Background:
The protein mesothelin is found on many kinds of tumors. The drug LMB-100 targets cancer
cells that make this protein. Researchers want to see if LMB-100 combined with another drug
can help people with these tumors.
Objective:
To find a safe dose of LMB-100 plus tofacitinib in people with pancreatic cancer, bile-duct
cancer, and other solid tumors that make mesothelin.
Eligibility:
People ages 18 and older with pancreatic cancer, bile-duct cancer, or any other solid tumor
with mesothelin that worsened after treatment or they could not receive standard treatment
Design:
Participants will be screened with:
- Medical history
- Tumor tissue sample. If they do not have a sample, they will have a biopsy.
- Physical exam
- Blood and heart tests
- Scans and x-rays: They may have a dye injected for the scans.
Participants will take the drugs in up to three 21-day cycles. They will take tofacitinib by
mouth twice a day on days 1-10 of each cycle. They will have LMB-100 injected into the blood
on days 4, 6, and 8 of every cycle. Patients that do not have a medi-port may need to have a
central vein access line placed.
Participants will take other drugs on the days they receive LMB-100.
Participants will repeat screening tests during the study. They may have a biopsy at the
start of the first 2 cycles.
If participants must stop the study, they will have a safety visit 3-6 weeks after their last
dose of the study drug. Some participants may then have visits every 6 weeks.
After treatment, participants will be contacted about once a year. They will be asked about
their cancer.
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%.
- Cholangiocarcinoma is a rare disease and just 3,000 patients are diagnosed with the
extrahepatic form yearly. The median overall survival of patients with advanced disease
receiving standard of care treatment is less than 1 year.
- Expression of mesothelin (MSLN) in pancreatic ductal adenocarcinoma (PDA) has been
examined in several published studies and ranges from 86 to 100%. Similar incidence of
expression has been observed in extrahepatic cholangiocarcinoma.
- In addition to pancreatobiliary tumors, many other solid tumor types also express MSLN
such as mesothelioma, colorectal, lung adenocarcinomas, epithelial ovarian, gastric and
triple negative breast cancers, as well as some tumors of squamous cell origin.
- LMB-100 and a closely related immunotoxin also targeting MSLN have been studied in
previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.
- Results from these studies showed that almost all patients formed anti-drug-antibodies
(ADAs) that neutralized subsequent injection of the product making it ineffective.
- Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the
treatment of rheumatoid arthritis and ulcerative colitis.
- Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs
against an immunotoxin closely related to LMB-100
- Co-administration of tofacitinib with immunotoxin increased immunotoxin serum half- life
in mice and enhanced anti-tumor efficacy
- This clinical trial will investigate whether co-administration of tofacitinib with LMB-
100 can prevent or delay the formation of ADAs and thus allow patients to receive
additional effective cycles of LMB-100.
Objectives:
- The primary objective of the dose escalation phase of this study is to assess the safety
and tolerability of LMB-100 given in combination with tofacitinib to patients with
pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma and other mesothelin-
positive solid tumors
- The primary objective of the expansion phase of this study is to determine whether co-
administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs through
cycle 2 of treatment (as measured by LMB-100 serum drug levels) in patients with
pancreatobiliary cancers.
Eligibility:
- Age >= 18 years
- Histologically confirmed solid tumor malignancy for which no curative therapy exists
- Participants must have received at least one prior systemic treatment regimen for their
disease OR be ineligible to receive available standard treatments for their disease OR
refused first-line standard systemic treatments but have been treated with other
anti-cancer agents.
Design:
- This is a Phase I study which will accrue up to 45 subjects total, accounting for screen
failure.
- Participants will be co-treated for 3 cycles with tofacitinib given orally for the first
10 days of each 21 day cycle, and LMB-100 given on days 4, 6 and 8.
- A 3+3 dose escalation schema will be used. Two dose levels are planned. One minus dose
level could be utilized if dose de-escalation is necessary.
- Following identification of an optimal dose and schedule, an expansion phase of 15
participants will be initiated at the optimal dose for patients with pancreatic
adenocarcinoma and extrahepatic cholangiocarcinoma. At least 8 participants in the
expansion phase must have pancreatic adenocarcinoma.
- Participants on the Dose Escalation and Dose Expansion Arms who appear to be obtaining
clinical benefit from LMB-100/tofacitinib after 3 cycles of treatment may elect to
receive additional cycles of therapy at the discretion of the PI.
- INCLUSION CRITERIA:
- Patients must have histologically confirmed solid tumor malignancy for which no
curative therapy exists.
- Pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma or epithelioid subtype of
mesothelioma, as determined by NCI Laboratory of Pathology, OR for all other tumor
types, at least 20% of tumor cells must express mesothelin. Determination can be made
using archival tumor tissue or fresh biopsy if archival tumor tissue is not available.
