E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory mantle cell lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Diffuse tumors affecting lymph nodes. |
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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 | PT |
E.1.2 | Classification code | 10026801 |
E.1.2 | Term | Mantle cell lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10026800 |
E.1.2 | Term | Mantle cell lymphoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this trial is to evaluate the efficacy of PCI-32765 in relapsed/refractory subjects with MCL |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to evaluate the safety of a fixed daily dosing regimen of PCI-32765 capsules in relapsed/refractory subjects with MCL. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men and women ≥ 18 years of age
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
3. Pathologically confirmed MCL, with documentation of either overexpression of cyclin D1 or t(11;14), and measurable disease on cross sectional imaging that is ≥ 2 cm in the longest diameter and measurable in 2 perpendicular dimensions per CT
4. Documented failure to achieve at least PR with, or documented disease progression after, the most recent treatment regimen
5. At least 1, but no more than 5, prior treatment regimens for MCL. (Note: Subjects having received ≥ 2 cycles of prior treatment with bortezomib, either as a single agent or as part of a combination therapy regimen, will be considered to be bortezomib-exposed.)
6. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
7. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)
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E.4 | Principal exclusion criteria |
1. Prior chemotherapy within 3 weeks, nitrosoureas within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks of first dose of study drug
2. Concurrent enrollment in another therapeutic investigational clinical study or have previously taken PCI-32765.
3. History of other malignancies within the past year except for treated basal cell or squamous cell skin cancer or in situ cervical cancer
4. Known central nervous system (CNS) lymphoma
5. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of PCI-32765 capsules, or put the study outcomes at undue risk
6. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
7. Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd degree block, bradycardia, or QTc ≥ 500 msec
8. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or symptomatic ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
9. Known history of Human Immunodeficiency Virus (HIV) or active infection with Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) or any uncontrolled active systemic infection
10. Lactating or pregnant
11. Will not agree to use highly effective contraception (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the study and for 30 days after the last dose of study drug (Note: applies to men and women of child-bearing potential only)
12. Any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) < 750 cells/mm3 (0.75 x 10 9/L) unless there is documented bone marrow involvement
b. Platelet count < 50,000 cells/mm3 (50 x 10 9/L) independent of transfusion support unless there is documented bone marrow involvement
c. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)
d. Creatinine > 2.0 x ULN |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is the ORR defined as a subject achieving either a PR or CR according to the revised International Working Group Criteria for NHL as
assessed by investigators. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be assessed throughout the duration of the study. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints for this study are as follows:
Efficacy:
- duration of response (DOR)
- progression-free survival (PFS)
- overall survival (OS)
Safety:
- frequency, severity, and relatedness of adverse events
- frequency of adverse events requiring discontinuation of study drug or dose reductions
- effect of PCI-32765 on peripheral B/T/NK cell counts
- effect of PCI-32765 on serum immunoglobulin levels
Pharmacokinetics:
- plasma PK of PCI-32765 and a major metabolite, PCI-45227
Patient Reported Outcomes:
- health-related quality of life |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be assessed throughout the duration of the study. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Austria |
Germany |
Poland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |