Clinical trial NCT02810418: Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in People With Previously Treated Metastatic and/or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors
Official title: A Phase Ib/II Study of Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in Participants With Previously Treated Metastatic and/ or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Neoplasms
Pancreatic Neoplasms
Keywords: Immunotoxin
Mesothelin
Antibody-based Therapeutics
Advanced Cancer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2016-06-23
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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. Other cancers that make mesothelin include mesothelioma, cholangiocarcinoma, thymic carcinoma, ovarian, lung, gastric, endometrial, cervical, and ampullary cancers. 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 and without nab-paclitaxel, a drug which treats pancreatic cancer.

Objectives:

Arm A- 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.

Arm B- To find a safe dose of LMB-100 when it is given as a continuous infusion over several days.

Eligibility:

Arm A- Adults age 18 and older with advanced pancreatic cancer that has worsened after anti-cancer therapy.

Arm B- Adults age 18 and older with advanced pancreatic cancer, mesothelioma or other solid tumor that makes mesothelin 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:

* For Arm A

  * Participants will get LMB-100 by an intravenous (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.
* For Arm B

  * Participants will get LMB-100 by an IV catheter as a continuous infusion beginning on day 1 and continuing for 2-4 days
  * Some participants will also get nab-paclitaxel by IV on days 1 and 8.

All participants will get this combination for up to 2 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 3-6 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.
* In initial and subsequent clinical testing, LMB-100 was found to have half-life of approximately 60 mins. This is shorter then that measured for previous RITs used in the clinical setting.

Primary Objectives:

* Arm A1 (Phase I, short infusion):

  --To determine the maximum tolerated dose of short infusion LMB-100 in combination nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer
* Arm B1(Continuous infusion single agent lead-in):

  --To determine the maximum tolerated dose of LMB-100 given in a continuous infusion format over 24 - 96 hours to patients with advanced solid tumors that express mesothelin
* Arm B2 (Continuous infusion combination therapy)

  --Establish a tolerated dose of LMB-100 given by continuous infusion in combination with nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer
* Arm A2 (Phase II, short infusion):

  * To determine the objective response rate (Partial Response (PR)+Complete Response (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria of short infusion 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 (Except for Arm B1 \[B Single Agent Lead-in\])
* For Arm B1 (Single Agent Lead-in), ONLY: Histologically confirmed solid tumor malignancy for which no curative therapy exists with at least 25% of tumor cells expressing mesothelin as determined by National Cancer Institute (NCI) Laboratory of Pathology. Determination can be made using archival tumor tissue or fresh biopsy.
* Treatment must include at least one prior chemotherapy regimen
* No nab-paclitaxel or paclitaxel treatment in the last four months (Except for Arm B1 \[Single Agent Lead-in\])
* Adequate organ function
* Participants with human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are eligible only for the Arm B1 (Single Agent Lead-in)

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 2 cycles
* In Arm A1 (Phase I, short infusion) 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
* Arm A2 (Phase II, short infusion), up to 20 evaluable participants (including those treated at the short infusion maximum tolerated dose (MTD) in the phase I study) will be enrolled.
* Arm B1 (Continuous infusion single Agent Lead-in), escalating doses of single agent LMB-100 will be administered. The study drug will be given as a continuous infusion for the 1, 2, 3, or 4 days of a 21-day cycle.
* Arm B2 (Continuous infusion, combination therapy) will be initiated after completion of both Arm A1 and Arm B1 Single Agent Lead-in. It will test a single dose level of LMB-100 based on data from the Lead-in given in combination with nab-paclitaxel. LMB-100 will be given as a continuous infusion for the 1, 2, 3 or 4 days of a 21-day cycle. Nabpaclitaxel will be given on Day 1 and Day 8.
* The Arm A2 (Phase II, short infusion) portion of the 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 short infusion 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 criteria: * INCLUSION CRITERIA:
* For participants who will be receiving nab-paclitaxel (all arms except Phase I Arm B Single Agent Lead-in)

  * Histologically confirmed recurrent, advanced or metastatic pancreatic ductal adenocarcinoma as determined by National Cancer Institute (NCI) Laboratory of Pathology.
  * No treatment with paclitaxel or nab-paclitaxel within 4 months prior to initiation of study therapy
  * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
  * Adequate hematological function: neutrophil count of greater than or equal to 1.0 x 10(9) cells/L, platelet count of greater than or equal to 95,000/microliters, hemoglobin greater than or equal to 9 g/dL
  * Measurable disease as per the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria v 1.1
  * For participants who will NOT receive nab-paclitaxel (Arm B1 Single Agent Lead-in only)
  * Histologically confirmed solid tumor malignancy for which no curative therapy exists with at least 25% of tumor cells expressing mesothelin as determined by NCI Laboratory of Pathology. Determination can be made using archival tumor tissue or fresh biopsy. Subjects with epithelioid mesothelioma and pancreatic adenocarcinoma are automatically eligible and are not required to have this test.
  * ECOG performance status (PS) 0-2.
  * Adequate hematological function: neutrophil count of greater than or equal to 1.0 x 10(9) cells/L, platelet count of greater than or equal to 85,000/microliters, hemoglobin greater than or equal to 8.5 g/dL
  * Measurable and/or evaluable disease as per the RECIST Criteria v 1.1
* For all arms of the protocol

