Mesothelin-Targeted Immunotoxin LMB-100 in People With Malignant Mesothelioma

Phase 1

Completed

Conditions: Mesothelioma

Interventions: Drug: LMB-100
Drug: nab-paclitaxel

Registration Number: NCT02798536

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

LMB-100 is a man-made protein. It is attracted to the mesothelin protein. This is found in many tumors, including mesothelioma. But it is found in only a very small number of normal tissues. After binding to mesothelin on tumors, LMB-100 attacks and kills cancer cells. Researchers want to test LMB-100 in people with advanced mesothelioma.

Objective:

To find a safe dose and anti-tumor activity of LMB-100 for people with advanced mesothelioma.

Eligibility:

Adults ages 18 and older with:

Advanced pleural or peritoneal mesothelioma that has not responded to platinum-based

therapy

Adequate organ function

Design:

Participants will be screened with:

Samples of tumor tissue or tumor fluid. These can be new or from a previous procedure.

Medical history

Physical exam

Blood, urine, and heart tests

Chest x-rays

Computed tomography (CT) or magnetic resonance imaging (MRI) scans

Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans

Participants will get LMB-100 on days 1, 3, and 5 of each 21-day cycle. It will be given through an intravenous (IV) catheter, a tube inserted in an arm vein. They will get standard medicines before each infusion to help prevent side effects. Each infusion lasts about 30 minutes. They will be monitored for up to 2 hours after.

During each cycle, participants will repeat the screening tests.

Participants will get the study drug for up to 4 cycles or until their disease worsens or they have intolerable side effects.

About 4-6 weeks after their last infusion, participants will have a follow-up visit. They will repeat the study tests.

Participants will have follow-up scans every 6 weeks until their disease gets worse.

Participants will be called about once a year to see how they are doing.

Detailed Description: Background:

* Although mesothelioma patients with a limited tumor burden may benefit from surgical resection, most patients have advanced disease at diagnosis and are not candidates for cytoreductive surgery.

* For mesothelioma patients who are not eligible for curative surgery, the median survival with supportive care alone is 6 months whereas with the current standard treatment, a combination of cisplatin and pemetrexed, the median survival is 12 months.

* Mesothelin, a tumor differentiation antigen, is expressed in over 95% of epitheloid mesothelioma. Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in normal human tissue and its high expression in several tumors including mesothelioma.

* LMB-100 is a novel recombinant anti-mesothelin immunotoxin developed for the treatment of patients with solid tumors that express mesothelin. Mesothelin is targeted by linking a humanized fragment of the anti-mesothelin Fab to a de-immunized Pseudomonas exotoxin (PE).

* The clinical use of first generation immunotoxins such as SS1P was hampered mainly by their high immunogenicity. LMB-100 is a next generation PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity. LMB-100 has shown broad activity against different mesothelin expressing cancer cell lines and tumor xenograft models.

Objectives: Phase 1

To identify the recommended phase 2 dose (RP2D) of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma and evaluate potential efficacy of the identified RP2D.

-Phase 2

To determine the efficacy of LMB-100 with respect to objective response rate in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.

Eligibility:

* Age greater than or equal to 18 years

* Histologically confirmed advanced pleural or peritoneal mesothelioma

* Subjects must have had at least 1 prior chemotherapy regimen with last dose of previous therapy occurring at 3 weeks before the start of study treatment

* Adequate organ function

* Participants with central nervous system (CNS) metastases or prior pneumonectomy are excluded

Design:

* This is a Phase I, open-label study to evaluate the safety, pharmacokinetics, and activity of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.

* LMB-100 will be administered intravenously on days 1, 3 and 5 of each 21 day cycle for up to 4 cycles

* Tumor response will be assessed after every 2 cycles

* Optional tumor biopsies may be collected at baseline and after 2 cycles of therapy

* The accrual ceiling will be set at 30

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
A1/LMB-100 dose escalation (closed)	LMB-100	De-escalating doses of LMB-100 in up to 18 subjects
B2/LMB-100+ nab- paclitaxel dose expansion	LMB-100	Fixed dose of LMB-100 as determined in Arm B1 + fixed dose of nab-paclitaxel in up to 16 subjects
A2/LMB-100 dose expansion (closed)	LMB-100	Fixed dose of LMB-100 as determined in Arm A1 in up to 16 subjects
B1/LMB-100+ nab- paclitaxel dose escalation	LMB-100	De-escalating doses of LMB-100 + fixed dose of nab-paclitaxel in up to 12 subjects
B1/LMB-100+ nab- paclitaxel dose escalation	nab-paclitaxel	De-escalating doses of LMB-100 + fixed dose of nab-paclitaxel in up to 12 subjects
B2/LMB-100+ nab- paclitaxel dose expansion	nab-paclitaxel	Fixed dose of LMB-100 as determined in Arm B1 + fixed dose of nab-paclitaxel in up to 16 subjects

Primary Outcome Measures

Name	Time	Method
Recommended Phase 2 Dose (RP2D) of LMB100 + Nab-paclitaxel	3 weeks after initial dose	Highest administered dose of LMB-100 + nab-paclitaxel at which no more than 1 of 6 participants experiences a dose limiting toxicity (DLT). A DLT is any of the following events attributed to LMB-100 and occurring within 21 days after the first dose of LMB-100 such as Grade 4 neutropenia, Grade 3 and 4 febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia associated with bleeding episodes. Grade ≥ 3 non-hematological toxicity with the exception of alopecia (any grade), Grade 3 nausea and vomiting without appropriate treatment, Grade 3 diarrhea lasting for ≤ 2 days with no fever or dehydration.

Secondary Outcome Measures

Name	Time	Method
Number of Grade 3-5 Adverse Events Possibly, Probably, and/or Definitely Related to the LMB-100 +/- Nab-Paclitaxel	30 days after treatment	Adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is serious, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
Median Progression Free Survival (PFS)	At progression, up to 3.6 months	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was measured 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. The appearance of one or more new lesions is also considered progressions.
Number of Participants With LMB-100 Maximum Observed Serum Concentration (Cmax) of >100ng/mL	Cycle 1 and Cycle 2 (each cycle is 21 days), approximately 42 days	Number of participants with LMB-100 Maximum observed serum concentration (Cmax) of \>100ng/mL was measured by
Number of Participants at Recommended Phase 2 Dose (RP2D) With Partial or Complete Response by the Response Evaluation Criteria in Solid Tumors (RECIST)	End of treatment, an average of 57.6 days	Number of participants at maximum tolerated dose (MTD) with partial or complete response measured by the Response Evaluation Criteria in Solid Tumors (RECIST). 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. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.
Median Overall Survival (OS)	At death, up to 60.8 months	OS is defined as the duration of time from start of treatment to time of death.
Number of Participants With Anti-drug Antibodies (ADAs) Formation to LMB-100	Cycle 1 and Cycle 2 (each cycle is 21 days), approximately 42 days	ADAs formation to LMB-100 were measured by the enzyme-linked immunosorbent assay (ELISA). The presence of ADAs (i.e., positive) may indicate the participant may have poor blood levels.
Duration of Response (DOR)	time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented by computed tomography (CT) scans performed every 6 weeks.	The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Progressive disease was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.