E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Indolent Non-Hodgkin's Lymphoma |
|
E.1.1.1 | Medical condition in easily understood language |
Indolent (slow-growing) non-Hodgkin lymphoma (a type of blood 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 | PT |
E.1.2 | Classification code | 10065856 |
E.1.2 | Term | Non-Hodgkin's lymphoma unspecified histology indolent |
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 |
To evaluate the antitumor activity of inotuzumab ozogamicin in subjects with indolent NHL who have relapsed or are refractory to rituximab and chemotherapy, or anti CD-20 radioimmunotherapy (RIT), as measured by the Overall Response Rate (ORR). |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of inotuzumab ozogamicin in the treatment of subjects with indolent NHL
To evaluate CR, PFS, DR and OS in subjects with indolent NHL
To determine the ORR, CR, PFS, DR and OS in subjects with follicular NHL
To acquire data required for evaluation of the population pharmacokinetic (PK) profile of inotuzumab ozogamicin.
To evaluate the concentration-effect relationship of cardiac QT measures |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects who have been previously diagnosed with CD22-positive, indolent NHL (defined as follicular, marginal zone, or SLL) that has progressed after ≥2 prior systemic therapies.
2. Previous anticancer treatment given must have contained rituximab and chemotherapy, or anti CD20 RIT. Subjects must have exhibited no response or have progressed within 6 months from the completion of the most recent rituximab or rituximab containing therapy or within 12 months of the completion of RIT.
3. Measurable disease with at least one lymph node or tumor mass >1.0 cm in the greatest transverse diameter (GTD) and the product of the diameters (PD) ≥2.25cm2 as measured by CT or MRI.
4. Age 18 years or older. (For Japan: Age 20 years or older).
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (corresponds to Karnofsky Performance Status (KPS) ≥60%).
6. Life expectancy ≥12 weeks.
7. Adequate bone marrow function, defined as absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1,500/μL), hemoglobin >9.0 g/dL (>5.6 mmol/L), and platelet count ≥100 x 109/L (≥100,000/μL) with no packed red blood cell (PRBC) or platelet transfusions 2 weeks before the first dose of test article.
8. Serum creatinine ≤2.0 x upper limit of normal (ULN) and urine protein/creatinine ratio ≤0.5.
9. Adequate hepatic function, defined as total bilirubin ≤1.5 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 x ULN.
10. Negative serum pregnancy test within 1 week before first treatment if the subject is a woman of childbearing potential. A woman of childbearing potential is defined as one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
11. All female and male subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control for the duration of the study and for 28 to 56 days after the last dose of test article. A subject is biologically capable of having children if he or she is using contraceptives regardless if his or her sexual partner is sterile or using contraceptives.
12. Signed and dated institutional review board (IRB)/independent ethics committee (IEC)-approved informed consent form before any screening procedures are performed. |
|
E.4 | Principal exclusion criteria |
1. Candidate for potentially curative therapies in the opinion of the investigator.
2. History of, or suggestive of, veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS).
3. Prior allogeneic hematopoietic stem cell transplant (HSCT).
4. Autologous HSCT within the last 6 months before receiving test article.
5. Prior treatment with inotuzumab ozogamicin.
6. Subjects with intolerance to or who have had a severe allergic or anaphylactic reaction to any humanized monoclonal antibodies.
7. Major surgery, not related to debulking surgical procedures, within 28 days before the first dose of test article.
8. Have received any chemotherapy, cancer immunosuppressive therapy, growth factors (except erythropoietin), or investigational drugs/devices within 28 days before administration of the first dose of test article. Subjects receiving high doses of corticosteroids must have been tapered to a stable dose at least 14 days before the first dose of inotuzumab ozogamicin
9. Pregnant or breastfeeding women.
10. Clinical evidence of transformation to a more aggressive subtype of lymphoma or grade 3b follicular lymphoma.
11. Symptomatic central nervous system (CNS) NHL; a lumbar puncture is not required unless CNS involvement with NHL is clinically suspected.
12. Current or chronic hepatitis B or hepatitis C infection, or known seropositivity for human immunodeficiency virus (HIV). HIV testing may need to be performed in accordance with local regulations or local practice.
13. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition).
14. Any evidence of serious active infection (eg, requiring an IV antibiotic or antiviral agent within 4 weeks of test article administration; an active infection requiring oral anti-infective agents within 2 weeks of test article administration; or any other history of deep tissue infection suggestive of underlying immune system dysfunction [fascitis, deep tissue abscess, osteomyelitis, articular septic arthritis] within 12 months of test article administration).
15. Concurrent active malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. Subjects with previous malignancies are eligible provided that they have been disease free for 2 years or more.
16. Primary effusion lymphoma.
17. Left ventricular ejection fraction (LVEF) that is greater than Grade 1 (NCI CTCAE v3), or the presence of NYHA stage III or IV congestive heart failure.
18. Previous myocardial infarction or pulmonary hypertension within the past 6 months.
19. Known system vasculitides (eg, Wegener granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (eg, severe inflammatory disease).
20. History of chronic liver disease (eg, cirrhosis) or suspected alcohol abuse.
21. Administration of a live vaccine within 6 weeks of the first dose of test article.
22. Any major illness/condition or abnormal laboratory finding that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in the study.
23. History of clinically significant ventricular arrhythmia, prolonged QTc, or unexplained syncope.
24. Screening QTcF > 470 msec |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the confirmed overall response rate (ORR) at the time of the final analyses, which will be conducted approximately 12 months after the last indolent NHL patient received his/her last dose, or after all indolent NHL patients have completed disease follow-up, whichever occurs first. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 12 months after the last indolent NHL patient received his/her last dose, or after all indolent NHL patients have completed disease follow-up, whichever occurs first. |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy will include progression free survival (PFS) and duration of response performed in both the full analysis set (FAS) and per-protocol (PP) populations. The FAS will include all subjects who received at least 1 dose of test article with a complete baseline tumor assessment and at least 1 complete post baseline tumor assessment after test article treatment. The PP population will include all enrolled subjects who had no major protocol violations and who remained in the treatment phase of the study for at least 4 weeks with a complete baseline tumor assessment and at least 1 complete post baseline tumor assessment. The duration of response will be tracked from the time a response (CR, PR) has been established through 2 years from treatment initiation. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Last subject last visit (May 2013) |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Germany |
Hong Kong |
Hungary |
Korea, Republic of |
Netherlands |
Singapore |
|
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
|
The last follow-up visit of the last subject enrolled. |
|
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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |