Neoplasms

Symptoms and General Pathology

All Conditions

Carcinogenesis

Neoplastic Processes

All Drugs and Chemicals

Nicotine

Carbon Monoxide

Antimetabolites

Neurotransmitter Agents

Cigarette consumption in the context of their habit (not related to the particiapion under study).

Electronic cigarette consumption in the context of their habit (not related to the particiapion under study).

Nicotine replacement therapy (only patch) consumption in the context of their habit (not related to the particiapion under study).

No consumption in the context of their habit (not related to the particiapion under study).

Collection of 5 mL of urinary sample.The pregnancy test is done in each investigator center.

pregnancy test

Collection of 10 mL of urinary sample for cotinine analysis. The analysis is maid during the study and is centralised at the hospital Paul Brousse.

urinary cotinine assesment

Collection of 20 mL of urinary sample for NNN analysis. The analysis is maid at the end of the study and is centralised in a laboratory located at Strasbourg.

Urinary NNN assesement

This questionnaire will permit to assess the smoking habits of the participants.

Questionnaire (Fagerstrom test)

This test will permit to determinate if the participant are axposed to passive smoking or not.

Measurement of carbon monoxide levels expired

Patrick DUPONT, MD

Patrick Dupont, Dr

Patrick Dupont, MD

Multicenter, national study, non-randomized , controlled, comparative with 4 independent groups (20 participants in each group). There are 3 experimental groups ("smocker", "nicotine replacement therapy" an "electronic cigarette") and 1 control group ("without nicotine").

The main objective of the study is to compare the level of urinary NNN in the electronic cigarette users versus the nicotine replacement therapy (patch) users.

The study has only one visit taking place as below:

* Verification of inclusion and non-inclusion criteria.
* Collection of the informed consent of the subject Given the non-invasive nature of the procedure, a period of reflection will be given to the subjects, however, information and obtaining consent will be made during the same visit.
* Collection of 5 mL of required for the pregnancy test in women of childbearing age. This collection does not need to be fasting. If this test is positive, the subject will not be included in the study.
* Collection of 30 mL of urine needed for the cotinine and the NNN quantitative analysis.

This collection does not need to be fasting.

Then , the urine sample is divided into two vials stored at -80 ° C:

* a 10 mL vial for the cotinine analysis,
* a 20 mL vial for the NNN analysis.

  * Realization of the Fagerstrom test (FTCD) in order to evaluate subject smoking. This test is not done for the group 4 (group "without nicotine")
  * Measurement of carbon monoxide in exhaled air If after signing the consent, the subject realizes that he cannot urinate or he did not enough urine during the inclusion visiting, the subject can come back the next working day to make the urine collection.

Determination of Carcinogens Nicotine in Electronic Cigarettes Users

The determination of urinary NNN of will be performed at the end of the study only for subjects with cotinine / creatinine ratio adequate.

Assistance Publique - Hôpitaux de Paris

Rare Diseases

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Analgesics

Central Nervous System Depressants

Hematinics

Antineoplastic Agents

Amino Acids

Morphine

Liver Extracts

3-Iodobenzylguanidine

Ceritinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

All participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.

Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.

Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.

It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.

Biopsy

Tumor tissue will be sent to Foundation Medicine laboratory for molecular profiling.

Next Generation Sequencing

Participants will undergo different types of scans to look at your tumor. These scans include CT (computerized tomography), MIBG (meta-iodobenzylguanidine) PET (positron emission tomography), and MRI (magnetic resonance imaging). Participants may have more than one type of scan.

Tumor Scans

Participants will have needles inserted through their hip bone to remove fluid from inside the bone marrow. This test determines if participants have tumor in the bone marrow.

Bone marrow Tests

The exam includes taking participant weight, height, blood pressure, heart rate and respiratory rate and performing a examination of the participants body. The investigators may also check the participants vision with an eye chart.

Physical Exam

Participants will have their eyes will be evaluated using different instruments. Participants will also be asked to read an eye chart. The exams will take about 15 minutes.

Eye Exam

Standard blood tests will be done to measure different types of blood cells, to measure the amount of certain substances, and tests to check how well liver and kidneys are working. When possible, the investigators will take blood from the participants central line. If this is not possible, the investigators will take blood from a vein in the participants arm. First, the investigators will put some cream on the skin so that drawing blood will not be painful. Then the investigators will put a thin needle into the vein to draw the blood.

