Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Carcinoma

Recurrence

Hyperplasia

Carcinoma, Intraductal, Noninfiltrating

Neoplasm Recurrence, Local

Disease Attributes

Breast Diseases

Skin Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Carcinoma in Situ

Breast Carcinoma In Situ

Neoplastic Processes

Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Anticoagulants

Other Dietary Supplements

Tamoxifen

Citric Acid

Sodium Citrate

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Citrate

tamoxifen at daily dose of 5 mg for a total treatment time of 3 years

placebo at daily dose of 5 mg for a total treatment time of 3 years

placebo

Andrea DeCensi, MD

The aim of the study is to evaluate whether tamoxifen at a low dose of 5mg/d reduces in the long term the incidence of invasive breast cancer and ductal carcinoma in situ, DCIS (DIN 1c, 2, 3) of the breast, in woman operated for lobular intraepithelial neoplasia (LIN1, 2 and 3) or ER-positive ductal intraepithelial neoplasia (DIN 1b, DIN2, DIN3, 1a excluded) of the breast.

To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed.

Biomarker trials revealed that 5 mg/d was noninferior to 20 mg/d in inhibiting proliferation of breast cancer and normal endometrial tissue.

By contrast, the risk of endometrial cancer si dose-dependent, and the dose reduction can lead a substantial decrease. Morover a dose of 5 mg/day is associated with an overall decrease of the estrogenic activity of tamoxifen on insulin like growth factor (IGF-I), sex hormone-binding globulin (SHBG) and antithrombin-III, with a decrease of venous thromboembolic events. Moreover, tamoxifen exhibits a high tissue distribution, so that a dose of 5 mg/day attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro.

A prospective cohort study also showed that 10 mg on alternate days halves recurrence of DCIS in postmenopausal women.

It has been shown that the treatment of dysplasia or pre-cancer drives the reduction of the invasive neoplasms onset. This is a chemoprevention trial designed to validatate the low-dose Tamoxifen in women with diseases at high evolutionary risk. The demonstration of efficacy and safety of such a treatment for the prevention of the invasive breast cancer would lead improvements in term of survival and quality of life for the patients at increased risk.

Italian, multicenter, phase III trial: controlled, parallel group comparision, randomized (1:1) duble blind, tamoxifen 5 mg/d versus placebo administered for 3 years. A total of 500 women 75 years of age or younger with newly diagnosed non-invasive breast cancer have been included in the study. The long-term study implies a minimum 10 year follow up after treatment completion.

Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up

Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up

Authors are open to share data based on a request for collaboration that includes a data analysis plan.

Please send an e-mail to both: andrea.decensi@galliera.it; mpuntoni@ao.pr.it

Number of neoplastic events, i.e., invasive breast cancer or ductal carcinoma in situ of the breast from the start of treatment up to at least 16 years from treatment initiation.

Number of other non-invasive breast disorders (LCIS, atypical ductal or lobular hyperplasia), endometrial cancer, ovarian cancer, thromboembolic events; bone fractures, cardiovascular and thromboembolic events, clinically manifested cataracts and melanoma; change of mammographic density from the start of treatment up to at least 16 years from treatment initiation.

Blood concentrations of metabolites including circulating IGF-I,IGFBP-3, SHBG, hormones (testosterone, estradiol, SHBG, CRP), tamoxifen metabolites (4OH tamoxifen and endoxifen).

Esploratory analisis of some SNPS of the cytochrome P450 genes involved in tamoxifen metabolism such as CYP2D6.

Associazione Italiana per la Ricerca sul Cancro

European Institute of Oncology

Andrea DeCensi

Medical Oncology Director

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Neoplasms, Squamous Cell

* FDG-PET-scan in treatment mask for radiotherapy planning
* Accelerated radiotherapy IMRT/VMAT with SIB (34 fraction in 5.5 weeks)

* standard elective dose
* no intermediate dose-level
* visual interpretation of FDG-PET-scan

standard dose prescription

* de-escalation of elective dose
* intermediate dose-level
* standardized methods to evaluate FDG-PET-scan

FDG-PET guided gradient dose prescription

Prof. Dr. J.H.A.M. Kaanders

The objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and introduction of an intermediate dose-level in the treatment of head and neck cancer will results in less radiation sequelae and improved quality of life after treatment whilst the recurrence rate in electively irradiated lymph nodes should not be compromised.

