| Eligibility |
- 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, Center for Cancer Research (CCR),
National Cancer Institute (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 intra-tumoral injection
of LMB- 100.
5. Have measurable disease based on Response Evaluation Criteria in Solid Tumors
(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-Programmed
cell death protein 1 (PD-1)/Programmed death-ligand 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 -
hemoglobin >= 9 g/dL(a)
absolute neutrophil count >= 1,500/mcL
platelets >= 100,000/mcL
Hepatic
total bilirubin <= 2.5 X institutional upper limit of normal (ULN) OR direct
bilirubin <=ULN for participants with total bilirubin levels >1.5 X ULN
Aspartate aminotransferase (AST) and alanine aminotransferase (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
(glomerular filtration rate (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 adverse events (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 QT corrected for heart rate by Fridericia's cube root formula (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. Human immunodeficiency virus (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 ribonucleic acid (RNA) detected)
infection. or active hepatitis B virus (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.
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