Labs

If the participant is 11 years old or older or has already started having periods, the participant will be asked to take a pregnancy test before starting this study. The results will be shared with the participant but not with the participants' parent(s). We strongly encourage the participant to share the results with the parents. If the participant is found to be pregnant, the participant will not be able to continue participation in the study. About 1 teaspoon of blood (or urine if a urine test) will be needed.

Pregnancy Test

A team member will take the participant's medical history, along with a listing of any medications that are being taken. Throughout the study, participants will be asked to report if they think that anything bad has happened as a result of the study.

Interviews

This is a test of electrical activity of the heart. The investigators will put electrodes (sticky pads attached to wires) on the participant's chest, arms and legs. The electrocardiogram (ECG) will not be uncomfortable, but the participant will have to lie still. It does not hurt and takes about 15 minutes.

The participant will have an ultrasound of the heart taken to assess heart function. The investigators will put some gel on the skin and use a machine to take pictures of the heart.

Echocardiogram

Participants will take ribociclib once per day orally for Days 1-21 of a 28-day cycle.

Ribociclib

Participants will take ceritinib once per day orally for 28 days of a 28-day cycle.

Yael P Mossé, MD

John M Maris, MD

The purpose of this research study is to match genomic aberrations in tumor cells at time of relapse to rationally designed combinations of molecularly targeted agents. This study will be done in two parts:

Part I: Tumor will be accessed at study entry via a biopsy and subjected to deep sequencing to identify protocol-specified biomarkers for therapy assignment.

Part II: If the tumor contains a genetic change defined by the study as being actionable, and other criteria are met, participants will be assigned to therapy based upon the genetic changes identified in the tumor biopsy.

Next Generation Personalized Neuroblastoma Therapy

Next Generation Personalized Neuroblastoma Therapy (The NEPENTHE Trial)

The primary variable is the incidence of dose limiting toxicities (DLTs) during the first 28 days of therapy

Area under the plasma concentration time-curve from zero to the last measured concentration

To describe whether the assigned targeted therapy can mediate anti-tumor effects in subjects with relapsed or refractory high-risk neuroblastoma within the context of a phase 1/phase1b biomarker-driven trial. Percentage of patients with objective response will be according to the International Neuroblastoma Response Criteria.

Neuroblastomas undergo substantial mutational evolution during therapy, and relapsed disease is more likely to be driven by a targetable oncogenic pathway. Genomic alterations measured by next-generation sequencing at time of disease progression will be characterized and reported in a descriptive manner.

Novartis Pharmaceuticals

Foundation Medicine

Yael P Mosse

Principal Investigator

Blood and Lymph Conditions

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Immunomodulating Agents

JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.

JNJ-56022473 will be supplied as a lyophilized product containing 100mg of active pharmaceutical ingredient (50 mg/mL after reconstitution with 2.0 mL sterile water for injection). The JNJ-56022473 dose administered will be dependent upon the subject's weight at baseline. The JNJ-56022473 dose should be adjusted in case the subject's weight changes by \> 10%. JNJ- 56022473 will be administered in 250 mL IV infusion over approximately 180 minutes using an infusion pump.

JNJ-56022473

Bone marrow analyses and CBC with differential will be performed by a central laboratory. If the marrow cannot be aspirated, a biopsy should be performed.

Bone marrow analyses and CBC with differential

Characterization of LSCs and blasts (including CD123 and CD38 expression) will be performed as study-related analyses in the context of this protocol by central flow cytometry using bone marrow samples.

Flow cytometry analyses

Central biobanking of study samples (bone marrow, peripheral blood as well as a buccal swab) will be carried out in Dresden.

Central biobanking

A bone marrow biopsy is taken whenever it seems necessary to the investigator.

Histopathology analysis

The cytogenetic analysis with banding analysis (optional FISH) have to be performed at local labs. Therefore 2 - 5 ml of bone marrow will be collected and analysed.

Cytogenetic analysis

For serum chemistry 15 ml (2 x 7,5 ml) of peripheral blood have to be collected.

Serum chemistry

For CBC a minimum of 3 ml of peripheral blood have to be collected.

Automated CBC

Serum or urine pregnancy testing β-HCG with a sensitivity of at least 25 mIU/mL is to be done not more than 3 days prior to initiation of JNJ-56022473 in female patients with childbearing potential. Furthermore, serum or urine pregnancy testing has to be done after end of treatment (EoT) visit.

