| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory B Cell Acute Lymphoblastic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 compare the hematological remission, defined as CR (both CR and CRi), as reported by the external independent endpoint adjudication committee, in patients with relapsed/refractory ALL randomized to receive inotuzumab ozogamicin (Arm A) versus patients randomized to receive active comparator (Arm B). |
|
| E.2.2 | Secondary objectives of the trial |
Safety and efficacy endpoints will be compared between the inotuzumab ozogamicin arm and the active comparator arm and will include:
Key Secondary Objective:
• To compare the overall survival of patients with relapsed/refractory ALL.
Other Secondary Objectives:
• To compare the duration of response;
• To compare the progression-free survival;
• To compare the rate of stem-cell transplantation in patients;
• To characterize the safety and tolerability including the rate of VOD (veno-occlusive disease)/SOS (sinusoidal obstruction syndrome) following allogeneic stem cell transplant;
• To assess minimal residual disease levels and cytogenetics in patients achieving a CR/CRi;
• To determine the population pharmacokinetic parameters of inotuzumab ozogamicin and confirm sources of exposure variability;
• To compare patient-reported health-related quality of life (HRQOL) and patient-reported health status between treatment arms. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patient eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before patients are included in the study. Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Relapsed or refractory CD22-positive ALL ( ≥ 5 % marrow blasts, assessed by morphology; ie, M2 or M3 marrow) due to receive either salvage 1 or salvage 2 therapy and for which either arm of randomized study therapy offers a reasonable treatment option.
2. Ph+ ALL patients must have failed treatment with at least 1 second or third generation tyrosine kinase inhibitor and standard multi-agent induction chemotherapy;
3. Patients in Salvage late relapse should be deemed poor candidates for reinduction with initial therapy.
4. Patients with lymphoblastic limphoma and bone marrow involvement with ≥ 5% lymphoblasts by morphologic assessment;
5. Age 18 years or older;
6. ECOG performance status 0 – 2;
7. Adequate liver function, including total serum bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome, and aspartate and alanine aminotransferase (AST and ALT) ≤2.5 x ULN. If organ function abnormalities are considered due to tumor, total serum bilirubin must be ≤2 x ULN and AST/ALT≤2,5 x ULN;
8. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or any serum creatinine level associated with a measured or calculated creatinine clearance of ≥40 mL/min;
9. Male and female patients of childbearing potential and at risk of pregnancy must agree to use a highly effective method of contraception throughout the study and for a minimum of 90 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active. Female patients who are not of childbearing potential (ie, meet at least one of the following criteria):
• Have undergone hysterectomy or bilateral oophorectomy; or
• Have medically confirmed ovarian failure; or
• Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause.
10. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study; patients with mental capacity which requires the presence of a legally authorized representative will be excluded fro the study.
11. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1.Isolated extramedullary relapse (i.e. testicular or CNS);
2.Burkitt’s or mixed phenotype acute leukemia based on the WHO 2008 criteria;
3.Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for active disease within the prior 28 days, symptomatic CNS leukemia (i.e.cranial nerve palsies or other significant neurologic dysfunction) within 28 days. Recent use of prophylactic intrathecal medication is not a reason for exclusion.
4.Prior chemotherapy within ≤2weeks before randomization with the following exceptions: a,To reduce the circulating by lymphoblast count or palliation: ie, steroids, hydroxyurea, or vincristine; b,For ALL maintenance: mercaptopurine, methotrexate, vincristine, thioguanine, and tyrosine kinase inhibitors. Patients must have recovered from acute non hematologic toxicity (to≤Grade 1) of all previous therapy prior to enrollment.
5.Prior monoclonal antibodies within 6 weeks of randomization with the exception of rituximab which must be discontinued at least 2 weeks prior to randomization;
6.Prior allogeneic hematopoietic stem cell transplant (HSCT) or other anti-CD22 immunotherapy ≤ 4 months before randomization. Patients must have completed immunosuppression therapy for treatment of GvHD prior to enrollment. At randomization, patients must not have > grade 2 acute GvHD, or extensive chronic GvHD;
7.Peripheral absolute lymphoblast count ≥ 10,000 /µL (treatment with hydroxyurea and/or steroids/vincristine is permitted within 2 weeks of randomization to reduce the WBC count);
8.Known systemic vasculitides (eg, Wegener’s granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (such as HIV infection or severe inflammatory disease);
9.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;
10.Major surgery within ≤4 weeks before randomization;
11.Unstable or severe uncontrolled medical condition (eg, unstable cardiac function or unstable pulmonary condition);
12.Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been definitely treated with radiation or surgery. Patients with previous malignancies are eligible provided that they have been disease free for ≥2 years;
13.Cardiac function, as measured by left ventricular ejection fraction (LVEF) that is less than 45%, or the presence of New York Heart Association (NYHA) stage III or IV congestive heart failure;
14.Patients with active heart disease (NYHA class ≥ 3 as assessed by history and physical examination);
15.QTcF > 470 msec (based on the average of 3 consecutive ECGs);
16.Myocardial infarction ≤6 months before randomization;
17.History of clinically significant ventricular arrhythmia, or unexplained syncope not believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial block or higher degrees of AV block unless a permanent pacemaker has been implanted.
18.Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (eg. hypokalemia, hypocalcemia, hypomagnesemia);
19.History of chronic liver disease (eg, cirrhosis) or suspected alcohol abuse;
20.History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS);
21.Administration of live vaccine ≤6 weeks before randomization;
22.Evidence of uncontrolled current serious active infection (including sepsis, bacteremia, fungemia, or patients with a recent history (within 4 months) of deep tissue infections such as fascitis or osteomyelitis;
23.Patients who have had a severe allergic reaction or anaphylactic reaction to any humanized monoclonal antibodies;
24.Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for a minimum of 90 days after the last dose of investigational product;
25.Patients who are investigational site staff members or relatives of those site staff members or patients who are Pfizer employees directly involved in the conduct of the trial;
26.Participation in other studies involving investigational drug(s) (Phase 1-4) within 2 weeks from randomization to end of treatment visit;
27.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Dependent on individual patient response |
|
| E.5.2 | Secondary end point(s) |
• OS (Key secondary endpoint);
• DoR;
• PFS;
• Number of Transplants;
• Adverse events and laboratory abnormalities (CTCAE v3.0 grade, timing, seriousness and relatedness);
• MRD and cytogenetics in responding patients;
• PK;
• EORTC QLQ-C30 and EQ-5D. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Dependent on individual patient response |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | 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 | 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) | 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 | 70 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| China |
| Croatia |
| Czech Republic |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Serbia |
| Singapore |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| End of Trial in all participating countries is defined as the Last Patient Last Visit (inclusive of long term follow-up visits, see section 6.4 of the protocol), unless stopped earlier by the external data monitory committee (E-DMC). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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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