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Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in People With Previously Treated Metastatic and/or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors

Primary Purpose

Neoplasms, Pancreatic Neoplasms

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
LMB-100
Nab-Paclitaxel
Mesothelin Expression
LMB-100
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neoplasms focused on measuring Immunotoxin, Mesothelin, Antibody-based Therapeutics, Advanced Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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

Sites / Locations

  • National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm A1, Dose Level 1 (Phase 1, short infusion) 100µg/kg LMB-100

Arm A1, Dose Level-1 (Phase 1, short infusion) 65µg/kg LMB-100

Arm A2 (Phase 2, short infusion) 65µg/kg LMB-100

Arm B1, Dose Level 2 Phase I (Continuous infusion single agent lead-in)

Arm B1, Dose Level 1 Phase I (Continuous infusion single agent lead-in)

Arm B1, Dose Level 3R Phase I (Continuous infusion single agent lead-in)

Arm B2 Phase I (continuous infusion combination therapy)

Arm Description

Arm A1, Dose Level 1, Phase I Short Infusion 100µg/kg LMB-100 +125mg/m^2 nab-paclitaxel Dose level 1 (DL1) Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving short infusion LMB-100+nabpaclitaxel

Arm A1, DL-1, Ph I Short Infusion 65µg/kg LMB-100 +125mg/m^2 nab-paclitaxel

Arm A2, Phase 2 Short Infusion 65µg/kg LMB-100 +125mg/m^2 nab-paclitaxel Efficacy determination in patients with pancreatic cancer receiving short infusion LMB-100 + nabpaclitaxel

Arm B1, DL2, 48-hr Continuous Infusion Single Agent Lead-in 100µg/kg/day LMB-100 Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving continuous infusion LMB-100 as single agent

Arm B1, DL1, 48-hr Continuous Infusion Single Agent Lead-in 65µg/kg/day LMB-100

Arm B1, DL3R, 24-hr Continuous Infusion Single Agent Lead-in 100µg/kg LMB-100

Subjects with pancreatic cancer receiving continuous infusion LMB-100 combination therapy

Outcomes

Primary Outcome Measures

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
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.
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

Secondary Outcome Measures

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.
Overall Survival (OS)
OS is the average time from treatment initiation to death.
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.
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
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.
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.
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.

