Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma

• ClinicalTrials.gov Identifier: NCT04840615
• Recruitment Status: Recruiting
• First Posted: April 12, 2021
• Last Update Posted: February 15, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

Background:

Mesothelioma is a type of cancer. It originates in cells that line human body cavities. Most people have advanced disease when they are diagnosed. Researchers want to see if a combination of drugs can help.

Objective:

To find a safe dose of LMB-100 in combination with ipilimumab when LMB-100 is injected into tumors.

Eligibility:

Adults ages 18 and older with malignant pleural or peritoneal mesothelioma that cannot be cured with surgery and has not responded to standard first-line treatments for mesothelioma.

Design:

Participants will be screened with:

• Tumor biopsy or effusion, if needed
• Medical history
• Physical exam
• Blood and urine tests
• Imaging scans
• Heart and lung function tests
• Pregnancy test, if needed

Some screening tests will be repeated during the study.

Participants will get LMB-100 on Days 1 and 4 for up to 2 cycles. Each cycle lasts 21 days. They will stay in the hospital for about 8 days each time they get LMB-100. It will be injected into their tumor with needles.

Participants will get ipilimumab through a tube that is put in a vein. It will be given on Day 2 of the first 2 cycles and Day 1 of the next 2 cycles.

Participants will be assessed for how well they do daily activities. They will give blood and tissue samples for research.

Participants will have a safety visit 4 to 6 weeks after the last dose of the study drugs. Then they will have scans every 6 weeks until their disease gets worse. If their tumor gets bigger, they will have phone, video, or email follow-ups every 12 weeks.

Participants will be on this study for life....

Condition or disease	Intervention/treatment	Phase
Mesothelioma	Biological: LMB-100; Drug: ipilimumab	Phase 1

Detailed Description:

Background:

LMB-100, and a closely related immunotoxin, SS1P, also targeting mesothelin, given intravenously, have been studied in Phase 1 clinical studies for mesothelioma and pancreatic cancer.

LMB-100 given intravenously, results in systemic inflammation in patients, but as a single agent has limited anti-tumor efficacy.

Almost all patients develop neutralizing anti-LMB-100 antibodies after 2 cycles of therapy.

Intra-tumoral delivery of LMB-100 has been shown to induce immune cell infiltration in immune-competent mice, bearing murine malignant mesothelioma tumors. Combination with CTLA-4 blockage eradicates murine tumors by promoting anti-cancer immunity.

Ipilimumab is a fully human anti CTLA-4 monoclonal antibody, that is approved for treatment of melanoma and in combination with nivolumab for many solid tumors.

It is hypothesized that intra-tumoral delivery of anti-mesothelin immunotoxin LMB-100 in combination with ipilimumab will result in greater anti-tumor efficacy in patients with mesothelioma.

Objective:

To determine the safety and feasibility of intra-tumoral LMB-100 injection plus ipilimumab infusion in patients with mesothelioma

To identify the recommended phase 2 dose (RP2D) of intratumorally administered LMB-100 + ipilimumab in patients with malignant mesothelioma

Eligibility:

Histologically confirmed pleural or peritoneal mesothelioma not amenable to potentially curative surgical resection.

Have locally accessible disease suitable for intra-tumor injection of LMB-100. This includes superficial or visceral lesions.

Subjects must have received prior immune checkpoint therapy with anti-PD-1/PD-L1 inhibitors alone or in combination with anti-CTLA4 blocking antibodies, as well as platinum-based chemotherapy.

Age >= 18 years.

ECOG performance status of 0 or 1.

Adequate organ and bone marrow function

Subjects with clinically significant pericardial effusion are excluded

Chemotherapy within 3 weeks or radiotherapy within 2 weeks prior to start of study therapy is prohibited.

Subjects with active CNS metastasis are excluded

Subjects with active autoimmune disease for which they have received systemic immunosuppressive medications during the previous 2 years (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 or interstitial lung disease for which they had received glucocorticoids are excluded

Design:

This is an open-label, single center phase I dose escalation study of intratumorally administered LMB-100 followed by ipilimumab in subjects with malignant mesothelioma.

Subjects will receive intratumorally administered LMB-100, beginning g at dose level 1, in 21-day cycles. LMB-100 will be given on days 1 and 4 of cycle 1, and ipilimumab is given on day 1 of cycles 2-4.

Tumor biopsies will be performed prior to each administration of LMB-100, on day 1 of cycle 2 and after completion of ipilimumab therapy to evaluate changes in the tumor immune microenvironment.

Up to 14 evaluable subjects will be enrolled.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma
• Actual Study Start Date: June 11, 2021
• Estimated Primary Completion Date: January 31, 2024
• Estimated Study Completion Date: November 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1/Intratumoral LMB-100 Administration; Those with pleural or peritoneal mesothelioma receiving intratumoral administration of LMB-100 + ipilimumab for up to 4 cycles	Biological: LMB-100; administered into lesion on days 1 and 4 during cycle 1; Drug: ipilimumab; administered intravenously once per cycle up to three 21 day cycles. Administration will occur during cycles 2,3,4.

Outcome Measures

Primary Outcome Measures :

1. recommended phase 2 dose [ Time Frame: 21 days after first LMB-100 administration ]
   The highest dose at which fewer than 2 of 6 subjects experience a dose limiting toxicity
2. safety [ Time Frame: through disease progression ]
   fraction of patients who experience toxicity by grade and type will be tabulated by dose level

Secondary Outcome Measures :

1. objective response rate [ Time Frame: every 6 weeks until disease progression ]
   fraction of subjects who experience either a partial or complete response
2. duration of response [ Time Frame: disease recurrence or progression ]
   median time criteria are met for partial or complete response to the first date that recurrence or progression is documented
3. progression free survival [ Time Frame: disease progression ]
   median time from start of treatment to time of progression or death, whichever occurs first
4. Overall survival [ Time Frame: death ]
   median time from start of treatment to death from any cause

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:

  1. Histologically confirmed malignant pleural or peritoneal mesothelioma not amenable to potentially curative surgical resection. The diagnosis will be confirmed by the Laboratory of Pathology, CCR, NCI.
  2. Tumor must have epithelioid histology determined by the Laboratory of Pathology at the NCI. If the patient has biphasic histology, the epithelioid component must be >50%

  3. Have provided archival tumor tissue sample or able to provide newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.

     Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.

  4. Have disease locally accessible disease to suitable for intratumoral injection of LMB- 100.
  5. Have measurable disease based on RECIST 1.1. Lesions in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  6. Subjects must have received prior immune checkpoint therapy with anti-PD-1/PD-L1 inhibitors alone or in combination with anti-CTLA4 blocking antibodies, as well as platinum based chemotherapy.
  7. Age >= 18 years.
  8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Evaluation of ECOG is to be performed within 28 days prior to initiation of study therapy.

  9. Have adequate organ and marrow function as defined below:

     System and Laboratory Value

     Hematological<TAB>

     hemoglobin >= 9 g/dL(a)

     absolute neutrophil count >= 1,500/mcL

     platelets >= 100,000/mcL

     Hepatic

     total bilirubin <= 2.5 X institutional ULN OR direct bilirubin <=ULN for participants with total bilirubin levels >1.5 X ULN

     AST and ALT <= 2.5 X institutional ULN (<= 5 X ULN for participants with liver metastases)

     Renal

     Creatinine <=1.5 x ULN OR Measured or calculated(b) creatinine clearance (GFR can also be used in place of creatinine or CrCl) >= 50 mL/min for participant with creatinine levels; > 1.5 X institutional ULN

     Coagulation

     International normalized ratio (INR) OR prothrombin time (PT); Activated partial thromboplastin time (aPTT): <=1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

     ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

     1. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
     2. Creatinine clearance (CrCl) should be calculated per institutional standard.
  10. Must have left ventricular ejection fraction >50%.
  11. The effects of LMB-100 on the developing human fetus are unknown. For this reason and because ipilimumab is a Category C agent, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) while on study therapy and for four months after 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.
  12. Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 3 weeks prior to initiation of study therapy.

   Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 3 weeks after the last dose of the previous investigational agent. Patients with active devices will be excluded from the study

2. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to initiation of study therapy.
3. Has active systemic issues as bleeding diathesis or active infections
4. Presence of a clinically significant pericardial effusion
5. Has severe hypersensitivity (>=Grade 3) anti-CTLA4 therapies and/or any of their excipients.
6. Has received prior radiotherapy to the site of local administration
7. Subjects who have received LMB-100 previously
8. Has received prior systemic anti-cancer therapy including investigational agents within 3 weeks prior to initiation of study therapy. Patients who have received prior anti-PD-1/PD- L1 or CTLA4 antibodies are eligible. Any toxicity related to these agents must have resolved to grade 1 and they must not be on systemic immunosuppressive therapies (physiologic dose of steroids are permitted).
9. Has received prior radiotherapy to site other than target lesion within 2 weeks prior to initiation of study therapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (<=2 weeks of radiotherapy) to non-CNS disease.
10. Has not recovered from all AEs due to previous therapies to <=Grade 1 or baseline. Participants with <=Grade 2 neuropathy may be eligible. If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to initiation of study therapy.
11. Has received a live vaccine within 30 days prior to initiation of study therapy. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist(R)) are live attenuated vaccines and are not allowed.
12. Is receiving therapeutic anti-coagulation. Patients receiving prophylactic anticoagulation may be eligible if in the opinion of the study team, anti-coagulation may be stopped during the time of LMB-100 administration and tumor biopsies
13. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to initiation of study therapy.
14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
15. Has a QTcF interval >480 milliseconds
16. Has a history of (non-infectious) pneumonitis/interstitial lung disease(ILD) that required steroids or has current pneumonitis/ILD
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. A woman of childbearing potential who has a positive pregnancy test within 72 hours prior to initiation of study therapy. If the using a urine test and test positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 4 months after the last dose of trial treatment. Pregnant women are excluded from this study because LMB-100 + ipilimumab are agents with the potential for 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 + ipilimumab, breastfeeding should be discontinued if the mother is treated with LMB-100 + ipilimumab. These potential risks may also apply to other agents used in this study.
21. HIV positive patients will be excluded due to a theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
22. Positive for Hepatitis B or C (defined as Hepatitis B surface antigen reactive) or known active Hepatitis C virus (defined as HCV RNA detected) infection. or active HBV or HCV infection.
23. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
24. Has an active infection requiring systemic therapy.

Contacts and Locations

Contacts

Contact: Cathy I Wagner, R.N.; (240) 858-3159; cathy.wagner@nih.gov

Contact: Raffit Hassan, M.D.; (240) 760-6232; rh276q@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Raffit Hassan, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04840615
• Other Study ID Numbers: 10000059; 000059-C
• First Posted: April 12, 2021
• Last Update Posted: February 15, 2023
• Last Verified: January 20, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Clinical data in BTRIS will be shared throughout the course of the study and indefinitely with the permission of the investigator
• Access Criteria: Clinical IPD will be shared through the BTRIS database for open ended analysis. All BTRIS subscribers, generally limited to the NIH Clinical Center, may request data.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Immunotherapy; Checkpoint Inhibitor; anti CTLA-4

Additional relevant MeSH terms:

Mesothelioma; Mesothelioma, Malignant; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Ipilimumab; LMB-100; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunoconjugates; Immunologic Factors; Physiological Effects of Drugs