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

NCT02810418 | Completed Phase 1 Results FDA Drug FDA Device

• 2 other identifiers: 16012816-C-0128
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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....

Conditions

Neoplasms; Pancreatic Neoplasms

Keywords

Immunotoxin; Mesothelin; Antibody-based Therapeutics; Advanced Cancer

Outcome Measures

Primary Outcomes (3)

• 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

• 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)

• 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 Outcomes (7)

• Progression Free Survival (PFS)

  Time from treatment initiation to disease progression or death, an average of 1 year.

• Overall Survival (OS)

  Time from treatment initiation to death, up to 1-2 years.

• Proportion of Participants Disease Control Rate (DCR) at End of Treatment (EOT)

  up to 3 months

• Number of Participants With an Objective Response (OR) (Partial Responses + Complete Responses) in Phase 1 Arm A1

  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.

• Number of Participants With an Objective Response (OR) (Partial Response + Complete Response) in Phase 1, Arm B

  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.

Other Outcomes (12)

• Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)

  First 28 days following infusion of LMB-100 on Cycle 1, Day 1 through the duration of the study treatment up to 1 year.

• Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUCinf)

  For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1.

• Area Under the Serum Concentration Versus Time Curve Extrapolated to Infinity (AUCinf)/D (Dose)

  For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1.

Study Arms (7)

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

EXPERIMENTAL

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

Drug: LMB-100; Drug: Nab-Paclitaxel

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

EXPERIMENTAL

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

Drug: LMB-100; Drug: Nab-Paclitaxel

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

EXPERIMENTAL

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

Drug: LMB-100; Drug: Nab-Paclitaxel

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

EXPERIMENTAL

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

Drug: LMB-100; Device: Mesothelin Expression

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

EXPERIMENTAL

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

Drug: LMB-100; Device: Mesothelin Expression

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

EXPERIMENTAL

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

Drug: LMB-100; Device: Mesothelin Expression

Arm B2 Phase I (continuous infusion combination therapy)

EXPERIMENTAL

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

Drug: LMB-100; Drug: Nab-Paclitaxel

Interventions

LMB-100 DRUG

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.

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

Nab-Paclitaxel DRUG

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

Also known as: Abraxane

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 B2 Phase I (continuous infusion combination therapy)

Mesothelin Expression DEVICE

Research blood test for Arm B1 eligibility

Arm B1, Dose Level 1 Phase I (Continuous infusion single agent lead-in); Arm B1, Dose Level 2 Phase I (Continuous infusion single agent lead-in); Arm B1, Dose Level 3R Phase I (Continuous infusion single agent lead-in)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Pegna GJ, Lee MJ, Peer CJ, Ahmad MI, Venzon DJ, Yu Y, Yuno A, Steinberg SM, Cao L, Figg WD, Donahue RN, Hassan R, Pastan I, Trepel JB, Alewine C. Systemic immune changes accompany combination treatment with immunotoxin LMB-100 and nab-paclitaxel. Cancer Med. 2023 Feb;12(4):4236-4249. doi: 10.1002/cam4.5290. Epub 2022 Oct 8.

  PMID: 36208017 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms; Pancreatic Neoplasms

Interventions

LMB-100; 130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Paclitaxel; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Christine C. Alewine
• Organization: National Cancer Institute

christine.alewine@nih.gov

240-760-6146

Study Officials

• Christine C Alewine, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 22, 2016
• First Posted: June 23, 2016
• Study Start: August 3, 2016
• Primary Completion: January 2, 2019
• Study Completion: June 22, 2021
• Last Updated: March 15, 2022
• Results First Posted: February 2, 2021

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)