Full Information

First Posted
June 22, 2016
Last Updated
February 16, 2022
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02810418
Brief Title
Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in People With Previously Treated Metastatic and/or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
August 3, 2016 (Actual)
Primary Completion Date
January 2, 2019 (Actual)
Study Completion Date
June 22, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
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....
Detailed Description
Background: Pancreatic cancer is the fourth most common cause of cancer death in the United States, claiming more than 40,000 lives each year. Incidence nearly equals mortality with just 6% of participants living five years beyond their diagnosis. Most patients are diagnosed at an advanced stage, but even patients with early stage disease have a long term survival of less than 20%. Mesothelin is specifically a marker of adenocarcinoma in the human disease and is not expressed in preceding pre-malignant stages of tumor development Expression of mesothelin in pancreatic ductal adenocarcinoma (PDA) has been examined in several published studies and ranges from 86 to 100% Recombinant immunotoxins (RITs) are antibody-based therapeutics that carry a toxin payload. RITs that target mesothelin contain a genetically engineered variant of Pseudomonas exotoxin A (PE) in which the native cell-binding domain of PE is replaced by the mesothelin-binding antibody fragment. SS1P was the first mesothelin-targeted RIT tested in patients. LMB-100 contains a newly engineered PE fragment that has improved activity against most pancreatic cancer cell lines in vitro, and is also much less toxic than SS1P in preclinical models. The new PE contains modifications specifically designed to reduce immunogenicity of the molecule. Pre-administration of paclitaxel with SS1P was demonstrated to increase the amount of immunotoxin internalized by tumor cells and to reduce levels of shed mesothelin in the intra-tumoral environment so that more immunotoxin could bind tumor cells. The effect is even more pronounced with NAB-paclitaxel in a pancreatic cancer model. Initial clinical testing of LMB-100 was performed by Roche in a multi-center international first in human trial (NCT02317419). The agent was well tolerated and appeared to have decreased immunogenicity compared to SS1P based on preliminary results. In initial and subsequent clinical testing, LMB-100 was found to have half-life of approximately 60 mins. This is shorter then that measured for previous RITs used in the clinical setting. Primary Objectives: Arm A1 (Phase I, short infusion): --To determine the maximum tolerated dose of short infusion LMB-100 in combination nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer Arm B1(Continuous infusion single agent lead-in): --To determine the maximum tolerated dose of LMB-100 given in a continuous infusion format over 24 - 96 hours to patients with advanced solid tumors that express mesothelin Arm B2 (Continuous infusion combination therapy) --Establish a tolerated dose of LMB-100 given by continuous infusion in combination with nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer Arm A2 (Phase II, short infusion): To determine the objective response rate (Partial Response (PR)+Complete Response (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria of short infusion LMB-100 in combination with nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer Eligibility: Age greater than or equal to18 years Histologically confirmed recurrent, metastatic and/or advanced pancreatic ductal adenocarcinoma (Except for Arm B1 [B Single Agent Lead-in]) For 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 National Cancer Institute (NCI) Laboratory of Pathology. Determination can be made using archival tumor tissue or fresh biopsy. Treatment must include at least one prior chemotherapy regimen No nab-paclitaxel or paclitaxel treatment in the last four months (Except for Arm B1 [Single Agent Lead-in]) Adequate organ function Participants with human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are eligible only for the Arm B1 (Single Agent Lead-in) Design: This study is a Phase I/II open label study to assess the safety and efficacy of LMB-100 in combination with the standard of care agent nab-paclitaxel in participants metastatic and/or locally advanced pancreatic ductal adenocarcinoma Subjects will be treated for up to 2 cycles In Arm A1 (Phase I, short infusion) of the study, up to 3 dose levels will be evaluated. LMB-100 will be administered on days 1, 3 and 5 of a 21 day cycle and nab-paclitaxel will be administered on days 1 and 8 Arm A2 (Phase II, short infusion), up to 20 evaluable participants (including those treated at the short infusion maximum tolerated dose (MTD) in the phase I study) will be enrolled. Arm B1 (Continuous infusion single Agent Lead-in), escalating doses of single agent LMB-100 will be administered. The study drug will be given as a continuous infusion for the 1, 2, 3, or 4 days of a 21-day cycle. Arm B2 (Continuous infusion, combination therapy) will be initiated after completion of both Arm A1 and Arm B1 Single Agent Lead-in. It will test a single dose level of LMB-100 based on data from the Lead-in given in combination with nab-paclitaxel. LMB-100 will be given as a continuous infusion for the 1, 2, 3 or 4 days of a 21-day cycle. Nabpaclitaxel will be given on Day 1 and Day 8. The Arm A2 (Phase II, short infusion) portion of the study will be conducted in a Simon Minimax two stage phase II design. The first stage will enroll 13 evaluable participants, including the six participants treated at the short infusion MTD from phase I. If 1 or more has a response, then accrual would continue until a total of 20 evaluable participants have been enrolled.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neoplasms, Pancreatic Neoplasms
Keywords
Immunotoxin, Mesothelin, Antibody-based Therapeutics, Advanced Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A1, Dose Level 1 (Phase 1, short infusion) 100µg/kg LMB-100
Arm Type
Experimental
Arm Description
Arm A1, Dose Level 1, Phase I Short Infusion 100µg/kg LMB-100 +125mg/m^2 nab-paclitaxel Dose level 1 (DL1) Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving short infusion LMB-100+nabpaclitaxel
Arm Title
Arm A1, Dose Level-1 (Phase 1, short infusion) 65µg/kg LMB-100
Arm Type
Experimental
Arm Description
Arm A1, DL-1, Ph I Short Infusion 65µg/kg LMB-100 +125mg/m^2 nab-paclitaxel
Arm Title
Arm A2 (Phase 2, short infusion) 65µg/kg LMB-100
Arm Type
Experimental
Arm Description
Arm A2, Phase 2 Short Infusion 65µg/kg LMB-100 +125mg/m^2 nab-paclitaxel Efficacy determination in patients with pancreatic cancer receiving short infusion LMB-100 + nabpaclitaxel
Arm Title
Arm B1, Dose Level 2 Phase I (Continuous infusion single agent lead-in)
Arm Type
Experimental
Arm Description
Arm B1, DL2, 48-hr Continuous Infusion Single Agent Lead-in 100µg/kg/day LMB-100 Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving continuous infusion LMB-100 as single agent
Arm Title
