- Mesothelin is expressed in approximately half of all lung adenocarcinomas.
- LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing tumor
models including non-small cell lung cancer (NSCLC).- Programmed death ligand 1 (PD-1)
is an Ig superfamily member related to CD28 and CTLA-4 that has been shown to negatively
regulate antigen receptor signaling upon engagement of its ligands.
- Pembrolizumab, an IgG4 monoclonal antagonist antibody to PD-1, is FDA approved in the
frontline for advanced non-squamous NSCLC as a single agent with high PD-L1 expression
[tumor proportion score (TPS) >=50%] or in combination with platinum-based doublet
chemotherapy (PD-L1 unselected). It also approved in the second-line for high PDL1
expressing tumors (TPS >=1%).
- Combination treatment with LMB-100 plus pembrolizumab results in greater anti-tumor
efficacy in murine lung cancer model.
-To determine the objective response rate of LMB-100 followed by pembrolizumab in the
treatment of subjects with mesothelin-expressing non-squamous non-small cell lung cancer
(NSCLC) previously treated with immune checkpoint inhibitors.
- Histologically confirmed locally advanced or metastatic non-squamous, non-small cell
lung cancer lacking an EGFR sensitizing mutation, ALK or ROS1 gene rearrangement and not
amenable to potentially curative surgical resection or chemoradiation.
- Tumor mesothelin expression of at least 25% of tumor cells as determined by the
Laboratory of Pathology at the NCI.
- Subjects must have at least progressed after one prior platinum-based doublet
chemotherapy AND standard immune checkpoint inhibitor (ICI) with either frontline
single-agent pembrolizumab, or in combination with platinum-based doublet chemotherapy,
or second-line single-agent nivolumab, pembrolizumab, or atezolizumab.
- Age >= 18 years.
- This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab
in subjects with mesothelin expressing NSCLC who have progressed on standard therapies
- Subjects will receive LMB-100 at the single agent MTD (140mg/kg) on days 1, 3 and 5 of a
21-day cycle for up to 2 cycles and pembrolizumab 200 mg on day 1 of cycle 3 of a 21-
day cycle (or cycle 2 if disease progression is observed after 1 cycle) onwards until
disease progression (on or after pembrolizumab) or intolerable toxicity for a maximum of
2 years (unless second course initiated).
- The total accrual ceiling for the screening will be set at 100 total patients in order
to treat 23 subjects.
- INCLUSION CRITERIA:
Participants are eligible to be included in the study only if all of the following criteria
- Male and female participants who are at least 18 years of age on the day of signing
the informed consent will be enrolled in the study.
- Subjects must have histologically confirmed diagnosis of non-squamous non-small cell
lung cancer not amenable to potentially curative treatments (surgical resection,
definitive radiation therapy or a combined modality approach) or targeted agents to
actionable EGFR mutations or ALK or ROS1 gene rearrangement and excluding
neuroendocrine tumors. Activating KRAS mutations are allowed. The diagnosis must be
confirmed by the Laboratory of Pathology, CCR, NCI. Mutation confirmation may be done
by referring institutions or by one of the assays in the Protocol.
- Have provided archival tumor tissue sample or newly obtained fresh 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
- Histologically confirmed 25% of tumor cells expressing mesothelin as determined by NCI
Laboratory of Pathology. Determination can be made using archival tumor tissue or
- 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.
- Subjects must have received prior standard of care treatments for locally advanced or
- Patients must be more than 3 weeks out of systemic treatments, such as chemotherapy.
- All acute toxic effects of any prior radiotherapy, chemotherapy, immunotherapy, or
surgical procedure must have resolved to Grade less than or equal to 1, except
alopecia (any grade) and Grade 2 peripheral neuropathy.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Evaluation of ECOG is to be performed within 7 days prior to start of study therapy.
