination of the two drugs reduce tumor size. Arm B- To find a safe dose of LMB-100 when it is given as a continuous infusion over several days. Eligibility: Arm A- Adults age 18 and older with advanced pancreatic cancer that has worsened after anti-cancer therapy. Arm B- Adults age 18 and older with advanced pancreatic cancer, mesothelioma or other solid tumor that makes mesothelin that has worsened after anti-cancer therapy Design: Participants will be screened with medical history and physical exam. They will give blood, urine, and tissue samples. They will have scans and x-rays. During each 21-day cycle: - For Arm A - Participants will get LMB-100 by an intravenous (IV) catheter on days 1, 3, and 5. This is a tube inserted in a vein, usually in the arm. - Participants will get nab-paclitaxel by IV on days 1 and 8. - For Arm B - Participants will get LMB-100 by an IV catheter as a continuous infusion beginning on day 1 and continuing for 2-4 days - Some participants will also get nab-paclitaxel by IV on days 1 and 8. All participants will get this combination for up to 2 cycles or until their disease worsens or they have intolerable side effects. Participants will have blood and urine tests and scans throughout the study. Participants will have a safety follow-up visit 3-6 weeks after treatment ends. If their disease remains stable or improves, they will be scanned every 6 weeks until their disease gets worse. Even if their disease gets worse, they or their doctor will be called to talk about their cancer status....
Status | Completed |
Enrollment | 40 |
Est. completion date | June 22, 2021 |
Est. primary completion date | January 2, 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | - INCLUSION CRITERIA: - For participants who will be receiving nab-paclitaxel (all arms except Phase I Arm B Single Agent Lead-in) - Histologically confirmed recurrent, advanced or metastatic pancreatic ductal adenocarcinoma as determined by National Cancer Institute (NCI) Laboratory of Pathology. - No treatment with paclitaxel or nab-paclitaxel within 4 months prior to initiation of study therapy - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. - Adequate hematological function: neutrophil count of greater than or equal to 1.0 x 10(9) cells/L, platelet count of greater than or equal to 95,000/microliters, hemoglobin greater than or equal to 9 g/dL - Measurable disease as per the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria v 1.1 - For participants who will NOT receive nab-paclitaxel (Arm B1 Single Agent Lead-in only) - Histologically confirmed solid tumor malignancy for which no curative therapy exists with at least 25% of tumor cells expressing mesothelin as determined by NCI Laboratory of Pathology. Determination can be made using archival tumor tissue or fresh biopsy. Subjects with epithelioid mesothelioma and pancreatic adenocarcinoma are automatically eligible and are not required to have this test. - ECOG performance status (PS) 0-2. - Adequate hematological function: neutrophil count of greater than or equal to 1.0 x 10(9) cells/L, platelet count of greater than or equal to 85,000/microliters, hemoglobin greater than or equal to 8.5 g/dL - Measurable and/or evaluable disease as per the RECIST Criteria v 1.1 - For all arms of the protocol - Participants must have received at least one prior chemotherapy regimen for their disease. - Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of LMB-100 in combination with nab-paclitaxel in persons <18 years of age, children are excluded from this study. - Participants must be more than 14 days removed from most recent minor surgical procedure (such as biliary stenting), 28 days from most recent major surgical procedure, 14 days removed from most recent radiation therapy, chemotherapy or experimental drug treatment with published half-life known to be 72 hours or less and 28 days removed from last experimental drug treatment with unpublished or half-life greater than 72 hours. - All acute toxic effects of any prior radiotherapy, chemotherapy, experimental drug treatment or surgical procedure must have resolved to Grade less than or equal to 1, except alopecia (any grade) and peripheral neuropathy. - Serum albumin greater than or equal to 2.5 mg/dL without intravenous supplementation - Adequate liver function: Bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN). AST and ALT up to 5x ULN is permitted for patients with liver metastases. - Adequate renal function: creatinine clearance greater than or equal to 50 mL/min. - Must have left ventricular ejection fraction > 50% - Must have an ambulatory oxygen saturation of > 88% on room air - The effects of LMB-100 alone or in combination with nab-paclitaxel on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry until 3 months the last dose of study therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. - Ability of participant to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: - Exclusion criteria for all study arms - Known or