| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced stage Hodgkin's lymphoma |
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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 | 15.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10025319 |
| E.1.2 | Term | Lymphomas Hodgkin's disease |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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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 main objective of the trial is to show that ABVD-based response-adapted therapy for advanced-stage Hodgkin lymphoma, with treatment intensification in case of a positive FDG-PET/CT after one cycle of ABVD, has non-inferior efficacy compared with the intensive BEACOPPesc regimen.
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| E.2.2 | Secondary objectives of the trial |
♦ To assess the prognostic value of FDG-PET/CT after 1 cycle of BEACOPPesc (standard arm).
♦ To assess the prognostic value of serum TARC levels as tumor marker.
♦ To monitor treatment related toxicities with a focus on second malignancies, pulmonary toxicities and cardiotoxicity during therapy and during (long term) follow up. |
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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 |
This trial will prospectively investigate the value of serum TARC levels for disease activity and prognosis after one and four cycles of chemotherapy and directly compare it to FDG-PET imaging. Also serum samples will be collected after treatment and during follow-up to investigate the value of serum TARC as a marker for disease recurrence. Secondly, other potential prognostic biomarkers will be analyzed on the tissue, serum and DNA samples in a validation and explorative setting.
A separate cardiac side study will be performed primarily to monitor cardiotoxicity during therapy and during (long term) follow up and secondarily to investigate the relationship between acute and late cardiotoxicity, to evaluate tool(s) to detect asymptomatic left ventricular dysfunction and to test how can we identify people at risk to develop late cardiac damage. |
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| E.3 | Principal inclusion criteria |
* Previously untreated, histologically proven classical Hodgkin lymphoma
* Clinical stages III/IV (Ann Arbor, see Appendix F)
* Age 18-60
* WHO performance 0-2 (see Appendix C)
* FDG-PET/CT scan prospectively planned after one cycle of chemotherapy in all patients
* Adequate organ function:
♦ Heart:
New York Heart Association (NYHA) functional classification ≤ II (EF ≥ 50% or FS ≥ 25%)
No symptomatic coronary heart disease (stable angina pectoris is allowed),
No severe uncontrolled hypertension.
♦ Liver: Total Bilirubin ≤ 2 x UNL, alanine aminotransferase (ALT, SGPT) ≤ 3 x UNL, aspartate aminotransferase (AST, SGOT) ≤ 3 x UNL (exception: elevated values due to HL liver involvement).
♦ Kidney: creatinine clearance ≥ 60 ml/min (measured or calculated according to the method of Cockcroft), uric acid, calcium (all <UNL).
♦ Hematological: Hemoglobin ≥ 10 g/dl, Leukocyte concentration ≥ 3.0 x 109/L absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 75 x 109 /L. (exception: reduced values related to HL (e.g. BM infiltration, splenomegaly))
Patients with a buffer range from the normal values of +/- 10% for hematology and +/- 10% for biochemistry are acceptable.
* Patients of childbearing/reproductive potential should use adequate birth control measures during the whole duration of study treatment.
♦ Female subjects of childbearing potential (defined as any female subject unless she meets at least one of the following criteria: Age ≥50 years and naturally amenorrheic for ≥ 1 year {amenorrhea following cancer therapy does not rule out childbearing potential}, premature ovarian failure confirmed by a specialist gynecologist, previous bilateral salpingo-oophorectomy or hysterectomy, XY genotype, Turner syndrome or uterine agenesis.) must:
♦ Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml not more than 3 days before the start of study medication. This requirement also applies to women of childbearing potential who practice complete and continued abstinence
EORTC 20101-23101 H11
Version 1.0 14 / 115 August 06, 2012
♦ Male subjects must:
♦ Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy if their partner is of childbearing potential and has no contraception.
♦ Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.
* Written informed consent according to ICH/EU Good Clinical Practice, and national/local regulations
* No pregnancy or breast feeding
* No specific contraindications to BEACOPPesc therapy, so therefore:
♦ No poorly controlled diabetes mellitus
♦ No known HIV infection
♦ |
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| E.4 | Principal exclusion criteria |
No pregnancy or breast feeding
♦ No specific contraindications to BEACOPPesc therapy, so therefore:
♦ poorly controlled diabetes mellitus
♦ known HIV infection
♦ chronic active hepatitis B and/or hepatitis C
♦ concomitant or previous malignancies with the exception of basal cell skin tumors, adequately treated carcinoma in situ of the cervix and any cancer that has been in complete remission for > 5 years |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
-Primary end-point
♦ Freedom from treatment failure (FFTF) (definition see chapter 7)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Freedom from treatment failure will be measured from the date of randomization to the date of first occurrence of any of the following events:
♦ Progression during treatment or SD after 4 cycles of chemotherapy according to the IHP response criteria (requires a positive PET) (Ref. 36)
♦ Lack of complete remission at the end of protocol treatment, as defined by the IHP response criteria (Ref. 36); i.e. patients will be considered as failure only if active disease is confirmed by either a biopsy, or a repeated positive FDG-PET/CT scan 2-3 months after the previous scan
♦ Relapse
♦ Death from any cause
Patients free of these events are censored at the date of the most recent follow-up |
|
| E.5.2 | Secondary end point(s) |
-Secondary end-points include
♦ Response at the end of therapy (chemotherapy and radiotherapy, whenever applicable);
♦ Progression-free survival (PFS) (definition see chapter 7);
♦ Overall survival (definition see chapter 7);
♦ Serum TARC levels at baseline, during treatment and follow up;
♦ Frequency of acute toxicity and long-term toxicity in terms of second malignancies, cardiovascular and pulmonary events. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Progression-free survival will be measured from the date of randomization to the date of first occurrence of any of the following events:
♦ Progression
♦ Relapse
♦ Death from any cause
Patients free of these events are censored at the date of the most recent follow-up.
-Overall survival will be measured from the date of randomization to the date of death whatever the cause of death. Patients who are alive are censored at the date of the most recent follow-up.
-Refer to chapter 7 for the rest of evaluation criteria. |
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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 | No |
| 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 | 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 | No |
| 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) | No |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| 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 | 10 |
| 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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