| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory advanced B-cell malignancies:
chronic lymphocytic leukemia (CLL),
small lymphocytic lymphoma (SLL), B-cell non-Hodgkin’s lymphoma (NHL) (subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, and anti-CD20-refractory aggressive lymphomas) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or refractory advanced B-cell malignancies |
|
| 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 | 20.1 |
| 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 | 20.0 |
| 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 | 20.0 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study in Arm A is to determine the MTD or OBD of MEDI-551 in subjects with relapsed or refractory advanced B-cell malignancies and to determine the preliminary safety profile of MEDI-551.
The primary objective of Arm B is to determine the MTD or highest protocol-defined dose of MEDI-551 in the absence of exceeding the MTD in subjects with relapsed or rituximab-refractory CLL (defined as those with less than a PR or progression within 6 months after completing therapy with rituximab), to evaluate further the safety and tolerability of MEDI-551 at the dose selected in the dose-escalation phase in subjects with relapsed or rituximab-refractory CLL, and to evaluate the clinical activity of MEDI-551 at the dose selected in the dose-escalation phase in subjects with relapsed or rituximab-refractory CLL.
The primary objective of Arm D is to evaluate the clinical activity of MEDI-551 in subjects with any anti-CD20-refractory aggressive lymphomas. |
|
| E.2.2 | Secondary objectives of the trial |
Arm A
1)To determine the preliminary efficacy profile of MEDI-551 in subjects with advanced B cell malignancies (CLL, DLBCL, and FL)
2)To determine the PK of MEDI-551 in subjects with advanced B cell malignancies
3)To determine the effect of treatment with MEDI-551 on circulating lymphocyte populations and Ig levels, including time to recovery after treatment
4.)To determine the IM of MEDI-551 in subjects with advanced B-cell malignancies
Arm B
1)To evaluate the PK and IM of MEDI-551 at doses studied in subjects with relapsed or rituximab-refractory CLL
2)To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, including time to recovery of B-lymphocyte level
Arm D
1.)To determine the safety and tolerability of MEDI-551 in subjects with any anti-CD20-refractory aggressive lymphomas
2)To evaluate the PK and IM of MEDI-551
3)To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, including time to recovery of B-lymphocyte level |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Men or women at least 18 years of age or older at time of study entry
2)Written informed consent obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations
3)Diagnosis
◦Arm A: CLL (including SLL), DLBCL, or FL; SLL, DLBCL, and FL must be histologically confirmed
◦Arm B: Histologically confirmed SLL or previous confirmation of B-cell CLL with a characteristic immunophenotype by flow cytometry
◦Arm D: Histologically confirmed anti-CD20-refractory (defined as any subject with less than a PR to any prior anti-CD20-based therapy or progression within 6 months after completing therapy with any anti-CD20-based regimen, including maintenance rituximab) aggressive B-cell DLBCL, including FL transforming to DLBCL, transformed indolent lymphoma, MCL, or Grade 3b FL, according to the World Health Organization/American Joint Committee on Cancer criteria
4)Optional: Willing to provide a fresh tumor sample if a sufficient quantity of archival tumor sample is not available (Arms B and D)
5)Evaluable/measurable disease
◦Non-CLL B-cell malignancies (Arms A and D):
▪Histologically confirmed B-cell NHL (FL or DLBCL), transformed indolent lymphoma, and MCL: Measurable disease defined as ≥ 1 lesion ≥ 20 mm in one dimension or ≥15 mm in 2 dimensions as measured by conventional or high-resolution (spiral) computed tomography (CT). For Arm D: disease evaluable by the International Working Group criteria (Cheson et al, 2007)
▪Baseline PET or PET/CT scans must show positive lesions compatible with CT-defined anatomical tumor sites (only applicable for FL, DLBCL, MCL, transformed indolent lymphoma, and FL transforming to DLBCL)
◦CLL (Arms A and B):
