Symptoms and General Pathology

All Conditions

Neoplasms

Digestive System Diseases

Skin and Connective Tissue Diseases

Behaviors and Mental Disorders

Rare Diseases

Recurrence

Neoplasm Metastasis

Gastrointestinal Stromal Tumors

Disease Attributes

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Quality of Life

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Tyrosine Kinase Inhibitors

Imatinib Mesylate

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Maintenance of Imatinib at the last dose routinely taken by the patient in the 3 years period prior to randomization (either 300 or 400 mg/day). Increase dose up to 800 mg/day if relapse according to RECIST 1.1 criteria. Any relapse/progressive disease at 800 mg/day will lead to Imatinib permanent discontinuation and study discontinuation. In case of toxicity, Imatinib dose will be interrupted or adjusted in accordance with Imatinib Specific Product Characteristics (SPC).

Treatment corresponding to standard practice : interruption of Imatinib from the day of randomization. Reintroduction of Imatinib at 400 mg/day after first relapse according to RECIST 1.1 criteria; Then increase dose to 800 mg/day after 2d relapse. Any relapse/progressive disease at 800 mg/day will lead to Imatinib permanent discontinuation and study discontinuation. In case of toxicity, Imatinib dose will be interrupted or adjusted in accordance with Imatinib SPC.

Either 300 or 400 mg/day in accordance with the last dose routinely taken by the patient in the 3-year period before randomization. The treatment will be orally taken at time of meal with a large glass of water

Imatinib maintenance

Jean-Yves Blay, Pr

This is a 2 arms study concerning patients with primary GIST who followed an Imatinib adjuvant treatment for 3 years after surgery and who have a high risk of recurrence.

In the first arm, patients will continue Imatinib treatment for 3 more years, allowing to determine if the continuation of this treatment is efficient for disease control, in terms of Disease Free Survival improvement.

In the second arm, patients will discontinue the Imatinib treatment, as standard practice. This arm will allow to determine if the re-introduction of Imatinib at relapse is still an efficient treatment for the control of disease.

Gastrointestinal stromal tumours (GISTs) are rare mesenchymal neoplasms, mostly diagnosed between 55 and 60 years of age, which account for 5% of all sarcomas. Worldwide annual incidence is approximately 12 cases per million people, corresponding to approximately 800 new cases per year in France.

A large majority of GISTs harbour activating mutations in the proto-oncogenes KIT and/or PDGFRA, both coding cell-surface cytokine receptors with tyrosine-protein kinase activity.

Imatinib mesilate (Glivec®, Novartis Pharma SAS) is a selective tyrosine kinase inhibitor, leading to inhibition of KIT and PDGFRA signalling pathways. The introduction of imatinib has revolutionised the therapeutic management of GIST patients and has provided an unprecedented demonstration of the clinical benefit of a targeted therapy for patients with advanced/metastatic solid tumors. First results from prospective trials conducted with imatinib in GIST patients have demonstrated a 300% increase in median overall survival, and a likely 100% increase in 5 and 10-year survival as compared to cytotoxic chemotherapy.

The successful use of imatinib in the treatment of advanced GISTs and the significant risk of recurrence of advanced GISTs have prompted the investigation of the clinical benefit of imatinib as a post-operative adjuvant therapy. Two prospective randomized Phase III trials have demonstrated that adjuvant imatinib treatment significantly prolong overall survival (OS) and recurrence-free survival (RFS) when given for 3 years. To date, imatinib is also indicated in the adjuvant setting after complete resection of primary, localized, KIT-positive GIST at high risk of recurrence. However, the optimal treatment duration remains unclear and it should be determined whether

1. prolonged use of adjuvant imatinib beyond 3 years may enable to reduce the risk of GIST recurrence and to improve overall survival, and
2. imatinib rechallenge is efficient for treating recurrence after completion of 3-year adjuvant imatinib therapy.

This trial is an open-label, randomized, multicenter phase III study aiming to determine the clinical impact of maintaining imatinib treatment beyond 3 years in the adjuvant setting for patients with resected GISTs at high risk of recurrence according to the National Comprehensive Cancer Network Task Force on GIST (NCCN) risk classification.

Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)

A Randomized Multicenter Phase III Trial Evaluating the Interest of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)

Time from the date of randomisation to the first documented relapse or death due to any cause. Patients with no event at the time of analysis will be censored at the date of the last adequate tumour assessment. The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.

Time from the date of randomization until the date of death due to any cause and censored at the date of last contact for patients alive at last contact. The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.

Time from the date of randomization until the date of first relapse under Imatinib treatment (i.e first relapse in the "Imatinib maintenance arm" and relapse after reintroduction of Imatinib in the "Interruption of Imatinib arm"). The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.

Percentage of patients in Complete Response (CR) after reintroduction of Imatinib treatment for patients assigned to the interruption arm and who experience GIST recurrence. CR is assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

The assessment of safety will be based mainly on the frequency of AE based on the Common Toxicity Criteria version 4 grade. AE will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. Patients with at least either one serious AE, or one grade 3-4, or one AE requiring the interruption of study treatment, will be described by study arm and compared using a Pearson's Chi2 test or a Fisher's exact test, if adequate. Patients will be analyzed according the duration of exposure to imatinib

QoL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire (QLQ-C30). Descriptive statistics (e.g. means and medians) will be used to summarize the scored scales at it scheduled assessment time point of the questionnaire. The distribution of time to definitive health-related QoL deterioration by study arms will be estimated using the Kaplan-Meier method. The time to definitive deterioration is defined as the time from the date of randomization to the date of event, wich is defined as \> 10 points decrease from baseline of QLQ-C30 global score (items 29 and 30) or death due to any cause. If patient has not had an event, time to QoL deterioration will be censored at the date of last adequate evaluation.

Centre Leon Berard

Blood and Lymph Conditions

Immune System Diseases

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Anti-Infective Agents

Peposertib

Trichostatin A

Participants received MSC2490484A capsules 100 milligram (mg) orally, once daily (QD) from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.

Participants received MSC2490484A capsules 200 mg orally, QD from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.

Participants received MSC2490484A capsules 150 mg orally, twice daily (BID) from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.

Participants received MSC2490484A capsules 200 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.

Participants received MSC2490484A capsules 300 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.

Participants received MSC2490484A capsules 400 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.

Participants received MSC2490484A capsules 400 mg recommended Phase II dose (RP2D) orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.

Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.

MSC2490484A (M3814)

Medical Responsible

MSC2490484A is an investigational drug that is being evaluated for the treatment of subjects with advanced solid tumors or chronic lymphocytic leukemia (CLL) that likely differs from other cancers in how it repairs damaged DNA (genetic material). This is a first-in-man Phase I study, which means that it is the first time the study drug is being used in humans. The main purpose is to determine the highest dose that does not cause unacceptable side effects. The second is to determine the appropriate dose to use in future research for subjects with cancer. Othergoals of the study are to learn about the drug's safety and side effects, how it affects the tumor, and how the body processes the drug.

This is a Phase I, first-in-human, open-label, dose escalation, and dose expansion trial designed to explore the safety, tolerability, PK and PD profiles, and clinical activity of MSC2490484A administered daily as a single agent to subjects with advanced solid tumors or CLL likely to have alterations in DNA repair mechanisms.

Dose Escalation : Subjects will receive MSC2490484A continuously at the starting dose of 100 mg once daily. Sequential treatment cohorts will receive ascending doses of MSC2490484A once daily or twice daily (if determined to be appropriate by the Safety Monitoring Committee \[SMC\]) following a standard "3+3" design. The SMC will make dose escalation decisions based on review of available safety, tolerability, Pharmacokinetic (PK), and Pharmacodynamic (PD) data. Once the maximum tolerated dose (MTD) has been established, an Recommended Phase II Dose (RP2D) will be defined by the SMC, either at the MTD level or another dose level, depending on the available data on safety, efficacy, PK, and PD observed in the trial. The SMC may decide to stop dose escalation at any time during the trial.

Up to 12 subjects will be enrolled at the RP2D/Optimal biologic dose (OBD) to confirm safety and tolerability and explore the PK and PD profile of MSC2490484A.

Expansion cohorts: Once subjects have been evaluated at the RP2D, additional subjects will be enrolled into 2 or more expansion cohorts (20 evaluable subjects per expansion cohort) to evaluate clinical efficacy in tumors likely to have alterations in the DNA repair mechanism (eg, CLL and other tumor types). Subjects are evaluable for efficacy if they have received at least 1 dose of study drug and have radiographic baseline. Subjects who are not evaluable for efficacy will be replaced.

