Infections

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Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Blood and Lymph Conditions

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Pseudomonas Infections

Mesothelioma

Mesothelioma, Malignant

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Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Lung Neoplasms

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Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Malignant Mesothelioma

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Antibodies, Monoclonal

Pemetrexed

Cisplatin

Immunoglobulins

Immunotoxins

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Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunologic Factors

Folinic Acid

Folate

Vitamin B9

Assigned dose level of SS1(dsFv)PE38 on days 1, 3 \&amp; 5 of a 21 day cycle for 2 cycles

Multicycle SS1P

500 mg/m\^2 on day 1 of each 21 day cycle until disease progression

75 mg/m\^2 on day 1 of each 21 day cycle until disease progression

Patients 1 - 3 of single cycle cohort. 45 mcg/kg of SS1(dsFv)PE38 on 4 or 5 days (depending on dose level) of cycle 1 only.

Single cycle SS1P

Raffit Hassan, M.D.

Background:

Standard therapy for mesothelioma is a combination of the drugs pemetrexed and cisplatin. However, the benefits of this treatment are limited, and in most treated patients the disease continues to worsen.

SS1(dsFV)PE38 is a genetically engineered drug. It contains an antibody that binds to a certain protein on mesothelioma cells and a toxin (type of poison) made from a product of a bacterium called Pseudomonas aeruginosa. It is hoped that the antibody will attach to the cancer cells, allowing the toxin to enter and kill the cells.

Objectives:

To find out if SS1(dsFV)PE38, together with pemetrexed and cisplatin is safe and tolerable in patients with mesothelioma.

To determine the maximum tolerated dose of SS1(dsFV)PE38 (the highest dose that does not cause unacceptable side effects).

To see if SS1(dsFV)PE38 given with pemetrexed and cisplatin has any effect on patients tumors.

To learn how the body breaks down SS1(dsFV)PE38.

Eligibility:

Patients 18 years of age and older with epithelial pleural mesothelioma whose disease cannot be cured with surgery, and have not had prior treatment with chemotherapy.

Design:

Treatment with pemetrexed, cisplatin and SS1(dsFV)PE38 in two 21-day cycles as follows:

* Day 1 - Intravenous (through a vein) infusions of pemetrexed and cisplatin.
* Days 1 and 2 - Intravenous solution to prevent dehydration that might occur with SS1(dsFV)PE38.
* Days 1, 3 and 5 Intravenous infusion of SS1(dsFV)PE38. Small groups (3 to 6) of patients are given SS1(dsFV)PE38 at a certain dose level. If the first group experiences no significant side effects, the next group a higher dose. This continues in succeeding groups until the maximum tolerated study dose (highest dose that patients can be given safely) is determined.

Continuing standard treatment with additional cycles of pemetrexed and cisplatin.

Evaluations during the treatment period:

* Physical examination, including vital signs and body weight checks, and pregnancy test for women who can become pregnant.
* Questions about medications and side effects.
* Blood and urine tests.
* Disease evaluation with CT, chest X-ray, and possibly PET scans, lung function tests, pulse oximetry, performance of daily activities and quality-of-life questionnaires.

Post-treatment evaluations:

* Clinic visits at months 1, 3, 6, 12, 15, 18 and 21 for physical examination and disease assessment.
* End-of-study visit for blood tests, vital signs and weight measurements, disease assessment, electrocardiogram, pregnancy test for women who can become pregnant

Background:

SS1P (dsFv) PE38, is a recombinant immunotoxin targeting the tumor antigen mesothelin that is highly expressed in malignant mesothelioma. The maximum tolerated dose (MTD) of SS1 dsFv has been established in a phase I study.

Combination therapy with pemetrexed plus cisplatin is the standard first line therapy for malignant mesothelioma, but results in a median overall survival of only 12.1 months.

Combination of SS1(dsFv)PE38 with pemetrexed plus cisplatin could result in improved outcomes for patients with mesothelioma.

Objectives:

To determine the MTD of SS1(dsFv)PE38 that can be safely administered in combination with pemetrexed plus cisplatin in patients with mesothelioma.

To characterize the toxicity profile of SS1(dsFv)PE38.

