Mesothelin-Targeted Immunotoxin LMB-100 in Combination With SEL-110 in Subjects With Malignant Pleural or Peritoneal Mesothelioma

Phase 1

Terminated

Conditions: Mesothelioma

Interventions: Drug: LMB-100
Drug: SEL-110

Registration Number: NCT03436732

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

Mesothelioma is cancer of the tissue that lines some organs. A new drug, LMB-100, may bind to a protein on mesothelioma tumors and kill cancer cells. But sometimes the body makes antibodies that reduce how well LMB-100 works. Researchers want to see if adding the drug SEL-110 to LMB-100 will prevent these antibodies from forming.

Objective:

To learn how safe and tolerable LMB-100 plus SEL-110 is in people with advanced mesothelioma.

Eligibility:

Adults ages 18 and older who have pleural or peritoneal mesothelioma that has not responded to prior platinum-based therapy

Design:

Participants will be screened with

* Medical history

* Physical exam

* Blood and urine tests

* Sample of tumor tissue. This can be from a previous procedure.

* Scan of the chest, abdomen, and pelvis. Participants will lie on a table in a scanner that takes pictures. A special dye may be injected in a vein.

* Positron emission tomography (fludeoxyglucose positron emission tomography (FDG-PET)) scan. A sugar attached to a chemical that gives off a signal will be injected before the scan.

* Heart function tests

The study will be done in 21-day cycles. Participants will get the study drugs for up to 4 cycles. They will get them through an intravenous (IV) catheter (a tube inserted in a vein, usually in the arm):

* LMB-100 for about 30 minutes on day 1, day 3, and day 5 of each cycle

* SEL-110 for about 1 hour on day 1 of each cycle

Participants will get standard medicines to help prevent side effects.

Participants will repeat some screening tests during each cycle and about 5 weeks after the last dose of study drug.

Detailed Description: Background:

* LMB-100 and a closely related immunotoxin also targeting mesothelin have been studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.

* Results from these studies showed that the majority of patients formed anti-drug-antibodies (ADAs) that neutralized subsequent injection of the product making it ineffective.

* In a small subset of patients that did not form ADAs to the product, good response and regression of tumors was seen.

* In a different application SEL-110, a biodegradable nanoparticle containing rapamycin, has been shown in clinical trials to prevent the formation of ADAs to an immunogenic enzyme when co-administered. Preclinical data show that SEL-110 also prevents the formation of ADAs to LMB-100.

* This clinical trial will investigate whether SEL-110 when administered with LMB-100 is able to prevent the formation of ADAs and thus allow patients to receive multiple, effective injections of LMB-100.

Objectives:

-The primary objective of the study is to assess the safety and tolerability of LMB-100 in combination with SEL-110.

Eligibility:

Primary Inclusion Criteria

* Greater than or equal to 18 years of age

* Histologically confirmed epithelial or biphasic pleural or peritoneal mesothelioma not amenable to potentially curative surgical resection.

* Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

* Patients must have had at least one prior chemotherapy regimen that includes pemetrexed and cisplatin or carboplatin. There is no limit to the number of prior chemotherapy regimens received.

* Patients for whom no standard curative therapy exists

Primary Exclusion Criteria:

* Known or clinically suspected central nervous system (CNS) primary tumors or metastases including leptomeningeal metastases.

* Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results.

* Evidence of active or uncontrolled infections.

* Live attenuated vaccinations 14 days prior to treatment

* Pregnant women are excluded from this study

Design:

* This is a Phase I, single center, dose escalation study of LMB-100 in combination with SEL-110

* Patients will receive the combination using a dose escalation scheme in which different doses of LMB100 and SEL-110 will be evaluated.

* Patients will receive 4 cycles of LMB-100 with SEL-110. A cycle will consist of intravenous (i.v.) infusion of SEL-110 on Day 1 of the cycle followed immediately by an i.v. infusion of LMB-100, then on Days 3 and 5 of the cycle patients will receive an i.v. infusion of LMB-100 only. Treatment cycles will be separated by 21 days.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
2/Dose Expansion	LMB-100	Dose expansion - patients with mesothelioma treated with LMB-100+SEL-110 at recommended phase 2 dose (RP2D)
1/Dose Escalation	LMB-100	Dose escalation - patients with mesothelioma treated with LMB-100+SEL-110 at escalating doses
1/Dose Escalation	SEL-110	Dose escalation - patients with mesothelioma treated with LMB-100+SEL-110 at escalating doses
2/Dose Expansion	SEL-110	Dose expansion - patients with mesothelioma treated with LMB-100+SEL-110 at recommended phase 2 dose (RP2D)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Grade ≥3 Adverse Events Related to Study Drug at Dose Level 140 mcg/kg and 100 mcg/kg	Day 85	Here are the grade ≥3 adverse events at each dose level assessed by the Common Terminology Criteria in Adverse Events CTCAE v5.0. 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. Grade 3 is Severe or medically significant but not immediately life-threatening;hospitalization or prolongation of hospitalization indicated; disabling;limiting self care ADL (i.e., bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Grade 4 is life-threatening consequences;urgent intervention indicated. Grade 5 is death related to adverse event.
Maximum Tolerated Dose (MTD)	Day 21	MTD is defined as the highest tested dose of LMB-100 and SEL-110 at which no more than 1 of 6 subjects experience a dose limiting toxicity. A dose limiting toxicity is defined as any of the following: Grade 4 neutropenia for a minimum duration of 7 days. Grade 4 thrombocytopenia (≤25.0 x 10(9) cells/L), Grade 3 thrombocytopenia associated with bleeding episodes, and Grade 4 anemia. Grade ≥3 non-hematological toxicity with the exception of Alopecia (any grade), Grade 3 nausea and vomiting lasting \> 48 hours despite appropriate treatment, Grade 3 diarrhea lasting for ≤ 2 days with no fever or dehydration, and laboratory values of ≥ grade 3 that are judged not clinically significant by the investigator. Any other drug related toxicity considered significant enough to be qualified as a DLT in the opinion of the principal investigator. Inability to start cycle 2 within 3 weeks after completing cycle 1 due to drug-related adverse events.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Partial Response or Complete Response (PR + CR)	42 days	Response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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. Partial Response is at least a 30% decrease in the sum of the diameters of target lesion, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Fraction of Participants With Detectable LMB-100 in Blood After Cycle 4	Day 85	Blood is measured for a detectable level of LMB-100 in the blood. LMB-100 is either detectable in the blood or not. A detectable level of LMB-100 in the blood is considered a desirable outcome for the participant. Hence, the reverse is not a considered a desirable outcome for the participant.
Number of Participants With Serious and Non-Serious Adverse Events	Date treatment consent signed to date off study, approximately one month and 25 days for the 100 mcg/kg Arm/Group, and 9 months and 28 days for the 140 mcg/kg Arm/Group.	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in 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.