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

Phase 1

Completed

Conditions: Neoplasms
Pancreatic Neoplasms

Interventions: Drug: LMB-100
Drug: Nab-Paclitaxel
Device: Mesothelin Expression

Registration Number: NCT02810418

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm A1, Dose Level 1 (Phase 1, short infusion) 100µg/kg LMB-100	LMB-100	Arm A1, Dose Level 1, Phase I Short Infusion 100µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel Dose level 1 (DL1) Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving short infusion LMB-100+nabpaclitaxel
Arm A2 (Phase 2, short infusion) 65µg/kg LMB-100	LMB-100	Arm A2, Phase 2 Short Infusion 65µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel Efficacy determination in patients with pancreatic cancer receiving short infusion LMB-100 + nabpaclitaxel
Arm B1, Dose Level 3R Phase I (Continuous infusion single agent lead-in)	LMB-100	Arm B1, DL3R, 24-hr Continuous Infusion Single Agent Lead-in 100µg/kg LMB-100
Arm A2 (Phase 2, short infusion) 65µg/kg LMB-100	Nab-Paclitaxel	Arm A2, Phase 2 Short Infusion 65µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel Efficacy determination in patients with pancreatic cancer receiving short infusion LMB-100 + nabpaclitaxel
Arm B1, Dose Level 2 Phase I (Continuous infusion single agent lead-in)	Mesothelin Expression	Arm B1, DL2, 48-hr Continuous Infusion Single Agent Lead-in 100µg/kg/day LMB-100 Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving continuous infusion LMB-100 as single agent
Arm B2 Phase I (continuous infusion combination therapy)	Nab-Paclitaxel	Subjects with pancreatic cancer receiving continuous infusion LMB-100 combination therapy
Arm A1, Dose Level 1 (Phase 1, short infusion) 100µg/kg LMB-100	Nab-Paclitaxel	Arm A1, Dose Level 1, Phase I Short Infusion 100µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel Dose level 1 (DL1) Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving short infusion LMB-100+nabpaclitaxel
Arm A1, Dose Level-1 (Phase 1, short infusion) 65µg/kg LMB-100	LMB-100	Arm A1, DL-1, Ph I Short Infusion 65µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel
Arm A1, Dose Level-1 (Phase 1, short infusion) 65µg/kg LMB-100	Nab-Paclitaxel	Arm A1, DL-1, Ph I Short Infusion 65µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel
Arm B1, Dose Level 1 Phase I (Continuous infusion single agent lead-in)	Mesothelin Expression	Arm B1, DL1, 48-hr Continuous Infusion Single Agent Lead-in 65µg/kg/day LMB-100
Arm B1, Dose Level 3R Phase I (Continuous infusion single agent lead-in)	Mesothelin Expression	Arm B1, DL3R, 24-hr Continuous Infusion Single Agent Lead-in 100µg/kg LMB-100
Arm B1, Dose Level 2 Phase I (Continuous infusion single agent lead-in)	LMB-100	Arm B1, DL2, 48-hr Continuous Infusion Single Agent Lead-in 100µg/kg/day LMB-100 Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving continuous infusion LMB-100 as single agent
Arm B1, Dose Level 1 Phase I (Continuous infusion single agent lead-in)	LMB-100	Arm B1, DL1, 48-hr Continuous Infusion Single Agent Lead-in 65µg/kg/day LMB-100
Arm B2 Phase I (continuous infusion combination therapy)	LMB-100	Subjects with pancreatic cancer receiving continuous infusion LMB-100 combination therapy

Primary Outcome Measures

Name	Time	Method
Objective Response (OR) (Partial Responses + Complete Responses) in Phase 2 Subjects of Short Infusion LMB-100+ Nab-paclitaxel	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	OR is defined as partial responses + complete response in participants in the phase 2 Arm A portion of the study assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is a disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters
Maximum Tolerated Dose (MTD) of Short Infusion LMB-100 + Nab Paclitaxel	21 days after LMB-100 is administered (end of cycle 1)	MTD is defined as the highest dose tolerated without exceeding a pre-set number of adverse events in Phase 1, Arm A.
Maximum Tolerated Dose (MTD) of Continuous Infusion LMB-100	21 days after LMB-100 is administered (end of cycle 1)	MTD is defined as the highest dose tolerated without exceeding a pre-set number of adverse events in Phase 1, 1 Arm B, single agent lead-in

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Time from treatment initiation to death, up to 1-2 years.	OS is the average time from treatment initiation to death.
Progression Free Survival (PFS)	Time from treatment initiation to disease progression or death, an average of 1 year.	PFS is the average time from treatment initiation to disease progression or death. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. And the appearance of one or more new lesions.
Proportion of Participants Disease Control Rate (DCR) at End of Treatment (EOT)	up to 3 months	DCR is the proportion of participants with stable disease, partial response or complete response at end of treatment. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete Response is disappearance of all target lesions. Stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.
Number of Participants With an Objective Response (OR) (Partial Responses + Complete Responses) in Phase 1 Arm A1	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.	OR is defined as partial response + complete response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is a disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters
Number of Participants With an Objective Response (OR) (Partial Response + Complete Response) in Phase 1, Arm B	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.	OR is defined as partial responses + complete response in participants in the phase 1 Arm B portion of the study assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is a disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Number of Participants With Adverse Events Attributed to LMB-100	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.	Grade 1-4 adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 observed in subjects with pancreatic cancer. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. Grade 4 is life-threatening consequences.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).	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.	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). 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.