To study the pharmacokinetics of SS1(dsFv)PE388.

To observe anti-tumor activity, if any of SS1(dsFv)PE38 in combination with pemetrexed plus cisplatin.

Eligibility:

Subjects with histologically confirmed epithelial pleural mesothelioma.

No prior radiotherapy (except palliative localized radiotherapy),systemic chemotherapy or biologic therapy for pleural mesothelioma.

Design:

This is a phase I dose-escalation study of SS1(dsFv)PE38 in combination with pemetrexed plus cisplatin.

The dose of pemetrexed plus cisplatin will be the standard dose approved for malignant mesothelioma. The dose of SS1(dsFv)PE38 will be escalated to find the safe dose in combination with pemetrexed plus cisplatin.

SS1(dsFv)PE38 will be administered concurrently with pemetrexed plus cisplatin in cycles one and two, and subjects will receive additional cycles of pemetrexed and cisplatin as per standard practice.

Patients will be assessed for response every 6 weeks.

An additional Single Cycle of SS1(dsFv)PE38 Cohort will involve up to 16 patients who will receive SS1(dsFv)PE38 administered for four or five doses during the first cycle concurrently with pemetrexed and cisplatin; subjects in this cohort will receive additional

cycles of pemetrexed and cisplatin as per standard practice

SS1(dsFV)PE38 Plus Pemetrexed and Cisplatin to Treat Malignant Pleural Mesothelioma

A Phase 1, Single Center, Dose-Escalation Study of SS1(dsFv)PE38 Administered Concurrently With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Epithelial Pleural Mesothelioma

list of adverse events and highest dose at which fewer than 2 subjects experienced DLT

proportion of subjects experiencing complete response, partial response or stable disease as a best overall response

National Cancer Institute (NCI)

Leukemia

Leukemia, Hairy Cell

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hairy Cell Leukemia

Protective Agents

Immunotoxin HA22

Immunoconjugates

Patients will receive Moxetumomab Pasudotox intravenously (IV) over 30 minutes on days 1, 3, 5 of each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable toxivity, initiation of alternate therapy or documented CR.

Moxetumomab pasudotox

IV Bag Protectant for Moxetumomab pasudotox

MedImmune LLC

Background:

- Moxetumomab pasudotox is an experimental non-chemotherapy cancer treatment drug. It targets CD22, a molecule on the surface of essentially all hairy cell leukemia cells. Moxetumomab pasudotox binds to CD22, goes into the cell, and releases a toxin which kills the cell. In a phase I trial it had activity in relapsed/refractory hairy cell leukemia with safety profile supporting further clinical study (http://ncbi.nlm.nih.gov/pubmed/22355053). This is a phase III multicenter trial designed to confirm these results.

Background:

* Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 900 of the 44,000 new cases of leukemia/year in the US
* Over the last two decades, immunotoxin research has accumulated to support a role for CD22-targeted therapy in the treatment of HCL.
* Moxetumomab pasudotox is a recombinant immunotoxin containing an Fv fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin.
* Moxetumomab pasudotox has demonstrated a high complete response (CR) rate in patients with chemoresistant HCL and has shown activity in pediatric acute lymphoblastic leukemia as well.
* Modification of the structure of moxetumomab pasudotox has greatly improved binding and cytotoxicity toward CD22 expressing malignant cells compared to the precursor molecule. Preclinical and clinical studies have demonstrated that this increase in binding affinity results in improved antitumor activity and tolerability
* Currently there are no approved agents with significant efficacy for HCL patients after failure of standard therapy

Design:

* This is a multicenter, single-arm study of moxetumomab pasudotox in patients with relapsed/refractory hairy cell leukemia.
* 77 patients will be enrolled to receive moxetumomab pasudotox intravenously (IV) on days 1, 3 and 5 of each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable toxicity occurs, the subject begins alternate therapy, or documented CR (for subjects who have no assessable minimal residual disease and not to exceed 6 cycles). If less than or equal to 2 of the first 25 patients do not achieve durable CR, no additional patients will be accrued.
* The overall IRB accrual ceiling is currently set at 80 to allow for a small number of patients that cannot be assessed for response.

