Clinical Trials Register

Summary
EudraCT Number:	2010-020820-23
Sponsor's Protocol Code Number:	MI-CP218
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2010-09-23
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2010-020820-23

A.3

Full title of the trial

A Phase 1/2 Study of CAT-8015 in Adult Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

study is designed to determine the dose and safety of the drug CAT-8015 in cancer patients.

A.4.1

Sponsor's protocol code number

MI-CP218

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01030536

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	MedImmune
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MedImmune
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MedImmune
B.5.2	Functional name of contact point	Information Center
B.5.6	E-mail	clinicaltrialenquiries@medimmune.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	CAT-8015
D.3.2	Product code	CAT-8015
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	moxetumomab pasudotox
D.3.9.1	CAS number	1020748-57-5
D.3.9.2	Current sponsor code	CAT-8015
D.3.9.3	Other descriptive name	GCR-8015, HA22
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Indolent (follicular lymphoma [FL]) and aggressive (diffuse large B-cell lymphoma [DLBCL], mantle cell lymphoma [MCL], or CLL) B-cell malignancies.

E.1.1.1

Medical condition in easily understood language

cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10008976
E.1.2	Term	Chronic lymphocytic leukemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10061275
E.1.2	Term	Mantle cell lymphoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10067070
E.1.2	Term	Follicular B-cell non-Hodgkin's lymphoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10012818
E.1.2	Term	Diffuse large B-cell lymphoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objectives of this study are to determine the maximum tolerated dose (MTD) or optimal biologic dose (OBD) and safety profile of CAT-8015 in subjects with relapsed or refractory advanced B-cell NHL (DLBCL, FL, MCL) or CLL (including small lymphocytic lymphoma [SLL]).

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are:
•To describe the preliminary efficacy profile of CAT-8015 in subjects with relapsed or refractory advanced B-cell NHL (DLBCL, FL, MCL) or CLL (including SLL)
•To describe the pharmacokinetics of CAT-8015 in subjects with advanced B-cell malignancies
•To describe the immunogenicity of CAT-8015 in subjects with advanced B-cell malignancies and describe the relationship between treatment benefit and safety
•To determine the percent of expression of CD22 on tumor lymphocytes in these patient populations and to describe the relationship between treatment benefit and safety
•To investigate the following clinical and laboratory parameters as potential predictors of capillary (vascular) leak syndrome (CLS): orthostatic blood pressure, albumin levels, weight changes, edema, and pulmonary findings.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following criteria:
1)Subjects must be at least 18 years of age or older at the time of study entry.
2)Written informed consent and HIPAA authorization (applies to covered entities in the US only) must be obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations.
3)Subjects must have histologically-confirmed B-cell CLL (including SLL), DLBCL, MCL, or FL.
4)B-cell NHL (DLBCL, FL, MCL) subjects must:
•Have previous confirmation of B-cell NHL
•Subjects with DLBCL or MCL, must have relapsed or refractory disease after at least one prior regimen containing rituximab, either alone or in combination, and be ineligible for any available standard line of therapy known to be life-prolonging or life-saving.
•Subjects with FL, must have relapsed or refractory disease after at least two prior regimens, one of which included rituximab, either alone or in combination, and be ineligible for any available standard line of therapy known to be life-prolonging or life-saving.
•Have measurable disease (at least one lesion ≥ 20 mm in one dimension or ≥ 15 mm in two dimensions as measured by conventional or high resolution [spiral] computed tomography (CT)
•Not be a candidate for a hematopoietic stem cell (HSC) or bone marrow (BM) transplant
5)B-cell CLL subjects must:
•Have previous confirmation of B-cell CLL with a characteristic immunophenotype by flow cytometry
•Have relapsed or refractory disease after at least 2 prior lines of treatment, at least 1 of which must have contained rituximab and be ineligible for any available standard line of therapy known to be life-prolonging or life-saving
•Not be a candidate for an HSC or BM transplant
•Have symptomatic disease that requires treatment
6)Karnofsky Performance Status ≥ 70
7)Life expectancy of ≥ 12 weeks
8)Toxicities from previous cancer therapies must have recovered to Grade < 2.
9)Adequate hematological function defined as:
•Hemoglobin ≥ 9 g/dL
•Absolute neutrophil count ≥ 1500/mm3
•Platelet count ≥ 75,000/mm3 (except for CLL subjects with evidence of bone marrow disease, who must have a platelet count ≥ 50,000/mm3)
10)Adequate organ function defined as follows:
•Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2 × institutional upper limit of normal (ULN), except in the case of liver involvement ≤ 5 × ULN
•Bilirubin ≤ 1.5 × ULN, except in the case of subjects with documented Gilbert’s disease ≤ 2.5 × ULN
•Creatinine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation (Cockcroft and Gault, 1976) or by 24-hour urine collection for determination of creatinine clearance
11)Prothrombin time (PT)-international normalized ratio (INR)/partial thromboplastin time (PTT) ≤ 1.5 × ULN, or for patients on anticoagulation therapy, status within therapeutic range
12)Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must use adequate contraception from screening through 90 days after the last dose of CAT-8015. An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. In this study, where medications and devices containing hormones are allowed, the recommended methods of contraception are described in Table 4.2.1-1. Sustained abstinence is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Non-sterilized males who are sexually active with a female of child-bearing potential must use adequate contraception (Table 4.2.1-1) from screening through 90 days after the last dose of CAT-8015;
Females or female partners not of childbearing potential must have been surgically sterilized (eg, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or postmenopausal (defined as at least 1 year since last regular menses). Sterilized males must be at least 1-year post vasectomy
13)Male subjects with partners of child-bearing potential must be surgically sterile or use a contraceptive method as described above from the time of the initiation of CAT-8015 through 90 days after the last dose of CAT-8015.
14)For the expansion phase only, subjects with DLBCL, FL, and MCL only, disease must be evaluable by the International Working Group criteria (Cheson et al, 2007).