- Have adequate organ and marrow function as defined below:
- Patients must have normal organ and marrow function as defined below:
- hemoglobin greater than or equal to 9g/dL or 5.6 mmol/L
- absolute neutrophil count greater than or equal to 1,500mcL
- platelets greater than or equal to 100,000/mcL
- total bilirubin less than or equal to 2.5 x the upper limit of normal range (UNL)
OR direct bilirubin less than or equal to ULN for participants with total
bilirubin levels of greater than 1.5 X ULN
- AST and ALT less than or equal to 2.5 x ULN OR less than or equal to 5 x ULN for
subjects with metastatic disease to the liver
- creatinine greater than or equal to 1.5 x ULN OR creatinine clearance greater
than or equal to 50 mL/min for participants with creatinine levels greater than
1.5 X ULN
- International normalized ratio (INR) or prothrombin time (PT) or activated
thromboplastin time (aPTT) greater than or equal to 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
- Must have left ventricular ejection fraction >50%.
- The effects of LMB-100 on the developing human fetus are unknown. For this reason and
because anti-PD-1 antibodies such as pembrolizumab are assumed to be teratogenic:
- A male participant must agree to use contraception during the treatment period
and for at least 180 days after the last dose of study treatment and refrain from
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP) OR
- A WOCBP who agrees to follow the contraceptive guidance during the treatment
period and for at least 180 days after the last dose of study treatment.
- 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
- Ability of subject to understand and the willingness to sign a written informed
- Subjects with non-life-threatening immune-related endocrinopathies or AEs reduced
to Grade 1 or 0 after withholding ICI or medical intervention are eligible as
long as the AE resolved within 12 weeks of last dose and not requiring
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment. Note: Participants who have entered the follow-up phase of an
investigational study may participate as long as it has been 4 weeks after the last
dose of the previous investigational agent.
- 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
first dose of study treatment.
- Subjects who have received prior therapy with LMB-100.
Has received prior systemic anti-cancer therapy including investigational agents within 4
weeks prior to start of study therapy.
- Note: Participants must have recovered from all AEs due to previous therapies to
<=Grade 1 or baseline. Participants with <=Grade 2 neuropathy may be eligible.
- Note: If participant received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting study
- Has received prior radiotherapy within 2 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not
require corticosteroids, and not have had radiation pneumonitis. A 2-week washout
is permitted for palliative radiation (<=2 weeks of radiotherapy) to non-CNS
- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following:
measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,
Bacillus Calmette Gu(SqrRoot)(Copyright)rin (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.
- 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 start of study therapy.
- 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.
- Has a history of (non-infectious) pneumonitis/interstitial lung disease (ILD)
that required steroids or has current pneumonitis/ILD
- 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
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to start of
study therapy. If the urine test is 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.
- Is pregnant or breastfeeding or expecting to conceive or father children within
the projected duration of the study, starting with the screening visit through
180 days after the last dose of trial treatment. Pregnant women are excluded from
this study because LMB-100 + pembrolizumab 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 + pembrolizumab, breastfeeding should be discontinued if the mother
is treated with LMB-100 + pembrolizumab. These potential risks may also apply to
other agents used in this study.
- Has a known history of Human Immunodeficiency Virus (HIV). 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. (Note: No HIV testing is required)
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen
[HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA
[qualitative] is detected) infection. or active HBV or HCV infection. (Note: No
testing for Hepatitis B and Hepatitis C is required.)
- 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.
- Has an active infection requiring systemic therapy.
- Participants with contra-indication and/or history of severe hypersensitivity
reactions to any components related to LMB-100 or pembrolizumab (or any other
immune checkpoint inhibitor such as PD1, PDL-1 and CTLA4).
- Active or uncontrolled infections.
- Subjects who experienced severe or life-threatening immune-related AEs with prior
immune checkpoint therapy requiring medical intervention (steroid or
immunosuppressant drugs) and permanent discontinuation of therapy, will be
excluded. These include, but not limited to colitis, autoimmune hepatitis,
hypophysitis, hyperthyroidism, nephritis, myocarditis, GBS, encephalitis.
- Subjects with a history of pneumonitis that required steroids will be excluded.
- Recruitment Strategies
Information about the study will be posted on sites such as clinicaltrials.gov and the CCR
recruitment website. Subjects will also be drawn from patients seen at the thoracic clinic
at the NIH Clinical Center as well as from referrals from outside providers. Social media
platforms managed by NIH/NCI may also be used to publicize the study. There is no plan to
advertise this study at this time.