Uwe Platzbecker, Prof.

Lionel Adés, Dr.

The outcome of HMA-refractory patients with MDS or AML is dismal with a median survival of 5 months after failure, representing a significant unmet medical need due to the very limited treatment options. In this context, a specific targeting of the leukemic stem cell (LSC) seems a promising option to selectively combat the leukemic progenitor cells. In fact, CD123 is overexpressed in AML and MDS progenitors making it an attractive target for immunotherapy-based approaches. JNJ-56022473 is a promising compound that has been engineered with regard to this strategy and the current phase II trial has the aim to evaluate the overall hematological response rate at 3 months in HMA refractory/relapsed AML and MDS patients.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies of the pluripotent hematopoietic stem cells characterized by clonal hematopoiesis and progressive bone marrow failure. Clinically, patients suffer from fatigue and are at high risk of infections or bleeding. Also, MDS patients are endangered by progression to secondary acute myeloid leukemia (AML), a disorder of early hematopoietic progenitor cells characterised by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues.

Up to now, allogeneic transplantation is considered the only curative option for both MDS and AML patients. However, as MDS and AML mainly manifest in the 7th and 8th decade of life, only a limited number of patients tolerating bone marrow transplantation and are therefore eligible for this procedure. In fact, comorbid conditions are common among the elderly such as heart disease, renal insufficiency and vascular disease thus influencing the ability to withstand exhausting transplantation procedures.

Hence in recent years, novel therapeutic strategies have been developed and hypomethylating agents (HMAs) azacitidine and decitabine have emerged as new therapeutic options. In 2009, azacitidine was the first HMA in use having received approval for treatment of MDS and AML patients with 20-30% blasts. In 2012, also the sister compound decitabine got approval for treatment of AML patients ≥ 65 years of age and in 2015, azacitidine's approval was extended to AML patients ≥ 65 years of age that are considered unfit for allogeneic transplantation with \> 30% blasts.

However, despite the efficacy and reported activity, only 50% of patients respond to the treatment with HMAs and the majority of them do relapse. Also the outcome of HMA- refractory patients is dismal with a median survival of 5 months after failure and hence MDS and AML patients with HMA failure represent a significant unmet medical need due to the poor prognosis and very limited treatment options.

In this context, a specific targeting of the leukemic stem cell (LSC) seems a promising option to selectively combat the leukemic cells. In fact, CD123 (also known as interleukin-3-Rα) is expressed in different hematological malignancies, among others in MDS and AML. Interestingly, CD123 is expressed by the majority of AML blasts and it is also overexpressed by CD34+ CD38- LSCs compared with normal hematopoietic stem cells and other normal tissues. These features make CD123 an attractive target for anti-leukemia therapy. Recent data suggests that treatment with HMA can induce expression of CD123 on AML tumors opening up the potential that HMA failure patients may have even higher expression levels of CD123.

Indeed, JNJ-56022473 is a promising compound that has been engineered with regard to this strategy. JNJ-56022473 is a humanized monoclonal antibody that targets the alpha chain of the interleukin-3-receptor and is optimized at the Fcγ region for enhanced activation of antibody- dependent cell-mediated cytotoxicity (ADCC) via natural killer cells.

Recently, JNJ-56022473 has been evaluated in a phase I study with AML patients at high risk for early relapse. There was a clear dose dependency on depletion of peripheral CD123 cell populations such as pDC and basophile with complete and sustained depletion seen in pts at doses ≥3 mg/kg Given the encouraging results of this phase I trial we now propose a phase II trial to evaluate JNJ-56022473 in AML patients as well as in MDS patients that have failed or are refractory to HMA- treatment.

The clinical trial will be accompanied by a translational research program which aims at elucidating specific immune responses mediated by JNJ-56022473, in particular by descriptive and functional analyses. In this context bone marrow and peripheral blood will be collected during the study as well as before and after therapy.

Constitutive overexpression of the α-subunit of the interleukin-3 receptor i.e. IL-3Rα, is a hallmark of the early AML progenitor cell population (i.e. leukemic stem cells) as well as leukemic blasts and IL-3Rα is also overexpressed in myelodysplastic syndromes. In fact, CD123 is unique to the IL-3 receptor and is responsible for the high specificity and low affinity binding of IL-3. Upon ligand binding, the α-subunit CD123 associates with the βc-subunit (CD131) to form a high-affinity receptor complex initiating an intracellular signaling cascade through phosphorylation and activation of at least 3 distinct signal transduction pathways: the JAK/STAT-kinase, MAP-kinase-, and PI3-kinase-pathways. Under physiological conditions, activation of the IL-3 receptor induces proliferative, anti-apoptotic, and differentiating signals.

JNJ-56022473 (CSL362) is a second generation antibody developed from the murine 7G3 anti- CD123 monoclonal antibody (mAb) in a stepwise process of humanization, affinity maturation, and Fc engineering. To enhance the cytotoxicity of the first-generation antibody CSL360, the proprietary Xencor (Xmab®) technology was applied and two amino acid mutations (S239D and I332E) were introduced into the Fc region. These amino acid substitutions led to improved binding to CD16 (FcγRIIIa) on natural killer (NK) cells and significantly enhanced the ability to induce ADCC.

The JNJ-56022473 drug product that will be used in this study is produced in a different cell line with a different process compared with CSL362, the drug product used in the phase I study CSLCT-AML-11-73 described below. Comparability testing of JNJ-56022473 and CSL362 has shown the antibodies to behave similarly in biophysical, biochemical, and preclinical assessments. The primary structure, charge heterogeneity, size heterogeneity, purity, higher order structure, and process impurities were found to be highly similar between CSL362 and JNJ56022473. Pharmacodynamic (PD) studies in cynomolgus monkeys showed similar levels of biological activity between CSL362 and JNJ-56022473 (ie, basophil and pDC depletion; NK cell number and activity). Additionally, the pharmacokinetic (PK) profiles of JNJ-56022473 following 30 and 100 mg/kg IV dosing of cynomolgus monkeys are highly similar to those of CSL362. Following the first weekly intravenous dose, mean Cmax and AUC0-167h of JNJ-56022473 are 91% and 94% of those observed for CSL362, respectively.

This is an open-label, single-arm, multicenter, phase II study of JNJ-56022473 in subjects suffering from MDS or AML. The trial will involve participating sites from Germany and France. Up to a maximum of 43 subjects will be enrolled in the study.

JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.

For patients who still benefit from the treatment and are graded as responders after the time period defined above, treatment will continue as long as medically indicated. End of study as a whole will be 16 months after LPFV (maximum of 26 treatment cycles plus follow up of three months). Data obtained after the end of the study (EoS) for patients who still responding will be reported under separate cover.

Single Agent JNJ-56022473 in MDS and AML Patients FAILING HYPOMETHYLATING AGENT BASED THERAPY

Single Agent JNJ-56022473 in MDS and AML Patients Failing Hypomethylating Agent Based Therapy

Overall hematological response rate at 3 months (either CR, PR, marrow-CR, HI, SD)

GWT-TUD GmbH

Musculoskeletal Diseases

Infections

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Skin and Connective Tissue Diseases

Arthritis

Uterine Cervical Neoplasms

Communicable Diseases

Spondylitis

Rheumatic Diseases

Spondylarthritis

Papillomavirus Infections

Bone Diseases

Bone Diseases, Infectious

Spinal Diseases

Joint Diseases

Female patients (18 to 65 years old) with spondyloarthritis or rheumatoid arthritis will undergo HPV screening and a have a close gynecologic follow-up.

Cervical smear will be obtained using an Ayre spatula and a cervical brush (Cervex-Brush®). HPV test will be performed using the CLART® HPV2 kit (Genomica).This kit enables the detection of 35 genotypes: HPV6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 43,44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 68, 70, 71, 72, 73, 81, 82, 83, 84, 85 et 89.

Cervical smear

Pregnancy test

Sexual activity questionnary

Fabienne COURY-LUCAS, MD

Gery Lamblin, MD

Gery Lamblin

Emmanuelle VIGNOT, MD

Emmanuelle Vignot, MD

Fabienne Coury-lucas, MD

Muriel PIPERNO, MD

Jean-Paul LARBRE, MD

Nathalie HOEN, MD

Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the two most common chronic inflammatory rheumatism, with a prevalence in the French population of 0.3% and 0.4%, according to the criteria European League Against Rheumatism / American College of Rheumatology (EULAR / ACR) 2010 and Assessemnt of SpondyloArthritis International Society (ASAS) 2009 respectively. In patients whose pathology is resistant to first-line treatment, such as methotrexate for rheumatoid arthritis and peripheral spondyloarthritis, or non-steroidal anti-inflammatory drugs for axial spondyloarthritis, the treatment is based on biotherapies, such as anti-inflammatory drugs. -TNF, to obtain effective control of the disease and prevent joint damage.

