Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors

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 principal investigator (PI).

• LMB-100 (Drug): Arms 1 and 2: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.
• Tofacitinib (Drug), also known as Xeljanz: Arms 1 and 2: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.
• Mesothelin Expression (Device): Test for mesothelin expression in tumor tissues for study eligibility

Primary outcomes

• Maximum Tolerated Dose (MTD) of LMB-100 With Tofacitinib [First cycle of treatment (21 days)]: MTD is defined as the maximum dose at which less than 33% of participants experience a dose-limiting toxicity (defined as any events occurring within the first cycle of treatment (21 days) such as any death not clearly due to the underlying disease or extraneous causes).
• Percentage of Participants With Pancreatobiliary Cancer and LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 Who Received LMB-100 at Maximum Tolerated Dose [Plasma LMB-100 levels during Cycle 2 treatment (each cycle = 21 days)]: This measure assessed how many participants have LMB-100 plasma drug levels higher than threshold (600 ng/mL) during Cycle 2 pharmacokinetics (PK) measurements, a sign of effective prevention of anti-LMB-100 antibodies. The validated enzyme-linked immunosorbent assay (ELISA) test was used to measure plasma LMB-100 concentration. Below 600ng/mL is considered a bad outcome and above 600ng/mL is considered a good outcome.
• Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Treated in the Dose Escalation Group [Throughout study treatment until 30 days post-completion, approximately 13 weeks]: Grade 1-5 adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 observed in participants with pancreatic cancer. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. Grade 4 is life-threatening consequences. Grade 5 is death related to adverse events.

Secondary outcomes

• Percentage of Participants With LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 in Dose Escalation [Plasma LMB-100 levels during Cycle 2 of treatment (each cycle = 21 days)]: This measure assessed how many participants in the dose escalation have LMB-100 plasma drug levels higher than threshold (600 ng/mL) during Cycle 2 pharmacokinetics (PK) measurements, a sign of effective prevention of anti-LMB-100 antibodies. The validated enzyme-linked immunosorbent assay (ELISA) test was used to measure plasma LMB-100 concentration. Below 600ng/mL is considered a bad outcome and above 600ng/mL is considered a good outcome.
• Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 [Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)]: The maximum observed analyte concentration in plasma was reported.
• Percentage of Participants Without Delayed Formation of Neutralizing Anti-LMB-100 Anti-drug Antibodies (ADAs) [Plasma LMB-100 levels during Cycle 3 treatment (each cycle = 21 days)]: This measure assessed how many participants have no LMB-100 plasma drug levels higher than threshold (600 ng/mL) during Cycle 3 pharmacokinetics (PK) measurements, a sign of effective prevention of anti-LMB-100 antibodies. The validated enzyme-linked immunosorbent assay (ELISA) test was used to measure plasma LMB-100 concentration. Below 600ng/mL is considered a bad outcome and above 600ng/mL is considered a good outcome.
• Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) of LMB-100 [Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)]: AUC is a measure of the serum concentration of LMB-100 over time. It is used to characterize drug absorption.
• Plasma Half-Life (T1/2) of LMB-100 [Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)]: Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
• Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Who Have Pancreatobiliary Cancer [Throughout study treatment until 30 days post-completion, approximately 13 weeks.]: Grade 1-4 adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 observed in participants with pancreatic cancer. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. Grade 4 is life-threatening consequences. Grade 5 is death related to adverse event.

Other outcomes

• Number of Participants With Serious and/or Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). [Throughout study treatment until 30 days post-completion, approximately 13 weeks.]: Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
• Number of Participants With a Dose-Limiting Toxicity (DLT) [First cycle (21 days)]: A dose limiting toxicity is defined as any events occurring within the first cycle of treatment (21 days) such as any death not clearly due to the underlying disease or extraneous causes, transaminitis that meets criteria for Hy's Law: grade ≥2 elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous elevation of total bilirubin to ≥ 2x ULN while alkaline phosphatase remains < 2x upper limit of normal (ULN). Some hematological toxicities, and Grade ≥3 non-hematological toxicities; and any other drug related toxicity considered significant enough to be qualifies as a DLT in the opinion of the principal investigator. Inability to start cycle 2 within 2 weeks after completing cycle 1 due to drug-related adverse events.