  * Participants must have received at least one prior chemotherapy regimen for their disease.
  * 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.
  * 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, 14 days removed from most recent radiation therapy, 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) and peripheral neuropathy.
  * Serum albumin greater than or equal to 2.5 mg/dL without intravenous supplementation
  * Adequate liver function: Bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5 x upper limit of normal (ULN). AST and ALT up to 5x ULN is permitted for patients with liver metastases.
  * 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 alone or 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 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:

* Exclusion criteria for all study arms

  * Known or clinically suspected central nervous system (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
  * 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 corrected QT interval by Fridericia (QTcF) interval of \> 470 ms, participants with baseline resting bradycardia \< 45 beats per minute, or baseline resting tachycardia\> 100 beats per minute.
* Exclusion criteria specific to patients who will be receiving nab-paclitaxel (all arms except Arm B1 Single Agent Lead-in)

  * Participants with contra-indication and/or history of severe hypersensitivity reactions to nab-paclitaxel
  * Participants with baseline peripheral neuropathy greater than grade 2
  * Human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection due to risk of progression while receiving immunosuppressive chemotherapy

Primary outcomes:
measure: Objective Response (OR) (Partial Responses + Complete Responses) in Phase 2 Subjects of Short Infusion LMB-100+ Nab-paclitaxel
timeFrame: Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment, up to 1 year
measure: Maximum Tolerated Dose (MTD) of Short Infusion LMB-100 + Nab Paclitaxel
timeFrame: 21 days after LMB-100 is administered (end of cycle 1)
measure: Maximum Tolerated Dose (MTD) of Continuous Infusion LMB-100
timeFrame: 21 days after LMB-100 is administered (end of cycle 1)
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Time from treatment initiation to disease progression or death, an average of 1 year.
measure: Overall Survival (OS)
timeFrame: Time from treatment initiation to death, up to 1-2 years.
measure: Proportion of Participants Disease Control Rate (DCR) at End of Treatment (EOT)
timeFrame: up to 3 months
measure: Number of Participants With an Objective Response (OR) (Partial Responses + Complete Responses) in Phase 1 Arm A1
timeFrame: Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment up to 1 year.
measure: Number of Participants With an Objective Response (OR) (Partial Response + Complete Response) in Phase 1, Arm B
timeFrame: Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment up to 1 year.
measure: Number of Participants With Adverse Events Attributed to LMB-100
timeFrame: Date treatment consent signed to date off study, approx. 11 mos, 8 days for A1DL1; 20 mos, 9 days for A1DL-1; 10 mos, 17 days for A2; 2 mos, 16 days for B1DL1; 14 mos, 30 days for B1DL2; 5 mos, 1 day for B2; and 4 mos, 15 days for B1DL3R.
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).
timeFrame: Date treatment consent signed to date off study, approx. 11 mos, 8 days for A1DL1; 20 mos, 9 days for A1DL-1; 10 mos, 17 days for A2; 2 mos, 16 days for B1DL1; 14 mos, 30 days for B1DL2; 5 mos, 1 day for B2; and 4 mos, 15 days for B1DL3R.
Other outcomes:
measure: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
timeFrame: First 28 days following infusion of LMB-100 on Cycle 1, Day 1 through the duration of the study treatment up to 1 year.
measure: Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUCinf)
timeFrame: For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1.
measure: Area Under the Serum Concentration Versus Time Curve Extrapolated to Infinity (AUCinf)/D (Dose)
timeFrame: For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1.
measure: Area Under the Serum Concentration Versus Time Curve Extrapolated to Last Measurement (AUClast)/D
timeFrame: For Arms B1 & B2: Pre-dose, end of loading dose, 2 and 6 hours after start of continuous infusion, end of infusion (EOI) and 2 hrs after EOI during Cycle 1 Day 1.
measure: Time Curve Extrapolated to Last Measurement (AUClast) for LMB-100
timeFrame: For Arms B1 & B2: Pre-dose, end of loading dose, 2 and 6 hours after start of continuous infusion, end of infusion (EOI) and 2 hrs after EOI during Cycle 1.
measure: The Total Clearance (CL) of LMB-100
timeFrame: For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1.
measure: Plasma Half-Life (T1/2) of LMB-100
timeFrame: For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1, Day 1.
measure: Volume of Distribution (Vd) of LMB-100
timeFrame: For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1, Day 1.
measure: Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 in Arm A1 and Arm A2
timeFrame: For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day. Pre-dose and end of infusion (EOI) during Cycle 2 Day 1.
measure: Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 in Arm B1 and Arm B2
timeFrame: For Arms B1 & B2: Pre-dose, end of loading dose, 2 and 6 hours after start of continuous infusion, end of infusion (EOI) and 2 hrs after EOI during Cycle 1 Day 1. Pre-dose, end of loading dose and EOI during Cycle 2 Day 1.
measure: Maximum Observed (Peak) Plasma Concentration (Cmax)/D (Dose) of LMB-100 in Arm A1 and Arm A2
timeFrame: For Arms A1 & A2: Pre-dose, end of infusion (EOI), 1, 2 and 4 hours after EOI during Cycle 1 Day 1. Pre-dose and end of infusion (EOI) during Cycle 2 Day 1.
measure: Maximum Observed (Peak) Plasma Concentration (Cmax)/D (Dose) of LMB-100 in Arm B1 and Arm B2
timeFrame: For Arms B1 & B2: Pre-dose, end of loading dose, 2 and 6 hours after start of continuous infusion, end of infusion (EOI) and 2 hrs after EOI during Cycle 1 Day 1. Pre-dose, end of loading dose and EOI during Cycle 2 Day 1.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Christine C Alewine, M.D.
role: PRINCIPAL_INVESTIGATOR
References: