| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Patients with Aggressive B-cell Non-Hodgkin Lymphoma , who Have Relapsed after Therapy with CHOP-R or an Equivalent Regimen and are Ineligible for Stem Cell Transplant |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012820 |
| E.1.2 | Term | Diffuse large B-cell lymphoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| 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 | 100000004864 |
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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 study is to evaluate the efficacy (as measured by progression-free survival [PFS]) of pixantrone + rituximab (pixantrone + R) compared with gemcitabine + rituximab (gemcitabine + R) in patients with a diagnosis of de novo diffuse large B-cell lymphoma (DLBCL), DLBCL transformed from indolent lymphoma, or follicular grade 3 lymphoma who have relapsed after at least 1 prior chemotherapy regimen and who are currently ineligible for high-dose (myeloablative) chemotherapy and stem cell transplant (SCT). |
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| E.2.2 | Secondary objectives of the trial |
To compare the two treatment arms with regard to the following secondary endpoints:
Overall survival
Overall response rate
Complete response rate
Safety
Exploratory Objectives
Assess the duration of overall response between treatments
Assess the duration of complete response (CR) between treatments
Determine the proportion of randomized patients who receive a stem cell transplant (SCT) after study treatment
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The objective of the PK sub-study is to characterize the PK profile of pixantrone when co-administered with rituximab.
PK Sub-Study Inclusion Criteria:
• Patient must have been randomized to the PIX306 pixantrone + rituximab arm at a participating clinical site. Patients newly randomized or already randomized in the pixantrone group can be included.
• Patients must be willing to participate in the PK sub-study and cooperate with the PK sampling schedule, as described in the written consent for participation in the sub-study. |
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| E.3 | Principal inclusion criteria |
Inclusion Criteria
1. Signed Institutional Review Board or Institutional Ethics Committee-approved Informed Consent Form
2. Age ≥ 18 years old
3. Diagnosis of DLBCL (de novo DLBCL or DLBCL transformed from indolent lymphoma) or follicular grade 3 lymphoma on the basis of a tissue biopsy.
4. Pathology and immunohistochemistry reports documenting the current histological diagnosis according to World Health Organization (WHO) classification must be reviewed by the sponsor or designee prior to randomization.
5. Number of prior therapies allowed:
Patients with de novo DLBCL must have received 1-3 prior regimens for DLBCL
Patients with follicular grade 3 lymphoma must have received 1-3 prior regimens for follicular lymphoma (any grade)
Patients with DLBCL transformed from indolent lymphoma must have received 1-4 prior regimens for NHL
6. Received a rituximab-containing multi-agent regimen (eg, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]; rituximab, cyclophosphamide, vincristine, prednisone [R-CVP]; or bendamustine-R)
7. Patients with DLBCL transformed from indolent lymphoma must have had a complete or partial response to a therapy for NHL lasting at least 12 weeks
8. Not eligible for high-dose (myeloablative) chemotherapy and SCT. Patients not eligible for stem cell transplant include those who:
relapsed after previous stem cell transplant
did not respond to a standard salvage regimen
did not mobilize an adequate number of stem cells for SCT
are unsuitable for SCT due to other medical conditions or age
do not wish to undergo SCT
have financial issues precluding SCT
are considered by the investigator as unsuitable for SCT for any other reason
9. At least 28 days from completion of last NHL therapy to randomization
10. At least one bidimensionally measurable site of disease that has not been previously irradiated: nodal disease ≥ 1.5 cm or extranodal disease > 1 .0 cm in short axes. Lesion must be PET-positive if PET scan is obtained.
11. Slides confirming diagnosis of follicular grade 3 lymphoma or DLBCL available for independent histology review
12. ECOG performance status (PS) ≤ 2
13. Life expectancy ≥ 12 weeks in investigator’s judgment
14. Left ventricular ejection fraction (LVEF) ≥ 45% by echocardiogram and normal serum troponin
15. Hemoglobin ≥ 8 g/dL (can be post transfusion)
16. Platelet count ≥ 100 x 109/L; platelet count ≥ 75 x 109/L permitted if documented bone marrow involvement
17. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; ANC ≥ 1.0 x 109/L permitted if documented bone marrow involvement
18. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN); patients with proven Gilbert’s syndrome and bilirubin ≤ 5 x ULN may be enrolled.
19. Aspartate aminotransferase (AST; also called serum glutamic-oxaloacetic transaminase
[SGOT]) and alanine aminotransferase (ALT; also called serum glutamic-pyruvic transaminase [SGPT]
20. Serum creatinine ≤ 2 x ULN
21. All acute toxicities related to prior treatment recovered to grade ≤ 1 except alopecia
22. Willingness and ability to comply with the visit schedule and assessments required by the study protocol
23. Due to the long retention time of rituximab in B cell-depleted patients, both males and females must agree to use effective birth control. Women of childbearing potential must use highly effective methods (defined as those resulting in a failure rate of <1% per year when used consistently and correctly) for the duration of study treatment and for 12 months after last dose of study drug. The contraceptive methods considered highly effective are intrauterine devices and hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices, or injections with prolonged release). |
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| E.4 | Principal exclusion criteria |
Exclusion Criteria
1. Any of the following as the only site(s) of disease: palpable lymph nodes not visible on imaging studies, skin lesions, or bone marrow involvement only
2. Primary refractory de novo DLBCL or primary refractory follicular grade 3 lymphoma, defined as documented progression within 12 weeks of the last cycle of the first-line multiagent regimen
3. Prior treatment with a cumulative dose of doxorubicin or equivalent exceeding 450 mg/m²
4. LVEF < 45% by echocardiogram
5. Active CTCAE grade 3/4 infection
6. Major surgery ≤ 28 days prior to randomization
7. Known acute or chronic hepatitis B or hepatitis C infection
8. Known seropositivity for human immunodeficiency virus (HIV)
9. Current CNS involvement by lymphoma
Any history or evidence of current leptomeningeal involvement by lymphoma is prohibited.
Patients with prior localized CNS involvement who have been without recurrence for ≥ 12 months and currently have a negative head MRI may be eligible; please discuss with the medical monitor.
10. Any experimental therapy ≤ 28 days prior to randomization
11. Myocardial infarction within the past 6 months
12. New York Heart Association class III or IV heart disease
13. Other malignancy within last 5 years. Exceptions are:
curatively treated basal cell/squamous cell skin cancer
carcinoma in situ of the cervix
superficial transitional cell bladder carcinoma
in situ ductal carcinoma of the breast after complete resection
localized, resected and/or low-risk prostate cancer may be eligible; please discuss with the medical monitor
14. Any contraindication or known allergy or hypersensitivity to any study drugs
15. Pregnant or lactating
16. Concomitant therapy with any anticancer agents, immunosuppressive agents, other investigational anticancer therapies. Low-dose corticosteroids for the treatment of non cancer-related illnesses are permitted
17. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study procedures or follow-up schedules
18. Severe and/or uncontrolled medical disease that could compromise participation in the study, or any medical or psychiatric condition that in the opinion of the investigator would make study drug administration hazardous or obscure the interpretation of data |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free Survival (PFS) is the only primary endpoint of the study. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression-free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death due to any cause (whichever occurs first). The progression date is the earliest time any progression is observed. Patients with no documented progression or death before the data cut off will be censored at the date of the last adequate radiological assessment. |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are Overall Survival (OS) , Overall response rate (ORR), Complete response rate (CR), and safety
Overall survival (OS) is defined as the time from randomization until death due to any cause. If the patient is alive or the survival status is unknown, the date of death will be censored on the date the patient was last known to be alive.
Overall Response Rate (ORR) is defined as the proportion of patients who achieve a CR or PR without additional therapy.
Complete Response (CR) rate is defined as the proportion of patients who achieve a CR without additional therapy.
Safety will be assessed by monitoring and recording adverse events, serious adverse events (SAEs), cardiac, hematologic and blood chemistry parameters, vital signs, performance status (PS), and any abnormal findings observed on physical examinations. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease assessments are scheduled at baseline and week 8, 16, 24 and end of treatment,
in the early follow-up:
FU week 8,16 and 24,
in the intermediate follow-up:
FU week 36, 48, 60, 72, 84 and 96,
in the survival follow up:
every 12 weeks until death or study determination |
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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 | Yes |
| 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) | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 |
| Belgium |
| Bulgaria |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
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| 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
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| End of Study (EOS) is defined as the date when the required OS events have occurred or the study is terminated. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 1 |
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