clinically suspected central nervous system (CNS) 2.1.2.1 primary tumors or metastases including leptomeningeal metastases. History or clinical evidence of CNS metastases unless they have been previously treated, are asymptomatic, and have had no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days. - Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant pulmonary disease other than that related to the primary cancer, uncontrolled diabetes mellitus, and/or significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or clinically significant pericardial effusion) - Any known diagnoses, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition (other than pancreatic adenocarcinoma) that would contraindicate the use of an investigational drug, interfere with tumor measurement or lead to an expected life expectancy of less than 6 months as judged by the investigator - Active or uncontrolled infections. - Live attenuated vaccinations within 14 days prior to treatment - Dementia or altered mental status that would prohibit informed consent - Pregnant women are excluded from this study because the effects of LMB-100 on the developing fetus are unknown and may have the potential to cause teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LMB-100, breastfeeding should be discontinued if the mother is treated with LMB-100. These potential risks may also apply to other agents used in this study. - Known hypersensitivity to any of the components of LMB-100 - Baseline corrected QT interval by Fridericia (QTcF) interval of > 470 ms, participants with baseline resting bradycardia < 45 beats per minute, or baseline resting tachycardia> 100 beats per minute. - Exclusion criteria specific to patients who will be receiving nab-paclitaxel (all arms except Arm B1 Single Agent Lead-in) - Participants with contra-indication and/or history of severe hypersensitivity reactions to nab-paclitaxel - Participants with baseline peripheral neuropathy greater than grade 2 - Human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection due to risk of progression while receiving immunosuppressive chemotherapy |
Country | Name | City | State |
---|---|---|---|
United States | National Institutes of Health Clinical Center | Bethesda | Maryland |
Lead Sponsor | Collaborator |
---|---|
National Cancer Institute (NCI) |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | A DLT is defined per protocol as events attributed to LMB-100 and occurring during the DLT period such as hematological toxicities: Grade 4 neutropenia, Grade 3 and 4 febrile neutropenia, Grade 4 thrombocytopenia, and Grade 3 thrombocytopenia associated with bleeding episodes. Grade =3 non-hematological toxicity with the exception of: Grade 3 nausea and vomiting without appropriate treatment, Grade 3 diarrhea lasting =2 days with no fever or dehydration, and isolated Grade 3 fever. Grade =4 non-hematological toxicity: infusion related reactions, and any other drug related toxicity qualified as a DLT per the discretion of the principal investigator. | First 28 days following infusion of LMB-100 on Cycle 1, Day 1 through the duration of the study treatment up to 1 year. | |
Other | Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUCinf) | Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0). It is used to characterize drug absorption. | For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1. | |
Other | Area Under the Serum Concentration Versus Time Curve Extrapolated to Infinity (AUCinf)/D (Dose) | The AUC is a measure of the serum concentration of the drug dose over time. It is used to characterize drug absorption. | For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1. | |
Other | Area Under the Serum Concentration Versus Time Curve Extrapolated to Last Measurement (AUClast)/D | The AUC is a measure of the serum concentration of the drug dose over time. It is used to characterize drug absorption | For Arms B1 & B2: Pre-dose, end of loading dose, 2 and 6 hours after start of continuous infusion, end of infusion (EOI) and 2 hrs after EOI during Cycle 1 Day 1. | |
Other | Time Curve Extrapolated to Last Measurement (AUClast) for LMB-100 | Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated to last measurement. It is used to characterize drug absorption. | For Arms B1 & B2: Pre-dose, end of loading dose, 2 and 6 hours after start of continuous infusion, end of infusion (EOI) and 2 hrs after EOI during Cycle 1. | |
Other | The Total Clearance (CL) of LMB-100 | The CL is a quantitative measure of the rate at which a drug substance is removed from the body. | For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1. | |
Other | Plasma Half-Life (T1/2) of LMB-100 | Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half. | For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1, Day 1. | |
Other | Volume of Distribution (Vd) of LMB-100 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1, Day 1. | |
