E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Relapsed /Refractory Classical Hodgkin's Lymphoma |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080208 |
E.1.2 | Term | Classical Hodgkin lymphoma |
E.1.2 | System Organ Class | 100000004864 |
|
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 determine metabolic complete remission (mCR) (PET-CT negative, Deauville scores 1-3 ) after 3 cycles of ESHAP-brentuximab vedotin (BV) vs ESHAP as salvage strategies in patients with relapsed / refractory classical Hodgkin’s Lymphoma (cHL).
|
|
E.2.2 | Secondary objectives of the trial |
1.To assess 2-year progression free survival (PFS) and 2-year overall survival (OS) in patients attaining a mCR and treated with BV consolidation 2.To evaluate duration of response and time to progression in patients treated with BV consolidation after attaining a mCR 3.To assess differences in toxicities between ESHAP-BV vs ESHAP 4.To quantify stem cell collection yield 5.To assess impact of second line therapy on 2-year PFS 6.To compare the outcome of patients that attained less than mCR assessing their ORR and CR rates after new line of treatment, time to next therapy (TTNT) and OS 7.To assess TTNT2 8.To evaluate the prognostic impact of a negative baseline PET-CT on PFS and OS 9.To evaluate the prognostic impact of metabolic tumor volume in PFS and OS 10.To determine short-term and mid-term toxicity 11.To assess quality of life of patients 12.To predict the risk to develop peripheral neuropathy 13.To explore the concordance between PEC-TC local and central evaluation |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients with classical HL CD30+ confirmed histologically (either at the time of diagnosis / at the time of first relapse) will be included in the trial. A biopsy at the time of relapse / demonstration of primary refractoriness is highly recommended. Patients diagnosed with 1st relapsed/refractory HL (treatment escalation or de-escalation, performed according to interim PET-CT result in first-line therapy, will still be considered as a single prior line, i.e., RATHL or LYSARC trials) will also be considered candidates for the trial. Each patient must meet all of the following inclusion criteria to be enrolled in the study: 1. Male or female patients 18 years or older up to 65 years of age 2. Voluntary written informed consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care 3. Female patient is either post-menopausal for at least 1 year before the screening visit or surgically sterile or if of childbearing potential, agree to practice 2 highly effective methods of contraception, at the same time, from the time of signing the informed consent through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse 4. Male patients, even if surgically sterilized, (i.e., status post-vasectomy) agree to practice effective barrier contraception during the entire study period and through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse 5. ECOG performance status 0 to 2 6. Measurable disease at time of enrolment (lymphadenopathy/ extranodal mass of at least 1.5 cm) 7. No evidence of neuropathy grade ≥2 8. Clinical laboratory values as specified below within 7 days before the first dose of study drug: • Absolute neutrophil count ≥ 1,500/µL unless there is known hematologic/solid tumor marrow involvement • Platelet count ≥ 75,000/ µL unless there is known marrow involvement of the disease • Total bilirubin must be < 1.5 x the upper limit of the normal (ULN) unless the elevation is known to be due to Gilbert syndrome. • ALT or AST must be < 3 x the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of hematologic/solid tumor in liver • Serum creatinine must be < 2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance > 40 mL/minute • Hemoglobin must be ≥ 8g/dL |
|
E.4 | Principal exclusion criteria |
1. Lymphocyte predominant nodular Hodgkin’s lymphoma 2. Prior treatment with brentuximab vedotin 3. Female patient who is both lactating and breast-feeding or have a positive serum pregnancy test during the screening period or a positive pregnancy test on Day 1 before first dose of study drug 4. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to the protocol. 5. Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of progressive multifocal leukoencephalopathy (PML) 6. Symptomatic neurologic disease compromising normal activities of daily living or requiring medic 7. Any sensory or motor peripheral neuropathy greater than or equal to Grade 2 8. Known history of any of the following cardiovascular conditions • Myocardial infarction within 2 years of enrollment • New York Heart Association (NYHA) Class III or IV heart failure (see Appendix #9)65 • Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities • Recent evidence (within 6 months before first dose of study drug) of a left-ventricular ejection fraction <50%
9. Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks prior to first study drug dose 10. Patients that have not completed any prior treatment chemotherapy and/or other investigational agents within at least 5 half-lives (or 28 days if the half-lives are unknown) of last dose of that prior treatment 11. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin. 12. Known human immunodeficiency virus (HIV) positive positive (in case of Anti-HIV positive result patient cannot be included in the study 13. Known hepatitis B surface or core antigen-positive (HBsAg/ HBcAg). In case of Anti HBc positive result, DNA-HBV must be determined and negative result will allow patient inclusion. known or suspected active hepatitis C infection. In case of Anti-HCV positive result, RNA-HCV must be determined and negative result will allow patient inclusion 14. Focal radiation therapy within 30 days prior to study recruitment 15. Major surgery within 28 days prior to randomization 16. Diagnosed or treated for another malignancy within 3 years before the first dose or previously diagnosed with another malignancy and have evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
To determine metabolic complete remission (mCR) (PET-CT negative, Deauville scores 1-3) after 3 cycles of ESHAP-brentuximab vedotin (BV) vs ESHAP as salvage strategies in patients with relapsed / refractory classical Hodgkin’s Lymphoma (cHL)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
After the 3 first cycles of BV-ESHAP or ESHAP |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints: 1- Progression Free Survival (PFS): time from entry onto the study until lymphoma progression or death as a result of any cause 2- Overall Survival (OS): time from entry onto the clinical trial until death as a result of any cause. 3- Duration of response (DOR): time from first documentation of CR or PR to disease progression or death from any cause, whichever occurs first 4- Time to Progression (TTP): time from study entry until lymphoma progression or death as a result of lymphoma. 5- Time to Next Treatment (TTNT): time from the end of primary treatment until the onset of the next therapy. 6- Time to Next Treatment 2 (TTNT2): time from study enrollment to initiation of second line of therapy due to disease progression. 7- Overall response rate, complete response rate 8- Prognostic impact of metabolic tumor volume
Patient reported outcomes: 9- Quality of life of patients
Secondary safety endpoints: 10- Toxicity 11- Peripheral neuropathy 12- Stem cell collection yield |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy timepoints: 1- Progression Free Survival: 2 years 2- Overall Survival: 2 years 3- Duration of response: throughout the study period 4- Time to progression: throughout the study period 5- Time to next treatment (TTNT): throughout the study period 6- Time to next treatment 2 (TTNT2): throughout the study period 7- Overall response rate, complete response rate: After the 3 first cycles of BV-ESHAP or ESHAP 8- Prognostic impact of metabolic tumor volume: throughout the study period
Patient reported outcomes: 9- Quality of life of patients: throughout the study period
Secondary safety timepoints: 10- Toxicity: throughout the study period 11- Peripheral neuropathy: throughout the study period 12- Stem cell collection yield: throughout the first 3 cycles of treatment |
|
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 | Yes |
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) | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
3 cycles of ESHAP followed by 16 cycles of BV |
|
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 | 35 |
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 |
Israel |
Austria |
Spain |
Greece |
Croatia |
|
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
|
Last visit of the last patient |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 |