Moxetumomab Pasudotox for Advanced Hairy Cell Leukemia

A Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/ Refractory Hairy Cell Leukemia

Durable CR was defined as overall response that meets blood, bone marrow and imaging criteria for CR, followed by a \>180 day duration of hematologic remission (HR). CR requires all of the following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (\>= 2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either \< 17 cm or have decreased by \>25% from its baseline.); HR requires normal complete blood count (CBC) as exhibited by: Neutrophils \>= 1.5 x 10\^9/L, Platelets \>= 100 x 10\^9/L, and hemoglobin \>= 11.0 g/dL without transfusions or growth factors for at least 4 weeks.

Durable CR was defined as overall response that meets blood, bone marrow and imaging criteria for CR, followed by a \>180 day duration of HR. CR requires all of the following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (\>= 2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either \< 17 cm or have decreased by \>25% from its baseline.); HR requires normal complete blood count (CBC) as exhibited by: Neutrophils \>= 1.5 x 10\^9/L, Platelets \>= 100 x 10\^9/L, and hemoglobin \>= 11.0 g/dL without transfusions or growth factors for at least 4 weeks.

The MRD status by blinded independent review refers specifically to results of central pathologist read of bone marrow biopsy by immunohistochemistry.

The CR with Positive or Negative MRD requires all of the following to be present:

* No evidence of leukemic cells in the peripheral blood and/or by routine H/E staining of bone marrow. Minimal Residual Disease: CR with HCL evident in blood or in bone marrow biopsy by immunohistochemistry.
* Resolution of any hepatomegaly, splenomegaly, and abnormal (\>= 2 cm minimum length) lymphadenopathy by CT or MRI. Although a normal spleen size is not defined, the maximum diameter of the spleen should be either \< 17 cm or have decreased by \>25% from its baseline.
* Normal CBC as exhibited by: Neutrophils \>= 1.5 x 10\^9/L, Platelets \>= 100 x 10\^9/L, and hemoglobin \>= 11.0 g/dL without transfusions or growth factors for at least 4 weeks.

The MRD status by investigator refers to results of investigator assessment of bone marrow biopsy or bone marrow aspirate by immunohistochemistry and/or flow cytometry.

The CR with Positive or Negative MRD requires all of the following to be present:

* No evidence of leukemic cells in the peripheral blood and/or by routine H/E staining of bone marrow. Minimal Residual Disease: CR with HCL evident in blood or marrow by flow cytometry.
* Resolution of any hepatomegaly, splenomegaly, and abnormal (\>= 2 cm minimum length) lymphadenopathy by CT or MRI. Although a normal spleen size is not defined, the maximum diameter of the spleen should be either \< 17 cm or have decreased by \>25% from its baseline.
* Normal CBC as exhibited by: Neutrophils \>= 1.5 x 10\^9/L, Platelets \>= 100 x 10\^9/L, and hemoglobin \>= 11.0 g/dL without transfusions or growth factors for at least 4 weeks.

Time to CR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of CR.

Duration of CR was defined as the duration from documentation of CR to the time of relapse from CR. Relapse from CR was defined as any CR criteria (blood counts, imaging or bone marrow) no longer consistent with CR. CR requires all of the following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (\>= 2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either \< 17 cm or have decreased by \>25% from its baseline); normal CBC as exhibited by: Neutrophils \>= 1.5 x 10\^9/L, Platelets \>= 100 x 10\^9/L, and hemoglobin \>= 11.0 g/dL without transfusions or growth factors for at least 4 weeks.

Duration of HR was defined as the duration from documentation of HR to the time of relapse. HR was defined as the blood counts required for CR as normal CBC as exhibited by: Neutrophils \>= 1.5 x 10\^9/L, Platelets \>= 100 x 10\^9/L, and hemoglobin \>= 11.0 g/dL without transfusions or growth factors for at least 4 weeks.

Duration of HR was censored on the date of the last hematologic assessment for participants who have no documented relapse based on blood count prior to data cutoff, dropout, or initiation of alternative anticancer therapy.

Time to HR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of HR. HR was defined as the blood counts required for CR as normal CBC as exhibited by: Neutrophils \>= 1.5 x 10\^9/L, Platelets \>= 100 x 10\^9/L, and hemoglobin \>= 11.0 g/dL without transfusions or growth factors for at least 4 weeks.

