| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory peripheral T-cell lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the white blood cells (T-lymphocytes) |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061871 |
| E.1.2 | Term | Non-Hodgkin's lymphoma transformed recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10034623 |
| E.1.2 | Term | Peripheral T-cell lymphoma unspecified |
| 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 |
| The objective is to evaluate the efficacy and safety of masitinib at 6 mg/kg/day in combination with dexamethasone, dexamethasone in combination with gemcitabine and the combination of masitinib at 6 mg/kg/day, dexamethasone and gemcitabine in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate the complementary efficacy (Progression Free Survival and Tumor Response) and safety in each treatment group of patients with relapsed or refractory peripheral T-cell lymphoma:
- masitinib at 6 mg/kg/day in combination with dexamethasone
- dexamethasone in combination with gemcitabine
- masitinib at 6 mg/kg/day in combination with dexamethasone and gemcitabine |
|
| 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 |
1. DNA analysis – mandatory:
This study is aimed at finding potential DNA mutations, amplification and/or deletion that might explain short or long survival, side effects and treatment response. An analysis of the regions coding for some kinases as c-kit, PDGF-R, FGF-R3, JAK, LYN, FYK, LCK) will be done and results will be correlated to the proteins expression. Before study treatment, a specimen from the tumor tissue (from either the biopsy of the original diagnosis of lymphoma and/or new biopsy (as bone marrow biopsy as requested by the study protocol) will be collected. The biopsies of the tumor will be fixed in formol and kept at room temperature.
AB science will also collect blood sample at baseline for the same purpose.
2. RNA analysis – mandatory for inclusion criteria:
The objective of this ancillary study is to evaluate modifications and amplification of genes coding for kinases and other genes that could be predictive of sensitivity and/or resistance to study treatment. Blood samples (Paxgene RNA tubes) will be drawn at screening or baseline (if not done at screening), for the RNA assays. Besides, RNA expression patterns will be performed on peripheral blood (Real-time PCR / Digital Gene Expression). These samples will be done according to the process described in the ‘Manual for pharmacogenomic study’ in order to identify potential variations of biomarkers and to correlate them to the efficiency or non-efficiency of the study treatment.
3. Pharmacogenomic analysis. A pharmaco-genomic study will be performed on blood and/or bone marrow biopsy in order to evaluate the association with efficacy and/or toxicity of study treatment.
4. Pharmacokinetics study for patients in group 1. This will be performed in group 1 (optional in group 1– only for French patient) to evaluate a potential interaction of dexamethasone on masitinib pharmacokinetic parameters.
5. In case a patient experiences either a severe neutropenia or severe skin toxicity, a specific pharmacogenomic blood sample will be taken. |
|
| E.3 | Principal inclusion criteria |
1. Patient with histologically/cytologically confirmed peripheral T-cell lymphoma (PTCL), using the WHO disease classification 2008:
- Adult T-cell lymphoma/leukemia (human T-cell leukemia virus [HTLV] 1+)
- Angioimmunoblastic T-cell lymphoma
- Anaplastic large cell lymphoma ALK+
- Anaplastic large cell lymphoma ALK-
- Peripheral T-cell lymphoma- NOS (not otherwise specified)
- Extranodal Natural Killer (NK)/T-cell lymphoma
- Enteropathy-associated T-cell lymphoma
- Hepatosplenic T-cell lymphoma
- Subcutaneous panniculitis T-cell lymphoma
- Transformed mycosis fungoides
2. Patient with documented progression of disease after at least 1 previous chemotherapy cycle
3. Patient with minimum 1 bidimensionally measurable disease (more than 1.5 cm) according to the Cheson criteria
4. Patient having Ann Arbor stage II–IV
5. Patient with ECOG Performance Status ≤ 2
6. Patients with adequate organ function
- Absolute neutrophils count (ANC) ≥ 1.5 x 109/L or > 1 x 109/L in case of medullary
involvement
- Haemoglobin ≥ 10 g/dL
- Platelets (PTL) ≥ 75 x 109/L
- AST and ALT ≤ 3x ULN (≤ 5 x ULN in case of liver metastases)
- Gamma GT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases)
- Bilirubin ≤ 1.5x ULN (≤ 3xULN in case of liver metastases)
- Normal Creatinine or if abnormal creatinine, creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula)
- Albuminaemia > 1 x LLN
- Proteinuria < 30 mg/dl (1+) on the dipstick. If proteinuria is ≥ 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours
7. Patient with life expectancy > 3 months
8. Man or woman, age ≥18 years
9. Body mass index > 18 and body weight > 40 kg
10. Female patient of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agrees to use a highly effective method of contraception and an acceptable method of contraception by her male partner during the study and for 3 months after the last treatment intake.