Clinical Phase I Study Investigating MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Advanced Solid Tumors or Chronic Lymphocytic Leukemia

A Multicenter, Open-Label, Dose-Escalating Phase I Trial of the DNA-PK Inhibitor MSC2490484A in Subjects With Advanced Solid Tumors or Chronic Lymphocytic Leukemia

Merck KGaA, Darmstadt, Germany

Breast Neoplasms

Hormones

Fulvestrant

Postmenopausal women with locally advanced or metastatic breast cancer who have failed 2 or more prior hormone therapies, or were intolerant to prior hormone therapy and have no endocrine therapeutic options.

This PMS aims to assess the efficacy, the safety and tolerability profile of Faslodex in everyday practice. Secondary objective of this PMS is to identify the frequency of serious adverse events or any unknown adverse events of Faslodex.

Faslodex Post Marketing Surveillance

AstraZeneca

Carcinoma

Carcinoma, Squamous Cell

Disease Progression

Neoplasms, Glandular and Epithelial

Neoplasms, Squamous Cell

Penile Cancer

Paclitaxel

Cetuximab

Albumin-Bound Paclitaxel

Cisplatin

Ifosfamide

Isophosphamide mustard

Antineoplastic Agents, Immunological

"Reference" arm; Patients will be treated with 6 cycles of Paclitaxel + Ifosfamide + Cisplatin (TIP treatment)

"Experimental" arm: Patients will be treated with 6 cycles of Paclitaxel + Ifosfamide + Cisplatin (TIP treatment) and weekly infusion of Cetuximab.

Cetuximab treatment will be administered on specific days within a 21-days-cycle and for a maximum of 6 cycles as follow :

CETUXIMAB I.V infusion of 400 mg/m2 on cycle 1 Day 0 for 2 hours, then 250 mg/m2 for subsequent infusions for 1 hour on Day 8, Day 15 and next cycles Day1, Day8, Day15.

In case of documented toxicities, 2 drugs doses reductions are allowed according specific algorithms indicated in protocol

The TIP combination of treatments will be administered on specific days within a 21-days-cycle and for a maximum of 6 cycles as follow :

PACLITAXEL I.V infusion of 175 mg/m2, for 3 hours, on Day 1 of the cycle.

IFOSFAMIDE I.V infusion of 1200 mg/m2, for 2 hours, on Day 1, Day 2, Day 3 of the cycle.

CISPLATINE I.V infusion of 25 mg/m2, for 1 hour, on Day 1, Day 2, Day 3.

In case of documented toxicities, 2 drugs doses reductions are allowed according specific algorithms indicated in protocol

Helen BOYLE, Doctor

The purpose of this study is to evaluate the efficacy and safety of Cetuximab in metastatic penile carcinoma

Penile carcinoma is a rare cancer type, particularly in our industrialized countries. Incidence is not well established but is estimated around 26000 annual new cases all around the world \[1\]. We don't have accurate estimation for France but regarding data from the literature, incidence rates in developed countries vary from 0.7 to 1.0/100000 men \[2\]. The mean age at diagnosis is about 60 years \[3\].

Different causes have been identified like history of Human PapillomaVirus (essentially HPV16), phymosis, absence of circumcision, tobacco use, and history of condyloma \[1\]. In addition, a lot of molecular genetic alterations are also responsible for penile cancer occurrence and development \[4\].

Histologically, most of these tumors are epidermoid cancers. Tumor spreads into inguinal lymphnodes, then into pelvic lymphnodes. Then retroperitoneal lymphnodes are involves before metastatic dissemination, often in lungs, liver and bones.

According to the French urology recommendations, treatment of localized penis cancer should be conservative, as far as possible \[5\]; Even if local recurrences rate varies from 15% to 30% of patients, no reduction of overall survival is observed in these patients \[7\].

The investigations regarding involvement of inguinal lymphnodes and distant organs are a key-point. Among the 10% of patients with loco regional recurrence \[6\], lymphadenectomy should be preferred to chemotherapy which should be recommended for metastatic patients or unresectable patients with regional lymphnodes involvement \[5\].

Numbers of treatments (monotherapy or associations) have been tested in penis cancer but the rarity of these tumors is a major obstacle to clinical research, due to small samples of patients. The best results seem to be obtained with platinum-based treatments (ORR up to 32.5% with a combination of cisplatin, methotrexate and bleomycine) \[8\] \[9\], but even if response rates are very promising, overall survival is still very short (median OS = 28 weeks) and treatment-related toxicities can be very important, even lethal \[9\].

The histological type of squamous cells carcinoma, which is the large majority of penile cancer, led Pagliaro et al. \[10\] to explore a combination of Paclitaxel, Ifosfamide and Cisplatin (TIP) as neoadjuvant treatment of locally advanced penile tumors. This association of chemotherapy agents had previously proven its efficacy in squamous cell carcinoma of the head and neck. Even if this study included a small number of patients (N=30) with penile carcinoma, it showed very promising results on primary objective (objective response rate = 50% with 10% of complete responses).

Despite these results and all previous researches, no chemotherapy agent has been submitted to health authority's approval in France. It results that there is no market approval for treatment of metastatic penile carcinoma.

However, based on the results of Pagliaro et al., the TIP is now considered by the French physicians as the recommended standard of care for patients with metastatic penile carcinoma \[5\].

From a biological point of view, Epidermal Growth Factor Receptor (EGFR) and K-ras status have been widely explored in the past few years in penile carcinoma.

EGFR seem to present high expression levels in such tumors, whatever the stage of disease. Among 17 patients studied by Lavens et al., expression of EGFR was 3+ (which is the highest grade of expression) in 14 cases and 2+ in 3 cases \[11\].

Andersson et al. analyzed 28 penis tumors and found a somatic mutation in 39% (n=11). Mutations have been detected in the following genes: PIK3CA (29%), HRAS (7%) and K-ras (3%) \[12\].

Dorff et al. studied EGFR expression and K-ras status in 28 other penile carcinomas. They noted an over expression of EGFR in all the samples but didn't find any K-ras mutation \[13\] while Valverde et al. found 22% of K-ras muted carcinomas (N=28) \[14\].

When present, K-ras mutations have been identified on exon 2 (codons 12 and 13) but rarely on exon 3 (codon 61). Mutational status can be easily explored by Polymerase Chain Reaction amplification.

EGFR expression seems to be correlated with differentiation grade while K-ras mutation seems to be correlated to the stage of disease \[13\] \[14\].

Cetuximab is a human/mouse chimeric monoclonal antibody. It has a specific and competitive binding to the extracellular domain of EGFR, leading to inactivation of self-phosphorylation of the receptor and inhibition of all the following intracellular signal chains. This has an antiproliferative effect on cancer cells, inhibits angiogenesis, reduces cells mobility and restores apoptosis.

Cetuximab has been widely studied in cancers with overexpression of Epidermal Growth Factor Receptors (EGFR), in particular in squamous cancers of head and neck \[15\], colorectal \[16\] and lung cancers \[17\].

Phases I studies showed that a dose in the range of 200mg/m² to 400mg/m² led to a good EGF receptor saturation \[18\]. Association of Cetuximab and radiation therapy showed an improvement on overall survival in patients with locally advanced head and neck cancers (median overall survival = 49 months versus 29 months in the radiotherapy-alone group) \[19\].

Cetuximab has also been associated to platinum-based chemotherapies (Cisplatin or Carboplatin) and 5-Fluorouracile in patients with head and neck cancer. Median overall survival was significantly better on the group of patients with Cetuximab (10.1 months vs 7.4 months; p=0.04). However, 82% of patients with Cetuximab experienced Commom Terminology Criteria for Adverse Event (CTCAE) grade 3/4 toxicities versus 76% in the other group \[20\].

Adverse events commonly noted with Cetuximab are cutaneous events, hypomagnesaemia, infection and grade 3/4 anorexia.

Cetuximab has also been studied as monotherapy in head and neck patients with responses rate of 13% and disease control rate of 46%. Cutaneous events were still the main toxicities \[21\].

One preliminary experience has been conducted in a patient with penile carcinoma, treated with an association of a taxane (Docetaxel) and Cetuximab. This treatment led to imaging and clinical signs of efficacy (decrease of 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (18-FDG) uptake, necrosis of metastatic mass, improvement of pain and performance status). The tolerance profile has been characterized by neutropenia and mild skin toxicity \[22\].

Another key-point is that the efficacy of Cetuximab is closely related to the presence of mutation on the gene coding for K-ras. Van Cutsem et al. showed that patients with wild-type K-ras colorectal cancers are much better responders to Cetuximab than patients with mutation \[23\].

K-ras mutation leads to a constitutive activation of the Ras pathway independently and can bypass the EGFR-driven signaling cascade and impair the clinical efficacy of EGFR.

K-ras status should always be determined before Cetuximab initiation and it would be interesting to know EGFR expression rates in order to correlate with responses to Cetuximab.

Finally, immunogenicity is a class effect of monoclonal chimeric antibodies; the incidence of Human Anti-Chimeric Antibodies (HACA) formation has been observed around 3.7% of patients treated with cetuximab. However, no apparent effect on the safety or antitumor activity of cetuximab has been observed in these patients \[Summary of Product Characteristics of Cetuximab\].

Given the fact that,

* the association of Paclitaxel, Ifosfamide and Cisplatin is efficient for the treatment of metastatic penile carcinoma and considered as the new "standard" of care in France,
* squamous cell carcinoma of the penis expresses EGF receptor,
* cetuximab has anti-tumor properties in EGF mediated cancers,
* response rates to cetuximab is much better in patient with wild-type K-ras,

We postulate that:

- the combination of Paclitaxel, Ifosfamide, Cisplatin with Cetuximab, will enable to provide a better Objective Response Rate (ORR) than the same combination used without Cetuximab.

As promising results obtained by Pagliaro are not resulting from a comparative phase III with a reference treatment, it cannot be considered as a validated new standard of care.

The proposed Phase 2 study will explore the optimal way to treat patients with metastatic penile carcinoma between two experimental schemes using a Simon's selection "pick the winner" randomized design.

Efficacy and Safety of Cetuximab in Metastatic Penile Carcinoma (PENILANE)

A Randomized Phase II Study to Evaluate the Efficacy and Safety of Cetuximab in Metastatic Penile Carcinoma

Patients will be treated by TIP +/- Cetuximab for 1 cycle of 21 days. Subsequent treatment cycles will be performed only if patients meet correct biological analyses as defined by protocol, with a maximum of 5 more cycles of 21 days. Thus, the treatment duration will vary between patients from 3 weeks to 18 weeks. The treatment efficacy will be evaluated 28 days after the day 1 of the last cycle administered. Thus ORR will be evaluated between 4 weeks to 20 weeks after randomization, according to the amount of administered cycles.

ORR is defined as the proportion of patients with best response consisting in a Complete Response (CR) or a Partial Response (PR) from the date of randomization to the date of the end of treatment visit (i.e 6 cycles of treatment as maximum) evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Safety profile is assessed throughout the study by incidence and intensity of Adverse Events displayed by patients using the CTCAE version 4.0

OS is defined as the time from the date of randomization to the date of death due to any cause. If a patient is not known to have died at the time of the analysis, OS will be censored at the date of last contact.

PFS is defined as the time from the date of randomization to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event at the time of the analysis, PFS will be censored at the date of last adequate tumor assessment.

Quality of life is assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30. It will be evaluated at Screening, at the beginning of cycle 4, and at the end of treatment i.e after 6 cycles maximum

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)	NCT02260505	Gastrointestina... Resected Gastro... Non-metastatic High Risk of Re... KIT Gene Mutati...	Imatinib mainte...	18 Years -	Centre Leon Berard
Clinical Phase I Study Investigating MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Advanced Solid Tumors or Chronic Lymphocytic Leukemia	NCT02316197	Advanced Solid ... Chronic Lymphoc...	MSC2490484A (M3...	18 Years -	Merck KGaA, Darmstadt, Germany
Faslodex Post Marketing Surveillance	NCT00860561	Breast Cancer		-	AstraZeneca
Faslodex Post Marketing Surveillance	NCT00860561	Breast Cancer		-	AstraZeneca
Efficacy and Safety of Cetuximab in Metastatic Penile Carcinoma (PENILANE)	NCT02014831	Squamous Cell C...	Cetuximab TIP	18 Years -	Centre Leon Berard

Spots Global Cancer Trial Database for safety profile