The OR was defined as number of participants with a best response of CR or PR. CR requires all of following to be present: No evidence of leukemic cells in peripheral blood and/or by routine H/E staining of bone marrow; Resolution of any hepatomegaly, splenomegaly, and abnormal (\>=2 cm minimum length) lymphadenopathy by CT or MRI (maximum diameter of spleen should be either \<17 cm or have decreased by \>25% from its baseline); normal CBC (Neutrophils \>=1.5 x 10\^9/L, Platelets \>=100 x 10\^9/L, and hemoglobin \>=11.0 g/dL) without transfusions or growth factors for at least 4 weeks. PR requires all of following for a period of at least 4 weeks: \>=50% decrease or normalization (\<5.0 x 10\^9/L) in peripheral blood lymphocyte count and \>=50% reduction in lymphadenopathy and in abnormal haepatosplenomegaly by CT or MRI from pre-treatment baseline value; normal CBC as mentioned above or 50% improvement in CBC values over baseline without transfusions or growth factors for at least 4 weeks.

Time to OR was defined as the time from the start of moxetumomab pasudotox administration to the first documentation of OR (CR or PR).

Duration of OR was defined as the time from the first documentation of objective response (CR or PR) to the date of relapse.

Duration of OR was censored on the date of last disease assessment or hematologic assessment for participants who have no documented relapse prior to data cut-off, dropout, or the initiation of alternative anticancer therapy.

The PFS was defined as the time from the start of moxetumomab pasudotox administration to the earliest date of a disease assessment showing a progressive disease/relapse, earliest date of hematologic relapse or date of death, whichever was earlier. The PFS was censored on the date of last disease assessment or hematologic assessment for participants who are alive with no documented relapse or PD prior to data cut-off, dropout, or the initiation of alternative anticancer therapy.

The TTF was defined as the time from the start of moxetumomab pasudotox administration to the date of the first of relapse, progressive disease, initiation of alternative anticancer therapy, or death due to disease or disease-related complication. The TTF was censored on the date of last disease assessment or hematologic assessment for participants who are alive with no documented relapse or PD prior to data cut-off, dropout, or the initiation of alternative anticancer therapy and also censored for death not accompanied by relapse.

An Adverse Event (AE) is any unfavourable and unintended sign, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. A serious adverse event (SAE) is an AE that results in death, initial or prolonged inpatient hospitalization, life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, or an important medical event. TEAEs and TESAEs are defined as AEs and SAEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug.

An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 30 days after the last dose of study drug (approximately 7 months).

An abnormal vital signs that were judged by the investigator to be medically significant were reported as AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 30 days after the last dose of study drug (approximately 7 months).

An abnormal ECG findings that were judged by the investigator to be medically significant were reported as AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 30 days after the last dose of study drug (approximately 7 months).

The Tmax of moxetumomab pasudotox is reported.

The Cmax of moxetumomab pasudotox is reported.

The Tlast of moxetumomab pasudotox is reported.

The AUC0-last of moxetumomab pasudotox is reported.

The AUC0-3hr of moxetumomab pasudotox is reported.

The AUC0-inf of moxetumomab pasudotox is reported.

The AUCExt of moxetumomab pasudotox is reported.

The CL of moxetumomab pasudotox is reported.

The t1/2 of moxetumomab pasudotox is reported.

Participants with ADA positive, nAb positive, cluster of differentiation 22 (CD22) positive of ADA positive/NAb positive, and pseudomonas exotoxin 38 (PE38) positive of ADA positive/NAb positive to moxetumomab pasudotox at any visit are reported.

Participants received intravenous infusion of moxetumomab pasudotox 40 µg/kg on Days 1, 3, and 5 of each 28-day cycle for up to 6 cycles, until documentation of complete response, progressive disease, initiation of alternate therapy, or unacceptable toxicity.

Moxetumomab Pasudotox 40 µg/kg

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Intent-to-treat (ITT) population included participants who entered into the study and treated with moxetumomab pasudotox.

Priti Patel

The ITT population included participants who entered into the study and treated with moxetumomab pasudotox.