▪Confirmed B-cell CLL/SLL with a characteristic immunophenotype by flow cytometry, and symptomatic disease requiring treatment
▪CT scans showing involvement of ≥ 1clearly demarcated lesions measuring ≥ 1.5 cm
6)Prior therapy
◦Arm A:
▪Histologically confirmed B-cell NHL (FL or DLBCL): Relapsed from or refractory to ≥ 1 prior regimen containing rituximab, either alone or in combination, and not be a candidate for hematopoietic SCT or BM transplant
▪B-cell CLL: Relapsed from or refractory to ≥ 2 prior lines of treatment, ≥ 1 of which must have contained rituximab
◦Arm B: Relapsed from or refractory to ≥ 2 prior chemotherapy regimens with ≥ 1 regimen containing rituximab
◦Arm D: Refractory to ≥ 1 regimen containing any anti-CD20-based therapy, including salvage regimens and maintenance rituximab. Refractory subjects are defined as any subject with less than a PR to any prior anti-CD20-based therapies or progressed within 6 months after completing therapy with any anti-CD20-based regimens, including maintenance rituximab. These subjects must not be eligible for hematopoietic SCT or BM transplant
7)Prior radiation therapy is allowed provided exposure does not exceed an area of 25% of marrow space and occurred ≥ 6 weeks prior to the first dose of MEDI-551 (Arm A only)
8)Karnofsky Performance Status ≥ 70
9)Life expectancy of ≥ 12 weeks
10)Adequate hematologic function
◦Arm A (except for CLL subjects with significant BM involvement by biopsy):
▪Hemoglobin ≥ 9 g/dL, (≥ 8 g/dL for subjects who are transfusion dependent)
▪Absolute neutrophil count ≥ 1500/mm3
▪Platelet count ≥ 75,000/mm3
◦Arms B and D must meet the following criteria:
▪Hemoglobin ≥ 8 g/dL
▪Absolute neutrophil count ≥ 1000/mm3
▪Platelet count ≥ 75,000/mm3
▪In the event of significant BM involvement, the above hematologic criteria will not be required for enrollment eligibility
11)Adequate organ function defined as follows:
◦AST and ALT ≤ 2 × institutional ULN
◦Bilirubin ≤ 1.5 × ULN except in the case of subjects with documented Gilbert’s disease, ≤ 2.5 × ULN
◦Serum creatinine ≤ 1.5 mg/dL or a calculated creatinine clearance of ≥ 60 mL/min as determined by the Cockcroft-Gault equation
12)Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must use highly effective contraception from screening and must agree to continue using such precautions for at least 180 days after the last dose of investigational product. A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly.
13)Non-sterilized males who are sexually active with a female of childbearing potential must use a highly effective method of contraception from at least Day 1 through 90 days after the last dose of investigational product
14)Negative serum beta human chorionic gonadotropin (βhCG) test (for women of childbearing potential only)
15)Females or female partners not of childbearing potential must have been surgically sterilized or postmenopausal (as defined above in inclusion criterion #12). Sterilized males must be at least 1 year post vasectomy |
|
| E.4 | Principal exclusion criteria |
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)History of allergy or reaction to any component of the MEDI-551 formulation
4)Receipt of any chemotherapy or small molecule targeted therapy (such as imatinib or other tyrosine kinase inhibitors, and including any experimental therapies) or radiation therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of MEDI-551
5)Receipt of any biological or immunological-based therapies (including experimental therapies) for leukemia, lymphoma, or myeloma (including, but not limited to, MAb therapy such as rituximab, or cancer vaccine therapies) within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of MEDI-551
6)Previous therapy directed against CD19, such as MAbs or MAb conjugates
7)Live or attenuated vaccines (other than experimental cancer vaccine therapy) within 28 days prior to receiving the first dose of MEDI-551
8)Evidence of significant active infection requiring antimicrobial, antifungal, antiparasitic, or antiviral therapy or for which other supportive care is given
9)Autologous SCT within 12 weeks prior to study entry (Arms A and D only)
10)Prior allogeneic SCT or organ transplant (Arms A and D only)
11)Human immunodeficiency virus (HIV) positive serology or AIDS
12)Active hepatitis B as defined by seropositivity for hepatitis B surface antigen (HBsAg) or positive hepatitis B core antibody. Subjects with hepatitis C antibody will be eligible provided that they do not have elevated liver transaminases
13)Ongoing ≥ Grade 2 toxicities from previous cancer therapies unless specifically allowed in the Inclusion/Exclusion criteria. Use of immunosuppressive medication other than steroids within 28 days before the first dose of MEDI-551
14)Use of systemic steroids within 7 days before the first dose of MEDI-551 (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 MEDI-551
15)Documented current central nervous system involvement by leukemia or lymphoma
16)Pregnancy or lactation
17)Previous medical history, or evidence, of an intercurrent illness that at the discretion of the principal investigator may compromise the safety of the subject in the study
18)Clinically significant abnormality on electrocardiogram (ECG). The corrected QT interval (QTc, Fridericia) must be < 470 milliseconds for men and < 490 milliseconds for women (Must be confirmed by at least 2 additional 12-lead ECGs at least 2 minutes apart such that average manually over-read QTcF based on 3 ECGs exceeds stated thresholds)
19)Any physical, social, or psychiatric condition that would prevent effective cooperation or participation in the study
20)Concurrent enrollment in another clinical study, unless in a follow-up period or it is an observational study
21)Employees of the clinical study site who are directly involved with the conduct of the study, or immediate family members of such individuals. These subjects may be treated at another site participating in the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Arm A:
1) MTD or OBD: DLTs
2) Safety: AEs, SAEs, laboratory evaluations, vital signs, physical examinations, and ECGs
Arm B:
1) MTD is defined as the highest dose where ≤ 1 out of 6 subjects experience a DLT during the DLT evaluation period or the highest protocol-specified dose not exceeding MTD: DLTs
2) Safety: AEs, SAEs, laboratory evaluations, vital signs, physical examinations, and ECGs
3) Clinical activity/efficacy: CR, duration of CR, PR, objective response, disease control, TTR, duration of objective response, duration of disease control, PFS, and OS
Arm D:
1) Clinical activity/efficacy: CR, duration of CR, PR, objective response, disease control, TTR, duration of objective response, duration of disease control, PFS, and OS |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) MTD or OBD determination: Approximately 16 months from the start of each arm
2) Preliminary safety profile of MEDI-551: Approximately 120 months from the start of each arm
3) Clinical activity/efficacy: Approximately 16 months from the start of Arms B and D. |
|
| E.5.2 | Secondary end point(s) |
Arm A:
1) Clinical activity/efficacy: CR, duration of CR, PR, objective response, disease control, TTR, duration of objective response, duration of disease control, PFS, and OS
2) Effect of MEDI-551 on circulating lymphocyte populations: circulating levels of blood mononuclear cells, including T-cells, B-cells, NK cells and monocytes
3) Pharmacokinetics: PK profiles and parameters, including maximum observed concentration (Cmax), AUC, clearance (CL), and t½, of MEDI-551
4) Incidence of anti-MEDI-551 antibodies based on samples obtained from each subject at multiple timepoints before and after dosing
Arm B:
1) Pharmacokinetics: PK profiles and parameters, including Cmax, AUC, CL, and t½, of MEDI-551
2) Incidence of anti-MEDI-551 antibodies based on samples obtained from each subject at multiple timepoints before and after dosing
3) Effect of MEDI-551 on B-lymphocyte levels in peripheral blood, including time to recovery of B-lymphocyte level
Arm D:
1) Safety: AEs, SAEs, laboratory evaluations, vital signs, physical examinations, and ECGs
2) Pharmacokinetics: PK profiles and parameters, including Cmax, AUC, CL, and t½, of MEDI-551
3) Incidence of anti-MEDI-551 antibodies based on samples obtained from each subject at multiple timepoints before and after dosing
4) Effect of MEDI-551 on B-lymphocyte levels in peripheral blood, including time to recovery of B-lymphocyte level
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Approximately 120 months to evaluate all secondary endpoints from the start of each arm. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
