Patient case: 73-year-old female with Pancreatic ductal adenocarcinoma. Genetic variant: ERBB3. Other conditions: Whipple, FNA.

Clinical trial: Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Nab-Paclitaxel in People With Previously Treated Metastatic and/or Locally Advanced Pancreatic Ductal Adenocarcinoma

Summary: Background:
  LMB-100 is a man-made protein designed to kill cancer cells. LMB-100 targets a cancer marker called mesothelin. Mesothelin is found on the surface of many different tumors, including pancreatic cancer, but is made by a very small number of normal tissues. After binding to the mesothelin on tumors, LMB-100 can attack and kill cancer cells. Researchers want to see how well it works when given with nab-paclitaxel, which treats pancreatic cancer.
  Objectives:
  To find a safe dose of LMB-100 with a fixed standard dose of nab-paclitaxel in people with advanced pancreatic cancer. To see how well the combination of the two drugs reduce tumor size.
  Eligibility:
  Adults age 18 and older with advanced pancreatic cancer that has worsened after anti-cancer therapy.
  Design:
  Participants will be screened with medical history and physical exam. They will give blood, urine, and tissue samples. They will have scans and x-rays.
  During each 21-day cycle:
  Participants will get LMB-100 by an IV catheter on days 1, 3, and 5. This is a tube inserted in a vein, usually in the arm.
  Participants will get nab-paclitaxel by IV on days 1 and 8.
  They will get this combination for up to 4 cycles or until their disease worsens or they have intolerable side effects.
  Participants will have blood and urine tests and scans throughout the study.
  Participants will have a safety follow-up visit 6 weeks after treatment ends. If their disease remains stable or improves, they will be scanned every 6 weeks until their disease gets worse. Even if their disease gets worse, they or their doctor will be called to talk about their cancer status.

Detailed description: 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%.
  -  Mesothelin is specifically a marker of adenocarcinoma in the human disease and is not expressed in preceding pre-malignant stages of tumor development
  -  Expression of mesothelin in pancreatic ductal adenocarcinoma (PDA) has been examined in several published studies and ranges from 86 to 100%
  -  Recombinant immunotoxins (RITs) are antibody-based therapeutics that carry a toxin payload. RITs that target mesothelin contain a genetically engineered variant of Pseudomonas exotoxin A (PE) in which the native cell-binding domain of PE is replaced by the mesothelin-binding antibody fragment. SS1P was the first mesothelin-targeted RIT tested in patients.
  -  LMB-100 contains a newly engineered PE fragment that has improved activity against most pancreatic cancer cell lines in vitro, and is also much less toxic than SS1P in preclinical models. The new PE contains modifications specifically designed to reduce immunogenicity of the molecule.
  -  Pre-administration of paclitaxel with SS1P was demonstrated to increase the amount of immunotoxin internalized by tumor cells and to reduce levels of shed mesothelin in the intra-tumoral environment so that more immunotoxin could bind tumor cells. The effect is even more pronounced with NAB-paclitaxel in a pancreatic cancer model.
  -  Initial clinical testing of LMB-100 was performed by Roche in a multi-center international first in human trial (NCT02317419). The agent was well tolerated and appeared to have decreased immunogenicity compared to SS1P based on preliminary results.
  Primary Objectives:
  -  Phase I:
  --To determine the maximum tolerated dose of LMB-100 in combination nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer
  -  Phase II:
  -  To determine the objective response rate (PR+CR) according to RECIST 1.1 criteria of
  LMB-100 in combination with nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer
  Eligibility:
  -  Age greater than or equal to18 years
  -  Histologically confirmed recurrent, metastatic and/or advanced pancreatic ductal adenocarcinoma
  -  Treatment must include at least one prior chemotherapy regimen
  -  No nab-paclitaxel or paclitaxel treatment in the last four months
  -  Adequate organ function
  -  Participants with HIV, active HBV or HCV infections are excluded
  Design:
  -  This study is a Phase I/II open label study to assess the safety and efficacy of LMB-100 in combination with the standard of care agent nab-paclitaxel in participants metastatic and/or locally advanced pancreatic ductal adenocarcinoma
  -  Subjects will be treated for up to 4 cycles
  -  In the phase I portion of the study, up to 3 dose levels will be evaluated. LMB-100 will be administered on days 1, 3 and 5 of a 21 day cycle and nab-paclitaxel will be administered on days 1 and 8
  -  In the phase II portion of the study, up to 20 evaluable participants (including those treated at the MTD in the phase I study) will be enrolled.
  -  The phase II study will be conducted in a Simon Minimax two stage phase II design. The first stage will enroll 13 evaluable participants, including the six participants treated at the MTD from phase I. If 1 or more has a response, then accrual would continue until a total of 20 evaluable participants have been enrolled.

Eligibility: -  INCLUSION CRITERIA:
  -  Histologically confirmed recurrent, advanced or metastatic pancreatic ductal adenocarcinoma as determined by NCI Laboratory of Pathology.
  -  Measurable and/or evaluable disease as per the RECIST Criteria v 1.1
  -  Participants must have received at least one prior chemotherapy regimen for their disease, but no paclitaxel or nab-paclitaxel within 4 months prior to initiation of study therapy.
  -  Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of LMB-100 in combination with nab-paclitaxel in persons <18 years of age, children are excluded from this study.
  -  ECOG performance status (PS) 0 2.
  -  Participants 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 or radiation treatment, 14 days removed from most recent chemotherapy or experimental drug treatment with published half-life known to be 72 hours or less and 28 days removed from last experimental drug treatment with unpublished or half-life greater than 72 hours.
  -  All acute toxic effects of any prior radiotherapy, chemotherapy, experimental drug treatment or surgical procedure must have resolved to Grade less than or equal to 1, except alopecia (any grade).
  -  Adequate hematological function: neutrophil count of greater than or equal to 1.0 times 10(9) cells/L, platelet count of greater than or equal to 100,000/microl, hemoglobin greater than or equal to 9 g/dL
  -  Serum albumin greater than or equal to 2.5 mg/dL without intravenous supplementation
  -  Adequate liver function: Bilirubin, AST and ALT < 2.5 times ULN
  -  Adequate renal function: creatinine clearance greater than or equal to 50 mL/min.
  -  Must have left ventricular ejection fraction > 50%
  -  Must have an ambulatory oxygen saturation of > 88% on room air
  -  The effects of LMB-100 in combination with nab-paclitaxel 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 thelast 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 2.1.2.1 primary tumors or metastases including leptomeningeal metastases. History or clinical evidence of CNS metastases unless 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 pancreatic adenocarcinoma) that would contraindicate the use of an investigational drug, interfere with tumor measurement or lead to an expected life expectancy of less than 6 months as judged by the investigator
  -  Active or uncontrolled infections.
  -  Live attenuated vaccinations within 14 days prior to treatment
  -  HIV or active HBV or HCV infection due to risk of progression while receiving immunosuppressive chemotherapy
  -  Dementia or altered mental status that would prohibit informed consent
  -  Pregnant women are excluded from this study because the effects of LMB-100 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, breastfeeding should be discontinued if the mother is treated with LMB-100. These potential risks may also apply to other agents used in this study.
  -  Known hypersensitivity to any of the components of LMB-100
  -  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 nab-paclitaxel
  -  Participants with baseline peripheral neuropathy grade 2 or above

Relevance to patient case: not relevant