Other | Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 in Arm A1 and Arm A2 | The maximum observed analyte concentration in serum was reported. | For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day. Pre-dose and end of infusion (EOI) during Cycle 2 Day 1. | |
Other | Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 in Arm B1 and Arm B2 | The maximum observed analyte concentration in serum was reported. | For Arms B1 & B2: Pre-dose, end of loading dose, 2 and 6 hours after start of continuous infusion, end of infusion (EOI) and 2 hrs after EOI during Cycle 1 Day 1. Pre-dose, end of loading dose and EOI during Cycle 2 Day 1. | |
Other | Maximum Observed (Peak) Plasma Concentration (Cmax)/D (Dose) of LMB-100 in Arm A1 and Arm A2 | The maximum observed analyte concentration of dose was reported. | For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1. Pre-dose and end of infusion (EOI) during Cycle 2 Day 1. | |
Other | Maximum Observed (Peak) Plasma Concentration (Cmax)/D (Dose) of LMB-100 in Arm B1 and Arm B2 | The maximum observed analyte concentration in serum was reported. | For Arms B1 & B2: Pre-dose, end of loading dose, 2 and 6 hours after start of continuous infusion, end of infusion (EOI) and 2 hrs after EOI during Cycle 1 Day 1. Pre-dose, end of loading dose and EOI during Cycle 2 Day 1. | |
Primary | Objective Response (OR) (Partial Responses + Complete Responses) in Phase 2 Subjects of Short Infusion LMB-100+ Nab-paclitaxel | OR is defined as partial responses + complete response in participants in the phase 2 Arm A portion of the study assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is a disappearance of all target lesions. 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 | Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment, up to 1 year | |
Primary | Maximum Tolerated Dose (MTD) of Short Infusion LMB-100 + Nab Paclitaxel | MTD is defined as the highest dose tolerated without exceeding a pre-set number of adverse events in Phase 1, Arm A. | 21 days after LMB-100 is administered (end of cycle 1) | |
Primary | Maximum Tolerated Dose (MTD) of Continuous Infusion LMB-100 | MTD is defined as the highest dose tolerated without exceeding a pre-set number of adverse events in Phase 1, 1 Arm B, single agent lead-in | 21 days after LMB-100 is administered (end of cycle 1) | |
Secondary | Progression Free Survival (PFS) | PFS is the average time from treatment initiation to disease progression or death. 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. And the appearance of one or more new lesions. | Time from treatment initiation to disease progression or death, an average of 1 year. | |
Secondary | Overall Survival (OS) | OS is the average time from treatment initiation to death. | Time from treatment initiation to death, up to 1-2 years. | |
Secondary | Proportion of Participants Disease Control Rate (DCR) at End of Treatment (EOT) | DCR is the proportion of participants with stable disease, partial response or complete response at end of treatment. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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. Complete Response is disappearance of all target lesions. Stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. | up to 3 months | |
Secondary | Number of Participants With an Objective Response (OR) (Partial Responses + Complete Responses) in Phase 1 Arm A1 | OR is defined as partial response + complete response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is a disappearance of all target lesions. 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 | Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment up to 1 year. | |
Secondary | Number of Participants With an Objective Response (OR) (Partial Response + Complete Response) in Phase 1, Arm B | OR is defined as partial responses + complete response in participants in the phase 1 Arm B portion of the study assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is a disappearance of all target lesions. 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. | Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment up to 1 year. | |
Secondary | Number of Participants With Adverse Events Attributed to LMB-100 | Grade 1-4 adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 observed in subjects with pancreatic cancer. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. Grade 4 is life-threatening consequences. | Date treatment consent signed to date off study, approx. 11 mos, 8 days for A1DL1; 20 mos, 9 days for A1DL-1; 10 mos, 17 days for A2; 2 mos, 16 days for B1DL1; 14 mos, 30 days for B1DL2; 5 mos, 1 day for B2; and 4 mos, 15 days for B1DL3R. | |
Secondary | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). 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. | Date treatment consent signed to date off study, approx. 11 mos, 8 days for A1DL1; 20 mos, 9 days for A1DL-1; 10 mos, 17 days for A2; 2 mos, 16 days for B1DL1; 14 mos, 30 days for B1DL2; 5 mos, 1 day for B2; and 4 mos, 15 days for B1DL3R. |
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