A summary of the study protocol can be found here: http://rdcu.be/qgMv

Uniform FDG-PET Guided Gradient Dose Prescription to Reduce Late Radiation Toxicity

Uniform FDG-PET Guided GRAdient Dose prEscription to Reduce Late Radiation Toxicity (UPGRADE-RT): a Randomised Controlled Trial With Dose Reduction to the Elective Neck in Head and Neck Squamous Cell Carcinoma

A Kaplan-Meier estimate will be calculated

UMC Utrecht

Amsterdam UMC, location VUmc

Maastro Clinic, The Netherlands

Radiotherapiegroep

Radboud University Medical Center

Digestive System Diseases

Crohn Disease

Intestinal Diseases

Inflammatory Bowel Diseases

Necrosis

Gastroenteritis

Gastrointestinal Diseases

Anti-Inflammatory Agents

Antirheumatic Agents

Antibodies

Immunoglobulins

Adalimumab

Tumor Necrosis Factor Inhibitors

Lengthening adalimumab dosing interval: The adalimumab injection interval during maintenance therapy (40 mg sc / 2 weeks) will be extended through a stepwise disease activity guided manner to 3 weeks and subsequently - after 24 weeks - to 4 weeks. If a step-down leads to recurrence of disease activity patients will return to the preceding effective dosing interval.

Standard care: patients will continue adalimumab maintenance treatment of 40mg per 2 weeks. Treatment decisions are made at the discretion of the treating physician.

Lengthening adalimumab dosing interval from 2 weeks to 3 weeks and -later- to 4 weeks.

Lengthening adalimumab dosing interval

Dr. Hoentjen, MD, PhD

Prof. dr. van der Woude, MD, PhD

Crohn's disease is a chronic inflammatory bowel disease. This disease can be treated with, among other things, biologicals such as adalimumab. Patients use adalimumab for a long time to maintain remission and to prevent relapse of the bowel inflammation. The disadvantages of this therapy are the high price and side effects (such as the higher risk of infection).

Currently, adalimumab is given every 2 weeks, by injection under the skin. The optimal time between two injections has never been investigated before. Prior research in patients with rheumatoid arthritis shows that disease remission can be maintained with longer injection-intervals. Our hypothesis is that this is the same for Crohn's disease patients. Our aim is to show non-inferiority of extending the adalimumab dosing interval, under strict disease monitoring in Crohn's disease patients in sustained (\>9 months) clinical remission, compared to standard care.

During the trial,174 patients with stable Crohn's disease will be divided into 2 groups. One group continues adalimumab injections with the same 2-week interval. And the other group will incrementally extend the interval to 4 weeks, under strict disease monitoring. If a step-down leads to recurrence of disease activity patients will return to the preceding effective dosing interval. Thus, we will investigate whether, and for whom, it is safe to extend the adalimumab injection interval.

Rationale

Adalimumab is both an effective induction and maintenance therapy for Crohn's disease (CD). Due to the risk of side effects (infections, injection reaction) and high costs, an extension of the injection interval is an attractive option. However, this strategy has not been evaluated yet in a randomized controlled trial in CD patients.

Objective

To assess non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening in CD patients in sustained (\>9 months) clinical remission, compared to standard dosing of every other week.

Study design

Multicenter, randomized controlled, open label non-inferiority trial, with two treatment arms.

Study population

Crohn's disease patients, in sustained clinical remission on adalimumab maintenance therapy.

Intervention

Intervention arm: The adalimumab injection interval during maintenance therapy (40 mg per 2 weeks) will be extended through a stepwise disease activity guided manner to 3 weeks and subsequently - after 24 weeks - to 4 weeks. If a step-down leads to recurrence of disease activity patients will return to the preceding effective dosing interval.

Control arm: patients will continue adalimumab maintenance treatment of 40mg per 2 weeks. Treatment decisions are made at the discretion of the treating physician.

Main study parameters/endpoints

Primary outcome: Cumulative incidence of persistent disease flares in 48 weeks of follow-up. A persistent flare is defined as two of three of the following criteria persisting for \> 8 weeks, despite dose escalation of adalimumab; FC \>250 µg/g, CRP≥10 mg/L, HBI ≥5. Non-inferiority is reached if the difference in cumulative incidence of persistent flares not exceeds the non-inferiority margin of 15%.

Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness.

Multicenter, randomized controlled, open label non-inferiority trial

Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients

A persistent flare is defined as two of three of the following criteria persisting for \> 8 weeks, despite dose escalation of adalimumab; FC \>250 µg/g, CRP≥10 mg/L, HBI ≥5. Non-inferiority is reached if the difference in cumulative incidence of persistent flares not exceeds the non-inferiority margin of 15%.

A transient flare is defined as two of three of the following criteria persisting for ≤ 8 weeks; FC \>250 µg/g, CRP≥10 mg/L, HBI ≥5.

(Serious) adverse events that are (possibly) related to adalimumab and the (Serious) adverse events that are (possibly) related to adalimumab interval lengthening in the intervention and control group, expressed as events/ 100 patient-years of follow-up.

Adalimumab drug levels at baseline measured by ELISA.

Fecal calprotectin (mg/kg) or C-reactive protein (mg/L).

Co-medication includes azathioprine, Co-medication includes azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate.

Dividing the difference in costs (based on medical consumption (by medical consumption questionnaire(MCQ)) and work productivity (by productivity cost questionnaire(PCQ))) by the difference in quality-adjusted life years (based on EuroQol-5D questionnaire).

Erasmus Medical Center

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Infections

Uterine Cervical Neoplasms

Papilloma

Virus Diseases

Vaccines

Immunologic Factors

3 doses of bivalent HPV vaccine (Cervarix) given at M0, M1 and M6

2 doses of bivalent HPV vaccine (Cervarix) given at M0 and M6

1 dose of bivalent HPV vaccine (Cervarix) given at M0

3 doses of nonavalent HPV vaccine (Gardasil9) given at M0, M2 and M6

2 doses of nonavalent HPV vaccine (Gardasil9) given at M0 and M6

1 dose of nonavalent HPV vaccine (Gardasil9) given at M0

head to head comparisons of different dose schedules and HPV vaccine types

bivalent HPV vaccine

nonavalent HPV vaccine

Deborah Watson-Jones, Dr

Cervical cancer is the most common cancer in women aged 15-44 years in East Africa, and mortality rates are very high. HPV vaccines are most effective if given to girls who have not yet acquired HPV infection. In Tanzania, HPV vaccine has been shown to be safe, acceptable and can be delivered with high coverage (\~80%). However, the cost of delivering HPV vaccine is considerably higher than costs for traditional infant/child vaccinations. This is primarily because of costs to establish outreach programmes and associated personnel costs including nurses who must spend significant time away from their posts to deliver vaccine, especially if multiple doses are needed. There is global interest in simplifying HPV vaccine delivery by reducing the number of doses. If a single dose could be given, this could halve the costs of delivery, making it more accessible to the populations that need it most. Recently, the WHO recommended that 2 doses of HPV vaccine could be given to young girls, based on studies in high and upper middle-income countries. However in Africa high rates of infections like malaria and worms can affect immune responses to vaccines. It is essential to know that reducing the number of doses does not reduce the protective immune response of these vaccines. The investigators are conducting a trial in Tanzanian girls aged 9-14 years to establish whether a single dose of HPV vaccine produces immune responses that are likely to be effective in preventing cervical cancer. Two different HPV vaccines, the bivalent (2-v) vaccine that protects against HPV 16/18 (the cause of 70% of cancers) and the 9-valent (9-v) vaccine that protects against 9 HPV types, will be compared. The trial will randomise 900 girls to 6 arms and follow them for 36 months. Girls will receive the 2-v or the 9-v HPV vaccine, as 1, 2 or 3 doses. Girls receiving 1 or 2 doses will be compared with those receiving 3 doses of the same vaccine, to ensure that the reduced dose regimen produces an immune response that is not inferior to 3 doses. Girls in the 1 and 2 dose arms will be enrolled in an extension and followed for up to 9 years, to examine the stability of immune responses. The immune responses in this study will also be compared with results from other countries where the vaccine has been shown to be protective. This will provide information about whether a reduced number of doses is likely to be protective in Africa. This work will be extremely important in informing future HPV vaccination strategies and will be one of the first randomised trials of 1 and 2 doses of any HPV vaccine in Africa.