Percentage of Participants With Durable Complete Response (CR) Assessed by Blinded Independent Central Review

Percentage of Participants With Durable CR by Investigator's Assessment

MRD negative CR

MRD positive CR

Percentage of Participants With Minimal Residual Disease (MRD) Positive or MRD Negative CR Assessed by Blinded Independent Central Review

Percentage of Participants With MRD Positive or MRD Negative CR by Investigator's Assessment

The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Time to CR was evaluated for participants who achieved CR per independent central review.

Time to CR Assessed by Blinded Independent Central Review

The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Duration of CR was evaluated for participants who achieved CR per independent central review.

Duration of CR Assessed by Blinded Independent Central Review

The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Duration of HR was evaluated for participants who achieved HR.

Duration of Hematologic Remission

The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Time to HR was evaluated for participants in the ITT population who achieved HR.

Time to Hematologic Remission

Percentage of Participants With Objective Response (OR) Assessed by Blinded Independent Central Review

Percentage of Participants With Objective Response by Investigator's Assessment

The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Time to OR was evaluated for participants who achieved OR per independent central review.

Time to Objective Response Assessed by Blinded Independent Central Review

The ITT population included participants who entered into the study and treated with moxetumomab pasudotox. Duration of OR was evaluated for participants who achieved OR per independent central review.

Duration of Objective Response Assessed by Blinded Independent Central Review

Progression-free Survival (PFS) Assessed by Blinded Independent Central Review

Time to Treatment Failure (TTF) Assessed by Blinded Independent Central Review

Any TEAEs

Any TESAEs

Safety population included participants who received at least 1 dose of moxetumomab pasudotox.

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Anaemia

Disseminated intravascular coagulation

Febrile neutropenia

Iron deficiency anaemia

Leukopenia

Lymphopenia

Neutropenia

Thrombocytopenia

Activated partial thromboplastin time prolonged

Lymphocyte count decreased

Lymphocyte count increased

Neutrophil count decreased

Platelet count decreased

White blood cell count decreased

Aspartate aminotransferase increased

Blood albumin decreased

Blood alkaline phosphatase increased

Blood bicarbonate decreased

Blood bilirubin increased

Blood creatinine increased

Blood triglycerides increased

Gamma-glutamyltransferase increased

Lipase increased

Hyperglycaemia

Hyperkalaemia

Hypermagnesaemia

Hypernatraemia

Hypertriglyceridaemia

Hypoalbuminaemia

Hypocalcaemia

Hypoglycaemia

Hypokalaemia

Hypomagnesaemia

Hyponatraemia

Haematuria

Haemoglobinuria

Proteinuria

Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs

Dyspnoea

Dyspnoea exertional

Hypertension

Hypotension

Pyrexia

Number of Participants With Abnormal Vital Signs Reported as TEAEs

Angina pectoris

Atrial fibrillation

Atrioventricular block first degree

Bundle branch block left

Left ventricular dysfunction

Palpitations

Pericardial effusion

Sinus bradycardia

Sinus tachycardia

Supraventricular tachycardia

Tachycardia

Ventricular arrhythmia

Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs

Cycle 1 Day 1

Cycle 1 Day 5

Cycle 2 Day 1

Pharmacokinetic (PK) population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point.

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox

The PK population included all participants who received at least 1 dose of moxetumomab pasudotox and provided at least 1 baseline and post-baseline concentration-time data point.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
SS1(dsFV)PE38 Plus Pemetrexed and Cisplatin to Treat Malignant Pleural Mesothelioma	NCT01445392	Mesothelioma	Multicycle SS1P Pemetrexed Cisplatin Single cycle SS...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Moxetumomab Pasudotox for Advanced Hairy Cell Leukemia	NCT01829711	Leukemia, Hairy...	Moxetumomab pas... IV Bag Protecta...	18 Years - 100 Years	MedImmune LLC
SS1(dsFV)PE38 Plus Pemetrexed and Cisplatin to Treat Malignant Pleural Mesothelioma	NCT01445392	Mesothelioma	Multicycle SS1P Pemetrexed Cisplatin Single cycle SS...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for pseudomonas exotoxin