| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Aggressive Non-Hodgkin Lymphoma (NHL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Hodgkin Lymphoma (NHL) is a type of cancer. NHL can cause masses to grow in the lymph nodes & other areas of the body. The exact cause for NHL is unknown. Treatment for NHL includes chemotherapy. |
|
| 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 | 10029547 |
| E.1.2 | Term | Non-Hodgkin's 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate efficacy as measured by overall survival (OS), with a goal of demonstrating the superiority of inotuzumab ozogamicin when administered in combination with rituximab, compared with an active comparator arm. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of inotuzumab ozogamicin in combination with rituximab compared to the active comparator arm;
To evaluate the efficacy of inotuzumab ozogamicin in combination with rituximab, as measured by overall (objective) response rate (ORR), progression free survival (PFS), and duration of response (DoR) compared to the active comparator arm;
To compare patient-reported health-related quality of life (HRQOL), lymphoma
specific symptoms, and health status between the treatment arms. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects with a diagnosis of CD20 and CD22-positive aggressive NHL (based on local immunophenotyping and histopathology) who have:
a. Refractory disease: defined as disease progression while receiving their most recent prior cytotoxic chemotherapy (single-agent immunotherapy as maintenance is not considered cytotoxic therapy);
b. Persistent disease: defined as stable disease or partial response at the completion of their most recent prior cytotoxic chemotherapy;
c. Relapsed/recurrent disease: defined as complete response at the end of their most recent prior cytotoxic chemotherapy with subsequent relapse or disease recurrence. Eligible aggressive subtypes identified per the 2008 World Health Organization classification include: a) DLBCL (including DLBCL with follicular elements), b) transformed indolent lymphoma with DLBCL, and c) primary mediastinal large B-cell lymphomas.
2. Subjects must have received prior rituximab and may have received up to 3 prior regimens containing cytotoxic chemotherapies
3. Subjects must not be candidates for intensive high-dose chemotherapy, with or without an autologous stem cell transplant (aSCT), due to one or more of the following factors: age, comorbid disease, performance status, prior high-dose chemotherapy, or persisting toxicities from prior chemotherapy.
4. Age 18 years or older.
5. Absolute neutrophil count (ANC) ≥1.0 x 109/L (1000/μL) and platelets ≥75 x 10to the power of 9/L (75,000/μL), unless related to bone marrow infiltration.
6. Serum creatinine ≤1.5 x the upper limit of normal (ULN) (or any serum creatinine level associated with a measured or calculated creatinine clearance of ≥40 mL/min).
7. Total bilirubin ≤1.5 mg/dL (25.65 μmol/L) unless Gilbert’s syndrome, aspartate and alanine aminotransferase (AST, ALT) ≤2.5 x ULN.
8. At least 1 measurable disease lesion that is ≥1.0 cm in 2 perpendicular dimensions, with the product diameter ≥2.25 cm2 by computed tomography (CT) or magnetic resonance imaging (MRI).
9. 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.
10. 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, including up to 6 weeks after the last dose of investigational product. A subject is biologically capable of having children regardless if he or she is using contraceptives or if his or her sexual partner is sterile or using contraceptives.
11. Provisions of written informed consent indicating that the subject has been informed of all pertinent aspects of the trial to be followed.
12. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests, and other procedures, including the completion of patient questionnaires. |
|
| E.4 | Principal exclusion criteria |
1. Prior allogeneic hematopoietic stem cell transplant (HSCT).
2. Within ≤6 months before first dose of investigational product:
a. Prior treatment with anti-CD22 antibodies;
b. Prior radioimmunotherapy.
3. Prior autologous stem cell transplant within ≤4 months before first dose of investigational product.
4. Contraindication to rituximab.
5. Contraindication to both investigator’s choice immuno-chemotherapy regimens.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 4 and/or a life
expectancy <12 weeks.
7. Subjects with known systemic vasculitides (eg, Wegener's granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (such as HIV infection or severe inflammatory disease).
8. Current or chronic hepatitis B or C infection as evidenced by hepatitis B surface antigen and anti-hepatitis C antibody positivity, respectively, or known seropositivity for human immunodeficiency virus (HIV). HIV testing may need to be performed in accordance with local regulations or local practice.
9. History of veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS).
10. Evidence of serious active infection (eg, requiring an intravenous [IV] antibiotic, antiviral, or antifungal agent), or subjects with a recent history of deep tissue infections such as fascitis or osteomyelitis.
11. Major surgery, not related to debulking surgical procedures, ≤28 days before first dose of investigational product
12. Chemotherapy, cancer immunosuppressive therapy, growth factors (except erythropoietin), or investigational drugs/devices ≤28 days before first dose of investigational product in this study. Subjects receiving high doses of corticosteroids must have been tapered to a stable dose at least 7 days before the first dose of investigational product
13. Pregnant or breastfeeding women.
14. Symptomatic central nervous system (CNS) NHL; a lumbar puncture is not required unless CNS involvement with NHL is clinically suspected.
15. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition).
16. Concurrent active malignancy other than nonmelanoma 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.
17. Primary effusion lymphoma, Burkitts, lymphoblastic, T-cell, indolent, and not otherwise specified lymphomas.
18. Cardiac function, as measured by left ventricular ejection fraction (LVEF) that is less than 50% or the presence of New York Heart Association (NYHA) stage III or IV congestive heart failure.
19. Previous myocardial infarction or pulmonary hypertension ≤6 months before first dose of investigational product.
20. History of clinically significant ventricular arrhythmia, prolonged QTc interval, or unexplained syncope.
21. Screening QTcF interval >470 msec (based on the average of 3 consecutive ECGs).
22. History of chronic liver disease (eg, cirrhosis) or suspected alcohol abuse.
23. Administration of a live vaccine ≤6 weeks before first dose of investigational product.
24. 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.
25. The person concerned has been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
26. Subjects who are investigational site staff members or subjects who are Pfizer employees directly involved in the conduct of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Progression free survival (PFS);
• Overall (objective) response rate (ORR);
• Duration of response (DoR);
• Patient-reported health-related quality of life, lymphoma specific symptoms, and health status for subjects in each treatment arm as measured by the Functional Assessment of Cancer Therapy for Lymphoma (FACT-Lym) and EuroQol-5D (EQ 5D) questionnaires. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Approximately every 3 to 6 months |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| Brazil |
| Bulgaria |
| Canada |
| Croatia |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Ireland |
| Lithuania |
| Mexico |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| 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 | 8 |
| 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 |
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