Human papillomavirus (HPV) infection is the primary cause of cervical cancer, a major public health problem in Africa. Currently there are three vaccines (Cervarix, Gardasil® and Gardasil-9®) that offer excellent protection against HPV infection with vaccine-related HPV genotypes. The objective of this trial is to demonstrate non-inferiority of immune responses with 1 dose of HPV vaccine compared with the recommended 2 or 3 doses of the same vaccine by evaluating HPV 16/18-specific seropositivity, antibody avidity and memory B cell responses at M36. Specifically, the investigators will determine whether a single dose of the 2-valent HPV vaccine (Cervarix, that protects against HPV 16/18 genotypes) or of a new 9-valent HPV vaccine (Gardasil-9,that protects against HPV 6/11/16/18/31/33/45/52/58) produces immune responses that are non-inferior to those observed with 3 doses of vaccine when given to HIV-negative 9-14 years old girls in a malaria-endemic region of Tanzania.

The trial will also determine whether the World Health Organization's (WHO) recently recommended 2 dose strategy for girls aged under 15 years produces similar immune responses in Sub-Saharan Africa (SSA) compared to the previously recommended 3 dose schedule. In addition, the cost-effectiveness of alternative dosing schedules and of the two vaccines will be explored.

The trial will enrol 900 girls who are resident in Mwanza into an un-blinded, individually-randomised trial with 6 arms. Arm A will comprise participants randomised to receive 3 doses of the 2-valent vaccine, Arm B those randomised to receive 2 doses of the 2-valent vaccine and Arm C those randomised to receive 1 dose of the 2-valent vaccine. Arms D, E and F will be those participants randomised to receive 3, 2 or 1 dose of the 9-valent vaccine, respectively.

The effect of different dose schedules and type of HPV vaccine on a range of immune responses will be measured up to 36 months after the first dose. In a trial extension that will extend follow-up, we will also determine whether the one dose schedule of these vaccines produces non-inferior immune responses to the recommended two dose schedule for up to 108 months, and examine the long-term stability of the immune responses to 9 years after the first dose.

The protocol will be harmonised, and laboratory procedures and immunological endpoints will be cross-validated, with those of a large HPV vaccine dose-reduction efficacy trial being planned by the NIH in Costa Rica to examine the protective effect of the same vaccines given as 1 or 2 doses. This trial will allow the examination of quality and durability of antibody responses, and safety and cost-effectiveness of reduced dose schedules compared to the originally recommended 3 dose schedule in a population with high burden of malaria and other infections that may affect vaccine immune responses.

A Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls

Proportion with HPV 16/18-specific seropositivity

HPV 16/18-specific seropositivity and antibody GMT

HPV 16/18-specific antibody avidity and memory B cell responses

HPV 6/11/31/33/45/52/58-specific antibody seropositivity

HPV 6/11/31/33/45/52/58-specific antibody GMT

incremental financial and economic costs of vaccination, using WHO costing tool

estimates of costs and effects of vaccination will be integrated into an existing HPV cost-effectiveness model (WHO CHOICE)

solicited adverse events considered to have a reasonable possibility of having been contributed to by the vaccine

unsolicited adverse events considered to have a reasonable possibility of having been contributed to by the vaccine

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up	NCT01357772	Carcinoma, Intr... Recurrence, Loc... Breast Neoplasm... Atypical Hyperp...	Tamoxifen placebo	18 Years - 75 Years	Ente Ospedaliero Ospedali Galliera
Uniform FDG-PET Guided Gradient Dose Prescription to Reduce Late Radiation Toxicity	NCT02442375	Head and Neck N... Carcinoma, Squa...	standard dose p... FDG-PET guided ...	18 Years - 80 Years	Radboud University Medical Center
Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients	NCT03172377	Crohn Disease i... Crohn Disease	Lengthening ada...	18 Years -	Radboud University Medical Center
Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up	NCT01357772	Carcinoma, Intr... Recurrence, Loc... Breast Neoplasm... Atypical Hyperp...	Tamoxifen placebo	18 Years - 75 Years	Ente Ospedaliero Ospedali Galliera
A Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls	NCT02834637	Human Papilloma...	bivalent HPV va... nonavalent HPV ...	9 Years - 14 Years	London School of Hygiene and Tropical Medicine
Uniform FDG-PET Guided Gradient Dose Prescription to Reduce Late Radiation Toxicity	NCT02442375	Head and Neck N... Carcinoma, Squa...	standard dose p... FDG-PET guided ...	18 Years - 80 Years	Radboud University Medical Center

Spots Global Cancer Trial Database for dose reduction