E.4

Principal exclusion criteria

Any of the following excludes the subject from participation in the study:
1)Any available standard line of therapy known to be life-prolonging or life-saving
2)Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal therapy for treatment of cancer
3)For CLL patients only, rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy
4)History of allergy or reaction to any component of the CAT-8015 formulation
5)Receipt of any chemotherapy or small molecule targeted therapy regimens (such as imatinib or other tyrosine kinase inhibitors, and including any experimental therapies) within 6 weeks prior to the first dose of CAT-8015
6)Receipt of any biological- or immunological-based therapies (including experimental therapies) for leukemia or lymphoma (including, but not limited to, monoclonal antibody therapy such as rituximab or cancer vaccine therapies) within 6 weeks prior to the first dose of CAT-8015
7)Prior radiation therapy will not be excluded, providing the volume of bone marrow treated is less than 25%.
8)Any history of prior pseudomonas-exotoxin (PE) immunotoxin administration, including CAT-8015, CAT-3888, or LMB-2 (anti-CD25 immunotoxin)
9)History of other invasive malignancy within 5 years except for cervical carcinoma in situ (CIS), non-melanomatous carcinoma of the skin or ductal carcinoma in situ (DCIS) of the breast that has been surgically cured
10)Evidence of significant active infection requiring antimicrobial, antifungal, antiparasitic or antiviral therapy or for which other supportive care is given
11)Autologous stem cell transplantation within 6 months prior to study entry
12)Allogenic stem cell transplantation or any other organ transplant
13)HIV-positive serology or AIDS
14)Active hepatitis B or C infection as defined by seropositivity for hepatitis B (HBsAg) or hepatitis C and elevated liver transaminases (defined as above the upper limit of normal per the institution normal ranges)
15)Use of immunosuppressive medication other than steroids within 7 days before the first dose of CAT-8015
16)Use of systemic steroids within 7 days before the first dose of CAT-8015 (inhaled and topical corticosteroids are permitted). Subjects may take replacement doses of steroids (defined as ≤ 30 mg/day hydrocortisone or the equivalent) if on a stable dose for at least 2 weeks prior to the first dose of CAT-8015.
17)Documented current central nervous system involvement by leukemia or lymphoma
18)Pregnancy or lactation
19)Other severe, concurrent diseases (eg, cardiac or pulmonary disease), mental disorders, or major organ malfunction (liver, kidney) that could interfere with the patient ability to participate in the study
20)Concurrent enrollment in another clinical study
21) Contraindication to corticosteroid administration

E.5 End points

E.5.1

Primary end point(s)

The MTD will be based on the Evaluable population for DLT. The number and percentage of subjects with a DLT will be presented by arm (FL or CLL/DLBCL/MCL), dose level, and overall. The OBD will be determined based upon analysis of all available subject data including safety, PK, pharmacodynamic, and response data.
Safety Assessments:
Safety endpoints include assessments of AEs, SAEs and changes in clinical and laboratory evaluations. The occurrence of AEs, abnormal laboratory values, and SAEs reported from the signing of an informed consent form through 30 days after last dose of CAT-8015 will be summarized for all subjects enrolled into the study. Adverse events and SAEs will be graded according to the NCI CTCAE v4.0 and summarized by system organ class using the Medical Dictionary for Regulatory Activities (MedDRA) preferred term, severity, and relationship to CAT-8015.
Efficacy Assessments
The efficacy profile of CAT-8015 will be assessed in subjects with the following advanced B-cell malignancies: CLL, DLBCL, FL and MCL. The efficacy profile will be assessed using CR rate, duration of CR, best response during study, objective response rate (ORR), time to response (TTR), duration of objective response, duration of stable disease, and progression-free survival (PFS).
Pharmacokinetic Assessment
Individual CAT-8015 plasma concentrations will be tabulated by treatment cycles along with descriptive statistics. Noncompartmental PK data analysis will be performed for Day 1 data of each treatment cycle with scheduled PK sample collection. If data allows, descriptive statistics of noncompartmental PK parameters (AUC, Cmax, CL, t1/2) will be provided. Due to the limited sampling schedule, population PK data analysis may be performed to better characterize the PK parameters of CAT-8015 in this patient population.
Immunogenicity of CAT-8015
The immunogenic potential of CAT-8015 will be assessed by summarizing the presence of anti-drug antibodies for all subjects. Immunogenicity results will be listed for each subject. The number and percentage of subjects who develop detectable anti-drug antibodies will be summarized. For subjects with a positive immunogenicity response, a cell-based assay will be used to determine if the antibodies neutralize CAT-8015 activity. The impact of anti-drug antibodies on PK will be assessed if data allow.
Predictors of CLS
The correlation of CLS and weight gain, albumin, hypotension, edema, hypoxia, and pulmonary AEs will be examined.

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

The secondary objectives of this study include evaluation of the preliminary efficacy profile of CAT-8015 in patients with the following advanced B-cell malignancies, CLL, DLBCL, FL, and MCL. Other secondary objectives include evaluation of the pharmacokinetics and immunogenicity of CAT-8015 in patients with advanced B-cell malignancies, percent CD22 expression on tumor lymphocytes in the study population, and protocol specified clinical and laboratory parameters as potential predictors of CLS.

E.5.2.1

Timepoint(s) of evaluation of this end point

Data analysis will be conducted at the end of study.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase 1/2

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised