Neoplasms

All Conditions

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Carboplatin

Pembrolizumab

Docetaxel

Fluorouracil

Cisplatin

docetaxel (T), cisplatin (P), 5 Fluorouracil (F) and pembrolizumab every 21 days followed by radiotherapy (RT) combined with carboplatin

Combination drugs : docetaxel (T), cisplatin (P), 5 Fluorouracil (F) and pembrolizumab every 21 days

TPF2

Radiotherapy (RT) combined with carboplatin

Radiotherapy with carboplatin

Chrisine LOVERA

Non-randomized phase I/II, open-labeled clinical study, 1-arm, multicenter, of docetaxel (T), cisplatin (P), 5-fluorouracil (F) and pembrolizumab every 21 days for 3 cycles followed by radiotherapy (RT) combined with carboplatin in untreated unresectable locally-advanced Head and Neck Squamous Cell Carcinoma (HNSCC).

The TPF and pembrolizumab combination will be called TP²F.

The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid tumors.

The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4, which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of murine PD-1 has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail, which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from, that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic cells (various tumor cells and stromal cells) as well as hematopoetic myeloid cells (dendritic cells and macrophages...). Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention.

Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

Fluorouracil (F) and pembrolizumab every 21 days followed by radiotherapy (RT) combined with carboplatin in untreated unresectable locally-advanced Head and Neck Squamous Cell Carcinoma (HNSCC).

Pembrolizumab and Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma (PICH Study)

Induction Therapy With Docetaxel, Cisplatin, 5-Fluoro Uracil and Pembrolizumab in Untreated Locally-advanced Unresectable Squamous Cell Head and Neck Carcinoma (Pembrolizumab and Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma. PICH Study)

To evaluate by using a "3+3 modified schedule" the Recommended Phase 2 Dose (RPD2), Dose Limiting Toxicities (DLT) and Maximal Tolerated Dose (MTD) of the association of pembrolizumab with induction therapy by docetaxel, cisplatin and 5-fluorouracil (TP²F) as first-line treatment for patients with locally-advanced unresectable HNSCC

Progression-free survival : To evaluate, in terms of progression-free survival rate at 12 months, the efficacy of the association of pembrolizumab with induction therapy by docetaxel, cisplatin and 5-fluorouracil (TP²F) as first-line treatment for patients with locally-advanced unresectable HNSCC ; in order to demonstrate that the addition of pembrolizumab to TPF can increase efficacy without increasing toxicity.

To document any antitumor activity observed with pembrolizumab in combination with docetaxel, cisplatin and 5 Fluorouracil

Overall survival rate at 2 years. It will be calculated from the date of study inclusion to the date of the event or to the last known contact of the patient, for those still event free at the time of the last follow-up until 24 months post treatment.

Best overall response rate after induction chemotherapy : Partial Response or Complete Response or Stable Disease after induction chemotherapy (qualitative data)

Best overall response rate after radiation therapy: Partial Response or Complete Response or Stable Disease after radiation therapy (qualitative data)

Objective response rate (ORR) will be determinated by evaluation of Complete Response (CR) and Partial Response (PR)

Progression-free survival (PFS) is defined by disease recurrence. It will be calculated from the date of study inclusion to the date of the event or to the last known contact of the patient, for those still event free at the time of the last follow-up until 12 months after the treatment.

Level of expression of PD1 will be determinated by using quantitative and qualitative data before and after treatment

Toxicity will be evaluated according to NCI-CTCAE v4.03

GORTEC

GERCOR - Multidisciplinary Oncology Cooperative Group

Centre Antoine Lacassagne

Nervous System Diseases

Symptoms and General Pathology

Rare Diseases

Brain Neoplasms

Disease Progression

Genetic Predisposition to Disease

Medulloblastoma

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Disease Susceptibility

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Brain Tumor, Childhood

Neuroepithelioma

Antirheumatic Agents

Micronutrients

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Leucovorin

Vincristine

Lomustine

Vinblastine

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Tubulin Modulators

Antimitotic Agents

Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks.

Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy.

Total treatment duration is 48 weeks.

Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age.

Total treatment duration is 39 to 48 weeks.

Reduced chemotherapy with Doxorubicin, VCR, HD-MTX, Carboplatin, and MTX intraventricularly Stratification of radiotherapy according to

* presence of metastasis
* germline mutation in TP53 (including mosaicism) Maintenance chemotherapy with VBL Total treatment duration is 1 year

Brain - 23.40 Gy in 13 daily fractions of 1.80 Gy Spine - 23.40 Gy in 13 daily fractions of 1.80 Gy Primary tumour boost - 30.60 Gy in 17 daily fractions of 1.80 Gy Total dose - 54 Gy Duration of radiotherapy 6 weeks

LR Arm after Amendment (Protocol version 11- 17 Nov 2014):

Brain - 18.0 Gy in 10 daily fractions of 1.80 Gy Spine - 18.0 Gy in 10 daily fractions of 1.80 Gy Primary tumour boost - 36.0 Gy in 20 daily fractions of 1.80 Gy Total dose - 54 Gy Duration of radiotherapy 6 weeks

Radiotherapy without Carboplatin

Starts 6 weeks after radiotherapy. 6 cycles alternating Regimen A and Regimen B. Regimen A (cycles 1, 3, 5): cisplatin 70 mg/m2 day 1, CCNU 75 mg/m2 day 1, vincristine 1.5 mg/m2 days 1, 8 and 15, Regimen B: (cycles 2, 4, 6): cyclophosphamide 1 x 1000 mg/m2 days 1-2, vincristine 1.5 mg/m2 day 1.

Interval after cycle A: 6 weeks, after cycle B: 3 weeks, for a total duration of 27 weeks.

Cumulative doses of chemotherapy drugs: cisplatin 210 mg/m2, lomustine (CCNU) 225 mg/m2, vincristine 18 mg/m2, cyclophosphamide 6 g/m2.

Reduced-intensity maintenance chemotherapy

Brain - 23.40 Gy in 13 daily fractions of 1.80 Gy Spine - 23.40 Gy in 13 daily fractions of 1.80 Gy Primary tumour boost - 30.60 Gy in 17 daily fractions of 1.80 Gy Total dose - 54 G Carboplatin 35 mg/m2 5 times/week.

Radiotherapy with Carboplatin

Starts 6 weeks after radiotherapy. 8 cycles alternating Regimen A and Regimen B. Regimen A (cycles 1, 3, 5, 7): cisplatin 70 mg/m2 day 1, CCNU 75 mg/m2 day 1, vincristine 1.5 mg/m2 days 1, 8 and 15 Regimen B: (cycles 2, 4, 6, 8): cyclophosphamide 1 x 1000 mg/m2 days 1-2, vincristine 1.5 mg/m2 day 1.

Interval after cycle A: 6 weeks, after cycle B: 3 weeks. Duration 36 weeks. Cumulative doses of chemotherapy drugs: cisplatin 280 mg/m2, lomustine (CCNU) 300 mg/m2, vincristine 24 mg/m2, cyclophosphamide 8 g/m2, carboplatin 1050 mg/m2 (in randomized patients).

Maintenance chemotherapy

Brain - 23.4 Gy in 13 daily fractions of 1.8 Gy Spine - 23.4 Gy in 13 daily fractions of 1.8 Gy Primary tumour boost - 30.6 Gy in 17 daily fractions of 1.8 Gy Boost to macroscopic metastases - 21.6 Gy in 12 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy

WNT-HR < 16 years

Brain - 36.0 Gy in 20 daily fractions of 1.8 Gy Spine - 36.0 Gy in 20 daily fractions of 1.8 Gy Primary tumour boost - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (cranial) - 14.4 Gy in 8 daily fractions of 1.8 Gy Metastases boost (spinal) - 9.0 Gy in 5 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 50.4 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy

WNT-HR >= 16 years

Doxorubicin 37,5mg/m² in 24h-infusion, days 1 and 2 (If administration of doxorubicin is not deemed appropriate, doxorubicin can be substituted by carboplatin 200mg/m²) VCR 1,5mg/m² (max. dose 2mg) in short infusion, days 1, 15, 29, 43 HD-MTX 5g/m²in two doses (0.5g/m² in 0.5h and 4.5g/m² in 23.5h), days 15 and 29 (+ Leucovorin) Carboplatin 200mg/m² in 1h-infusion, days 43, 44, and 45 MTX 2mg intraventricularly, days 1-4, 15, 16, 29, 30, 43-46

Induction Chemotherapy

* with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks
* clinical target volume (CTV): safety margin along typical spread 10 mm: 23.4.Gy in 13 fractions to CTV.
* focal RT boost to tumour bed and residual tumour (GTV) (boost: 30.6 Gy in 17 daily fractions of 1.8 Gy)

SHH-TP53 M0

craniospinal radiotherapy with boost to tumour bed, residual tumour and metastatic deposits with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks Brain - 23.4 Gy in 13 daily fractions of 1.8 Gy Spine - 23.4 Gy in 13 daily fractions of 1.8 Gy Primary tumour boost - 30.6 Gy in 17 daily fractions of 1.8 Gy Metastases boost (cranial) - 30.6 Gy in 17 daily fractions of 1.8 Gy Metastases boost (spinal) - 21.6 Gy in 12 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy

SHH-TP53 M+ (germline)

craniospinal radiotherapy with boost to tumour bed, residual tumour and metastatic deposits with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks Brain - 36.0 Gy in 20 daily fractions of 1.8 Gy Spine - 36.0 Gy in 20 daily fractions of 1.8 Gy Primary tumour boost - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (cranial) - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (spinal) - 9.0 Gy in 5 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45 Gy in 25 daily fractions of 1.80 Gy

SHH-TP53 (somatic)

Weekly VBL (5mg/m², max. 10mg/dose) for 24 weeks

Vinblastin Maintenance

Francois Doz, Prof. Dr.

Till Milde, Dr. med.

The study PNET 5 MB has been designed for children with medulloblastoma of standard risk (according to the risk-group definitions which have been used so far; e.g. in PNET 4). With the advent of biological parameters for stratification into clinical medulloblastoma trials, the ß-catenin status will be the only criterion according to which study patients will be assigned to either treatment arm PNET 5 MB - LR or to PNET 5 MB - SR, respectively. The initial diagnostic assessments (imaging, staging, histology, and tumor biology) required for study entry are the same for both treatment arms. With the amendment for version 12 of the protocol, patients who have a WNT-activated medulloblastoma with clinically high-risk features can be included in the PNET 5 MB WNT-HR study, and patients with a high-risk SHH medulloblastoma with TP53 mutation (both somatic or germline including mosaicism) can be included in the PNET5 MB SHH-TP53 study.

Data on patients with pathogenic germline alteration or cancer predisposition syndrome, who cannot be included in any prospective trial due to unavailability or due to physician or family decision, can be documented within the observational PNET 5 MB registry.

The aim of the LR-study is to confirm the high rate of event-free survival in patients between the ages of 3 to 5 years and less than 22, with 'standard risk' medulloblastoma with a low-risk biological profile. Patients eligible for the study will be those with non-metastatic medulloblastoma (by CSF cytology and centrally reviewed MRI imaging) at diagnosis and low-risk biological profile, defined as ß-catenin nuclear immuno-positivity by immuno-histochemistry (IHC). Patients will have undergone total or near-total tumour resection and will receive conventionally fractionated (once a day) radiotherapy with a dose of 54 Gy to the primary tumor and 18.0 Gy to the craniospinal axis. Following radiotherapy, patients will receive a reduced-intensity chemotherapy with a total of 6 cycles of chemotherapy consisting of 3 courses of cisplatin, CCNU and vincristine alternating with 3 courses of cyclophosphamide and vincristine.

The aim of the SR-study is to test whether concurrent carboplatin during radiotherapy followed by 8 cycles of maintenance chemotherapy in patients with 'standard risk' medulloblastoma with an average-risk biological profile may improve outcome. Patients eligible for the study will be those with non-metastatic medulloblastoma (by CSF cytology and centrally reviewed MRI imaging) at diagnosis and average-risk biological profile, defined as ß-catenin nuclear immuno-negativity by IHC. Patients will have undergone total or near-total tumour resection and will receive conventionally fractionated (once a day) radiotherapy with a dose of 54 Gy to the primary tumor and 23.4 Gy to the craniospinal axis. Following radiotherapy, patients will receive a modified-intensity chemotherapy with a total of 8 cycles of chemotherapy consisting of 4 courses of cisplatin, CCNU and vincristine alternating with 4 courses of cyclophosphamide and vincristine.

The primary aim of the WNT-HR study is to maintain a 3-year EFS over 80 %. The small number of patients does not allow neither conventional methods of test size and power, nor strict stopping rules. The 3-year EFS will be estimated by the Kaplan-Meier method at the end of the trial and its two-sided 95 % confidence interval will be calculated.

The primary endpoint of the SHH-TP53 study is event-free survival (EFS). The aim of the study is the comparison of EFS between patients receiving a dose reduced induction chemotherapy, radiotherapy and maintenance chemotherapy and a historic population from unpublished data.

International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

AN INTERNATIONAL PROSPECTIVE TRIAL ON MEDULLOBLASTOMA (MB) IN CHILDREN OLDER THAN 3 TO 5 YEARS WITH WNT BIOLOGICAL PROFILE (PNET 5 MB - LR and PNET 5 MB - WNT-HR), AVERAGE-RISK BIOLOGICAL PROFILE (PNET 5 MB -SR), OR TP53 MUTATION, AND REGISTRY FOR MB OCCURRING IN THE CONTEXT OF GENETIC PREDISPOSITION

Defined in 5 categorical variables:

no relapse, local relapse, distant relapse, local and distant relapse, death

measured as

1. subfertility (FSH \> 15 IU/L)
2. endocrine deficits (hormone supplementation necessary)
3. growth retardation (calculated as the difference in height standard deviation score from diagnose) 2 and 5 years after diagnosis and age of 18 years

measured on audiogram performed 2 years after diagnosis, grading according to Chang ototoxicity grading (Chang and Chinosornvatana 2010)

Measured as

1. presence, duration, and therapy of hydrocephalus symptoms (pre- and post-operatively)
2. presence of posterior fossa syndrome (cerebellar mutism survey after surgery, before radiotherapy)
3. cerebellar symptoms (brief ataxia rating scales 2 and 5 years after diagnosis and age of 18 years)
4. presence of symptoms for brain nerve dysfunction (2 and 5 years after diagnosis and age of 18 years)

measured with standardized questionnaires/ scores:

1. HUI3 (health status)
2. BRIEF (executive functions)
3. SDQ (behavioural outcome)
4. PedsQL (quality of life)
5. QLQ-C30 (quality of life)
6. MEES (neurological function, educational provision)
7. MFI (fatigue) 2 and 5 years after diagnosis and age of 18 years

measured as timely delivery of chemotherapy number of interruptions days during radiotherapy toxicities within 8 weeks after end of radiotherapy

measured by central MRI review postoperatively

measured 2 years after diagnosis grades 0, 1, 2, 3, 4

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pembrolizumab and Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma (PICH Study)	NCT03114280	Head and Neck S...	TPF2 Radiotherapy wi...	18 Years - 70 Years	Centre Antoine Lacassagne
International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma	NCT02066220	Brain Tumors	Radiotherapy wi... Reduced-intensi... Radiotherapy wi... Maintenance che... WNT-HR < 16 yea... WNT-HR >= 16 ye... Induction Chemo... SHH-TP53 M0 SHH-TP53 M+ (ge... SHH-TP53 (somat... Vinblastin Main...	3 Years - 21 Years	Universitätsklinikum Hamburg-Eppendorf

Spots Global Cancer Trial Database for radiotherapy with carboplatin