| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HAIRY CELL LEUKEMIA (HCL) CARRYING THE BRAF-V600E MUTATION |
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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] - Blood and lymphatic diseases [C15] |
| 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 determine the anti-tumor activity of the combination of Vemurafenib (orally administered) with Rituximab (intravenously administered) in HCL patients carrying the BRAF-V600E mutation and fulfilling the eligibility criteria for enrollment in this study |
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| E.2.2 | Secondary objectives of the trial |
- To assess the safety of the combination of Vemurafenib with Rituximab.
- To determine the time to response to the combination of Vemurafenib with Rituximab.
- To determine the duration of response to the combination of Vemurafenib with Rituximab.
- To assess (when a sufficient number of leukemic cells is available for analysis) the pro-apoptotic activity of the combination of Vemurafenib with Rituximab in purified leukemic hairy cells in vitro and to compare it to the clinical response.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female HCL patients ≥ 18 years of age.
2. Proven diagnosis of HCL according to the morphological and immunophenotypic criteria (co-expression of CD11c/CD25/CD103 and/or positivity for annexin-A1) of the World Health Organization (WHO-2008) classification of lymphoid neoplasms12, accompanied by the presence of the BRAF-V600E mutation as detected using a sensitive allele-specific polymerase chain reaction (AS-PCR) recently developed in our laboratory.
3. Patients with HCL must fall in one of the categories: i) Patients with HCL whose disease is refractory to therapy with purine analogues (no complete nor partial response, or relapse ≤1 year following treatment).
ii) Patients with HCL who relapse early (≥1 year and ≤2 years) after the first course of a purine analogue (pentostatin or cladribine), or who relapse whenever after a second or later course. If the relapse is accompanied by bone marrow hypoplasia (<20% hematopoietic cells on histological analysis), which would advise against chemotherapy with a purine analogue, the patient is eligible even if the relapse occurs >2 years after the first course.
iii) Because in some studies persistence of residual disease is statistically associated with higher probability of relapse we consider eligible for the study also patients that, after at least two courses of therapy (at least one of which including a purine analogue), still manifest a significant residual disease in the bone marrow (≥30% of leukemic hairy cells).
iiii)Patients with HCL who manifest severe side effects from therapy with purine analogues (prolonged and profound myelosuppression and immunosuppression, infectious complications, renal failure, vasculitis and autoimmune hemolytic anemia) or are deemed by the investigator medically unfit for chemotherapy with purine analogues (for example because of very old age and/or significant comorbidities).
4. Any prior treatment (chemotherapy and/or immunotherapy) must have been completed at least 12 weeks prior to initiation of study medication, except if no response to this treatment is already manifestly evident earlier.
5. ECOG PS of 0-2.
6. Patients must have recovered from all side effects of their most recent treatment for HCL.
7. Adequate renal and liver function as defined by the following laboratory values performed within 7 days prior to first dose of Vemurafenib and Rituximab: serum creatinine ≤2 times the upper limit of normal (ULN); serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤2.5 times ULN, alkaline phosphatase ≤2.5 times ULN and bilirubin ≤1.5 times the ULN. Higher values are acceptable if they are directly related to the disease.
8. Negative serum pregnancy test within 14 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year.
9. Fertile men and women must use an effective method of contraception during treatment and for at least 16 weeks (for men) and 12 months (for women) after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly (for example implants, injectables, or intrauterine devices). Oral contraceptives are not reliable due to potential drug-drug interaction. At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. [Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.]
10. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry.
11. Signed informed consent must be obtained prior to performing any study-related procedures (including tumor testing for the V600E BRAF mutation).
12. Clinical indication for treatment (except for HCL patients of category ìììì), i.e. the presence of one or more of the following: neuthrophils <1.5x109 per liter, hemoglobin <11 g per deciliter, platelets <100x109 per liter, bulky/symptomatic splenomegaly, recurrent disease-related opportunistic infections.
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| E.4 | Principal exclusion criteria |
1. Patients with a previous malignancy within the past 2 years are excluded except for patients with treated and controlled basal or SCC of the skin or carcinoma in-situ of the cervix or melanoma (or other tumors) carrying a BRAF-V600E mutation. Isolated elevation in PSA in the absence of radiographic evidence of metastatic prostate cancer is allowed.
2. Patients with HCL previously treated with a BRAF inhibitor.
3. Concurrent administration of any anti-cancer therapies (e.g. chemotherapy, other targeted therapy, experimental drug, etc.) other than those administered in this study and concurrent treatment on another therapeutic clinical trial.
4. Pregnant (negative serum pregnancy test is required in women of child-bearing potential) or lactating women.
5. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. Patients must be able to swallow tablets.
6. History of congenital long QT syndrome
7. Corrected QT (QTc) interval ≥500 msec at baseline or uncorrectable electrolyte abnormalities.
8. Active hepatitis infection or positivity for human immunodeficiency virus.
9. Uncontrolled medical illness.
10. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or which in the judgment of the investigator would make the patient inappropriate for entry into this study.
11. Unwillingness to practice effective birth control.
12. Inability to comply with other requirements of the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To achieve a complete remission (CR) rate of at least 60% at the end of Vemurafenib and Rituximab treatment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| at the end of vemurafenib and rituximab treatment |
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| E.5.2 | Secondary end point(s) |
-To summarise the type, incidence, severity, seriousness and relationship to the drug combination of adverse events (AE) and any laboratory abnormalities.
-To summarise the time to response, i.e. the time from start of treatment to the first documented objective response (including complete remission and partial response).
-To describe the duration of response (i.e., from the date of achievement of at least a partial remission to the date of relapse) in patients achieving at least a partial remission (PR) at the end of treatment.
-To study, in purified leukemic hairy cells, the in vitro effect of the combination Vemurafenib with Rituximab on the phosporylation status of MEK and ERK, as well as on cell survival and apoptosis.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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
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| LPLV (including 2 years of follow up) |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
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