Male patient with a female partner of childbearing potential who agrees to use a highly effective method of contraception and an acceptable method of contraception by his female partner during the study and for 3 months after the last treatment intake OR who agrees to use an acceptable method of contraception and a highly effective method of contraception by his female partner during the study and for 3 months after the last treatment intake.
Highly effective methods of contraception include:
-Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
-Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable,or implantable
-Intrauterine device (IUD)
-Intrauterine hormone-releasing system (IUS)
-Bilateral tubal occlusion
-Vasectomized male (azoospermia assessed medically)
-Sexual abstinence (Its reliability should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
Acceptable methods of contraception include:
-Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
-Male or female condom with or without spermicide
-Cap, diaphragm or sponge with spermicide
11. Patient able and willing to comply with study procedures as per protocol.
12. Patient able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe skin toxicity.
13. Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures are performed. |
|
| E.4 | Principal exclusion criteria |
1. Patient with:
- T-cell prolymphocytic leukemia
- T-cell large granular lymphocytic leukemia
- Mycosis fungoides, other than transformed mycosis fungoides
- Sezary syndrome
- Primary cutaneous CD30+ T-cell lymphoproliferative disorders
2. Patient with central nervous involvement of lymphoma
3. Patient with previous allogeneic stem cell transplantation
4. Patient who relapsed less than three months after an autologous stem cell transplantation
5. Patient presenting with cardiac disorders defined by at least one of the following conditions:
- Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)
- Patient with cardiac failure class III or IV of the NYHA classification
- Patient with severe conduction disorders which are not prevented by permanent pacing (atrioventricular block 2 and 3, sino-atrial block)
- Syncope without known aetiology within 3 months
- Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension
6. Patient with clinically uncontrolled infectious diseases and patient with Human Immunodeficiency Virus infection and/or hepatitis B or C infection
7. Patient with a history of any other malignancy within the 5 years prior to study treatment, except carcinoma in situ of the cervix or basal cell carcinoma of the skin
8. Pregnant or nursing woman
9. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or
current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent
10. Patient with known hypersensitivity to gemcitabine and/or excipients
11. Patients requiring medication, which are prohibited in the current protocol, including anticancer drugs other than masitinib and gemcitabine, corticosteroids other than dexamethasone, investigational drugs, live attenuated vaccines, drugs known to be at high risk of Stevens-Johnson or DRESS syndrome.
Washout:
- Patient with a major surgery or radiation therapy within four weeks of starting the study treatment
- Treatments with an investigational agent or anti-tumour therapy (any chemotherapy, radiotherapy,
immunotherapy or biologic agent) within 4 weeks prior to baseline
- Treatment with corticosteroids within 7 days prior to baseline (except prednisone at a maximal dose of 0.5
mg/kg/day for less than 1 month)
- Patients to be treated with gemcitabine will require a delay of at least four weeks between radiotherapy and the start of their treatment with gemcitabine. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Survival (OS) defined as time from randomisation until death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
Survival rates at W12, W24 and then every 24 weeks;
Overall Progression Free Survival (PFS)
Progression Free Survival (PFS) rates at W12, W24 and then every 24 weeks;
Overall Time to Progression (TTP);
TTP rate at W12, W24 and then every 24 weeks;
Response rate at W12, W24 and then every 24 weeks;
Best response rate during study treatment;
Duration of response;
Clinical benefit defined as time to reappearance or progression of lymphoma-related symptoms every 4 weeks until W24 and then every 12 weeks;
Time to next PTCL treatment.
Pain improvement (VAS)
Pharmacogenomic assessment : Relationship between genomic data and overall survival
Pharmacokinetics study (in group 1 – French patients only) to evaluate a potential interaction of dexamethasone on masitinib pharmacokinetic parameters.
Safety profile in each group using the NCI CTCAE v4.03 classification.
Other analysis: |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
Survival rate at Weeks 12, 24 and then every 24 weeks;
Progression Free Survival (PFS) rates at Weeks 12, 24, and then every 24 weeks;
Overall Time to Progression (TIP) and TIP rate at Weeks 12, 24, and then every 24 weeks;
Response rate at Weeks 12, 24, and then every 24 weeks, including documenting best response rate and duration during study treatment;
Clinical benefit defined as time to reappearance or progression of lymphoma- related symptoms every 4 weeks until Week 24 and then every 12 weeks. |
|
| 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 | 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) | Yes |
| 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 | 3 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Czech Republic |
| France |
| Germany |
| Greece |
| India |
| Italy |
| Korea, Democratic People's Republic of |
| Malaysia |
| Philippines |
| Romania |
| Serbia |
| Singapore |
| Slovakia |
| Spain |
| 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
|
| Patient treated with masitinib until disease progression, limiting toxicity or consent withdrawal in an optional extension phase. Gemcitabine and dexamethasone will be administrated up to 6 months (6 cycles). End of study treatment visit will be performed within 2 weeks after the last dose of study treatment. Follow-up every 12 weeks after the end of study treatment performed until patient's death. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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