Human papillomavirus (HPV) infection, the leading risk factor for cervical carcinoma, is the most common sexually transmitted infection (STI) with a particularly high prevalence among young women.

In addition, anti-TNF, used in the treatment of RA and SpA, and anti-IL6 receptor, used in that of RA, could have opposite effects on HPV-dependent oncogenesis.

Thus, patients with RA or SpA may have a higher risk than the general population of progression to cervical cytological abnormalities. Evaluation of the chronic carriage of HPV would then be a useful tool in the management of these patients.

Papillomavirus Load in Rheumatic Inflammatory Diseases

Papillomavirus chronic load is defined as a positive HPV test at the end of the study combined with at least 3 positive HPV tests during the 24 months follow-up.

Number of patients with a positive HPV test at enrollment

Number of patients with a negative HPV test at enrollment and having at least one positive HPV test during the 24 months follow-up

Number of patients with a positive HPV test at enrollment and having a negative HPV test at the end of the study.

Number of patients with low-grade and high-grade cytological abnormalities during follow-up among those who had normal cytology at enrollment.

Number of patients ,with normal cytology at enrollment, whose cervical smear indicates a regression in cytological abnormalities or a persistence of cytological abnormalities or a development of abnormalities into cervical cancer or dysplasia, during the 24 months follow-up.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Determination of Carcinogens Nicotine in Electronic Cigarettes Users	NCT02897401	Smoking Carcinogenesis ...	pregnancy test urinary cotinin... Urinary NNN ass... Questionnaire (... Measurement of ...	18 Years -	Assistance Publique - Hôpitaux de Paris
Determination of Carcinogens Nicotine in Electronic Cigarettes Users	NCT02897401	Smoking Carcinogenesis ...	pregnancy test urinary cotinin... Urinary NNN ass... Questionnaire (... Measurement of ...	18 Years -	Assistance Publique - Hôpitaux de Paris
Next Generation Personalized Neuroblastoma Therapy	NCT02780128	Neuroblastoma Cancer	Biopsy Next Generation... Tumor Scans Bone marrow Tes... Physical Exam Eye Exam Labs Pregnancy Test Interviews ECG Echocardiogram Ribociclib Ceritinib	1 Year - 21 Years	Children's Hospital of Philadelphia
Determination of Carcinogens Nicotine in Electronic Cigarettes Users	NCT02897401	Smoking Carcinogenesis ...	pregnancy test urinary cotinin... Urinary NNN ass... Questionnaire (... Measurement of ...	18 Years -	Assistance Publique - Hôpitaux de Paris
Single Agent JNJ-56022473 in MDS and AML Patients FAILING HYPOMETHYLATING AGENT BASED THERAPY	NCT02992860	Myelodysplastic... Acute Myeloid L...	JNJ-56022473 Bone marrow ana... Flow cytometry ... Central biobank... Histopathology ... Cytogenetic ana... Serum chemistry Automated CBC Pregnancy Test	18 Years -	GWT-TUD GmbH
Next Generation Personalized Neuroblastoma Therapy	NCT02780128	Neuroblastoma Cancer	Biopsy Next Generation... Tumor Scans Bone marrow Tes... Physical Exam Eye Exam Labs Pregnancy Test Interviews ECG Echocardiogram Ribociclib Ceritinib	1 Year - 21 Years	Children's Hospital of Philadelphia
Papillomavirus Load in Rheumatic Inflammatory Diseases	NCT03713736	Spondyloarthrit... Rhumatoid Arthi...	Cervical smear Pregnancy test Sexual activity...	18 Years - 65 Years	Hospices Civils de Lyon
Papillomavirus Load in Rheumatic Inflammatory Diseases	NCT03713736	Spondyloarthrit... Rhumatoid Arthi...	Cervical smear Pregnancy test Sexual activity...	18 Years - 65 Years	Hospices Civils de Lyon

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