Sex: All, ages: 18 Years to any

* 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 National Cancer Institute (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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. or by following carbohydrate antigen 19-9 (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 deficient Mismatch Repair (dMMR)/high levels of MicroSatellite Instability (MSI-H) disease must have received at least one prior anti-programmed cell death 1 (PD1) therapy, be ineligible to receive this treatment due to concurrent medical conditions or have refused this therapy.
* Eastern Cooperative Oncology Group (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 upper limit of normal (ULN) for all, aspartate aminotransferase (AST) and alanine aminotransferase (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 central nervous system (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 venous thromboembolism (VTE) prophylaxis for the duration of study treatment.
* Prior diagnosis of hematologic malignancy
* Active or uncontrolled infections (including tuberculosis, human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (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 tuberculosis (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 cytochrome P450 3A4 (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 corrected QT interval by Fredericia (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 anti-drug antibodies (ADAs) to drug)

Participant flow

Outcome results

• Maximum Tolerated Dose (MTD) of LMB-100 With Tofacitinib (Primary), Number, mcg/kg given days 4, 6, 8 every cycle: All Participants in Dose Escalation Dose Level 1, and Dose Level 2 100
• Percentage of Participants With Pancreatobiliary Cancer and LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 Who Received LMB-100 at Maximum Tolerated Dose (Primary), Number, Percentage of participants: Dose Expansion LMB-100, 100 mcg/kg 33.3
• Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Treated in the Dose Escalation Group (Primary), Count of participants, Participants: Dose Escalation Dose Level 1 LMB-100 100 mcg/kg 1; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg 2
• Percentage of Participants With LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 in Dose Escalation (Secondary), Number, Percentage of participants: Dose Escalation Dose Level 1 LMB-100 100 mcg/kg 75; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg
• Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 (Secondary), Mean, ng/mL: Dose Escalation Dose Level 1 LMB-100 100 mcg/kg 1644.43 +/- 343.08; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg 2160.67 +/- 797.9; Dose Expansion LMB-100, 100 mcg/kg 1466.4 +/- 257.25
• Percentage of Participants Without Delayed Formation of Neutralizing Anti-LMB-100 Anti-drug Antibodies (ADAs) (Secondary), Number, Percentage of participants: Dose Escalation Dose Level 1 LMB-100 100 mcg/kg 100; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg 0; Dose Expansion LMB-100, 100 mcg/kg 0
• Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) of LMB-100 (Secondary), Mean, h*ng/mL: Dose Escalation Dose Level 1 LMB-100 100 mcg/kg 2415.9 +/- 1041.2; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg 2918.5 +/- 2434.6; Dose Expansion LMB-100, 100 mcg/kg 2804.1 +/- 190.14
• Plasma Half-Life (T1/2) of LMB-100 (Secondary), Mean, hour (h): Dose Escalation Dose Level 1 LMB-100 100 mcg/kg 1.0 +/- 0.39; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg 0.8 +/- 0.22; Dose Expansion LMB-100, 100 mcg/kg 1.2 +/- 0.25
• Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Who Have Pancreatobiliary Cancer (Secondary), Count of participants, Participants: Dose Expansion LMB-100, 100 mcg/kg 4
• Number of Participants With Serious and/or Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). (Other pre specified), Count of participants, Participants: Dose Escalation- Dose Level 1 LMB-100 100 mcg/kg 7; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg 3; Dose Expansion LMB-100, 100 mcg/kg 6
• Number of Participants With a Dose-Limiting Toxicity (DLT) (Other pre specified), Count of participants, Participants: Dose Escalation Dose Level 1 LMB-100 100 mcg/kg 0; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg 2

Adverse events

Time frame: Throughout study treatment until 30 days post-completion, approximately 13 weeks.]

Serious adverse events by term

Other adverse events by term

8 more terms not shown.

• Results publication: Skorupan N, Peer CJ, Zhang X, Choo-Wosoba H, Ahmad MI, Lee MJ, Rastogi S, Sato N, Yu Y, Pegna GJ, Steinberg SM, Kalsi SS, Cao L, Figg WD, Trepel JB, Pastan I, FitzGerald D, Alewine C. Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers. Front Oncol. 2024 Apr 19;14:1386190. doi: 10.3389/fonc.2024.1386190. eCollection 2024. PMID 38706610

• Study Protocol and Statistical Analysis Plan (PDF, 2020-08-19)
• Informed Consent Form: Screening Consent (PDF, 2020-08-20)
• Informed Consent Form: Standard Consent (PDF, 2020-08-20)

• Christine C Alewine, M.D., Principal investigator, National Cancer Institute (NCI)