Arm B1, Dose Level 1 Phase I (Continuous infusion single agent lead-in)
Arm Type
Experimental
Arm Description
Arm B1, DL1, 48-hr Continuous Infusion Single Agent Lead-in 65µg/kg/day LMB-100
Arm Title
Arm B1, Dose Level 3R Phase I (Continuous infusion single agent lead-in)
Arm Type
Experimental
Arm Description
Arm B1, DL3R, 24-hr Continuous Infusion Single Agent Lead-in 100µg/kg LMB-100
Arm Title
Arm B2 Phase I (continuous infusion combination therapy)
Arm Type
Experimental
Arm Description
Subjects with pancreatic cancer receiving continuous infusion LMB-100 combination therapy
Intervention Type
Drug
Intervention Name(s)
LMB-100
Intervention Description
Arms A1 and A2 (short infusion): Administered intravenously (IV) on days 1, 3 and 5 of a 21 day cycle for a maximum of 2 cycles Arm B1 (continuous infusion): Administered IV for 24, 48, 72 or 96 hours continuously on the first 1 - 4 days or 24 hour infusions on days 1 and 4 (depending on dose level) of each 21 day cycle for a maximum of 2 cycles. Arm B2 (continuous infusion): Administered IV for 24,48, 72 or 96 hours continuously on the first 1 - 4 days or 24 hour infusions on days 1 and 4 (depending on dose level) of each 14 day cycle for a maximum of 3 cycles.
Intervention Type
Drug
Intervention Name(s)
Nab-Paclitaxel
Other Intervention Name(s)
Abraxane
Intervention Description
Administered intravenously (IV) on days 1 and for Arms A1, A2 and B1 on day 8 of each 14-21 day cycle for a maximum of 2 (Arms A1, A2 and B1) or 3 (Arm B2) cycles
Intervention Type
Device
Intervention Name(s)
Mesothelin Expression
Intervention Description
Research blood test for Arm B1 eligibility
Intervention Type
Drug
Intervention Name(s)
LMB-100
Intervention Description
A 40 mcg/kg loading dose of LMB-100 is administered over 30 minutes immediately prior to the start of each long infusion.
Primary Outcome Measure Information:
Title
Objective Response (OR) (Partial Responses + Complete Responses) in Phase 2 Subjects of Short Infusion LMB-100+ Nab-paclitaxel
Description
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
Time Frame
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
Title
Maximum Tolerated Dose (MTD) of Short Infusion LMB-100 + Nab Paclitaxel
Description
MTD is defined as the highest dose tolerated without exceeding a pre-set number of adverse events in Phase 1, Arm A.
Time Frame
21 days after LMB-100 is administered (end of cycle 1)
Title
Maximum Tolerated Dose (MTD) of Continuous Infusion LMB-100
Description
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
Time Frame
21 days after LMB-100 is administered (end of cycle 1)
Secondary Outcome Measure Information:
Title
Progression Free Survival (PFS)
Description
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 Frame
Time from treatment initiation to disease progression or death, an average of 1 year.
Title
Overall Survival (OS)
Description
OS is the average time from treatment initiation to death.
Time Frame
Time from treatment initiation to death, up to 1-2 years.
Title
Proportion of Participants Disease Control Rate (DCR) at End of Treatment (EOT)
Description
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.
Time Frame
up to 3 months
Title
Number of Participants With an Objective Response (OR) (Partial Responses + Complete Responses) in Phase 1 Arm A1
Description
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
Time Frame
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.
Title
Number of Participants With an Objective Response (OR) (Partial Response + Complete Response) in Phase 1, Arm B
Description
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.
Time Frame
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.
Title
Number of Participants With Adverse Events Attributed to LMB-100
Description
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.
Time Frame
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.
Title
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).
Description
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.
Time Frame
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.
Other Pre-specified Outcome Measures:
Title
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
Description
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.
Time Frame
First 28 days following infusion of LMB-100 on Cycle 1, Day 1 through the duration of the study treatment up to 1 year.
Title
Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUCinf)
Description
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.
Time Frame
For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1.
Title
Area Under the Serum Concentration Versus Time Curve Extrapolated to Infinity (AUCinf)/D (Dose)
Description
The AUC is a measure of the serum concentration of the drug dose over time. It is used to characterize drug absorption.
Time Frame
For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1.
Title
Area Under the Serum Concentration Versus Time Curve Extrapolated to Last Measurement (AUClast)/D
Description
The AUC is a measure of the serum concentration of the drug dose over time. It is used to characterize drug absorption
Time Frame
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.
Title
Time Curve Extrapolated to Last Measurement (AUClast) for LMB-100
Description
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.
Time Frame
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.
Title
The Total Clearance (CL) of LMB-100
Description
The CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Time Frame
For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1.
Title
Plasma Half-Life (T1/2) of LMB-100
Description
Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Time Frame
For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1, Day 1.
Title
Volume of Distribution (Vd) of LMB-100
Description
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.
Time Frame
For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1, Day 1.
Title
Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 in Arm A1 and Arm A2
Description
The maximum observed analyte concentration in serum was reported.
Time Frame
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.
Title
Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 in Arm B1 and Arm B2
Description
The maximum observed analyte concentration in serum was reported.
Time Frame
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.
Title
Maximum Observed (Peak) Plasma Concentration (Cmax)/D (Dose) of LMB-100 in Arm A1 and Arm A2
Description
The maximum observed analyte concentration of dose was reported.
Time Frame
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.
Title
Maximum Observed (Peak) Plasma Concentration (Cmax)/D (Dose) of LMB-100 in Arm B1 and Arm B2
Description
The maximum observed analyte concentration in serum was reported.
Time Frame
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christine C Alewine, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2016-C-0128.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in People With Previously Treated Metastatic and/or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors

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