- All patients must have evaluable disease (i.e. measurable per RECIST 1.1. or by
following CA19-9 tumor marker). Patients in the expansion cohort must have measurable
disease, per RECIST 1.1. evaluation of measurable disease.
- Patients must have received at least one prior standard systemic treatment regimen for
advanced disease OR be ineligible to receive available standards due to
co-morbidities, prior toxicity, lack of standard options for tumor type, or having
received all standards available for prior treatment of early stage disease OR have
refused first-line standard systemic treatment but have received prior anti-cancer
treatments.
- Patients with dMMR/MSI-H disease must have received at least one prior anti-PD1
therapy, be ineligible to receive this treatment due to concurrent medical conditions,
or have refused this therapy.
- ECOG performance status (PS) 0-2
- Age >=18 years. Because no dosing or adverse event data are currently available on the
use of LMB-100 alone or in combination with tofacitinib in persons with <18 years of
age, children are excluded from this study.
- Patients 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 and 14
days from radiation therapy, systemic treatments (such as chemotherapy), or
experimental drug treatment. All acute toxicities from prior treatment must have
resolved to grade 1 or less except alopecia, anemia, peripheral neuropathy, or
endocrinopathies corrected by replacement therapy.
- Adequate hematological function: neutrophil count of >= 1.5 x 10^3 cells/micro liters,
platelet count of >= 85,000/micro liters, hemoglobin greater than or equal to 9 g/dL
- Serum albumin >= 2.5 mg/dL without intravenous supplementation
- Adequate liver function: Bilirubin <2.5 x ULN for all, AST and ALT < 3 x ULN except
for patients with significant tumor burden in their liver where AST and ALT < 5x ULN
is acceptable in the absence of other etiologies for transaminitis
- Adequate renal function: creatinine clearance [Estimating glomerular filtration rate
(EGFR) method or measured] >= 50 mL/min. Measured clearance will be used if both
numbers are available.
- Must have left ventricular ejection fraction >= 50%
- Must have an ambulatory oxygen saturation of > 88% on room air
- The expansion phase patients must meet all eligibility criteria above AND must have
diagnosis of pancreatic adenocarcinoma or extrahepatic cholangiocarcinoma with
pathology confirmed to be consistent with one of these diagnoses by NCI Laboratory of
Pathology.
- The effects of LMB-100 alone or in combination with tofacitinib 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:
- Known or clinically suspected CNS primary tumors or metastases including
leptomeningeal metastases as CNS penetration of LMB-100 is expected to be poor. CNS
metastases are permitted if 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
mesothelin [+] cancer diagnosis) that would contraindicate the use of an
investigational drug, interfere with tumor measurement or lead to a life expectancy of
less than 6 months as judged by the investigator.
- Contraindication to receiving prophylactic doses of low-molecular weight heparin
(LMWH) or direct oral anticoagulants (DOAC) such as current active bleeding (except
for grade 1 hematuria or epistaxis), recent history of significant bleeding without
subsequent effective medical or surgical intervention, known history of gastric
varices, uncontrolled malignant hypertension, history of coagulopathy that confers
increased risk of bleeding. Patients on concurrent treatment with anti-platelet agents
such as aspirin or clopidogrel are eligible if deemed to have acceptable risk of
bleeding in consultation with Hematologist. Patients already receiving prophylactic or
therapeutic doses of anticoagulant (heparin-based or DOAC) for at least 4 weeks with
no indication of significant bleeding while on therapy are considered NOT to have a
contraindication to this therapy.
- Inability to administer or unwillingness to comply with recommended VTE prophylaxis
for the duration of study treatment.
- Prior diagnosis of hematologic malignancy
- Active or uncontrolled infections (including tuberculosis, HIV, HBV, or HCV) or
reasonable clinical suspicion of an active infection (such as cholangitis) as
tofacitinib suppresses lymphocyte signaling and will impair host response to infection
- Latent TB infection as identified by interferon-gamma release assay (IGRA). If IGRA is
indeterminate, tuberculin skin test (TST) may be used to determine status.
- Live attenuated vaccinations within 14 days prior to treatment.
- Use of a strong inhibitor or inducer of CYP3A4 within 14 days prior to enrollment or
similarly updated source for a list of such agents)
- Inability to take or digest oral medication.
- Dementia or altered mental status that would prohibit informed consent.
- Pregnant women are excluded from this study because the effects of LMB-100 and/or
tofacitinib 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 and/or tofacitinib, breastfeeding should be discontinued if the mother is
treated with either of these agents.
- Baseline 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 any components related to LMB-100 and tofacitinib.
- Patients who have previously received LMB-100 (and therefore have high-levels of
preexisting ADA s to drug)
