Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Dovitinib 500 mg taken orally once daily 5 days on / 2 days off, until disease progression

Patients will be treated with dovitinib (500 mg orally, once daily 5 days on/2 days off) until disease progression, intolerability, patient refusal, death or study drug discontinuation for any other reason. Dovitinib should be ingested at least 1 hour prior to a meal or at least 2 hours following a meal at approximately the same time each day.

If patients cannot tolerate the protocol-specified dosing schedule, dose reductions or treatment interruptions are permitted. When necessary, dovitinib may be reduced to 400 mg for 5 days on/2 days off. If an additional dose reduction is required, dovitinib may be reduced to 300 mg dose 5 days on/2 days off. Once dose is reduced due to an adverse event, it cannot be re-escalated. Patients are allowed only 2 dose reductions.

Dovitinib

Reuben Broom, MBChB, FRACP

The main purpose of this study is to find out how useful dovitinib is when given as the initial treatment to participants with advanced kidney cancer, that has spread to other parts of the body. The usefulness of dovitinib will be assessed by: how long the disease is controlled while participants are receiving the drug, the proportion of participants who get a reduction in the size of their tumours and how long participants live (both while on dovitinib and on any subsequent therapy they may receive).

If participants have secondary disease in the bones, the study will evaluate how useful dovitinib is in controlling this site of disease. In addition, this study will look for changes in the genetic makeup of tumour cells and see if some of these changes are associated with a benefit from dovitinib. The study will also compare and contrast the genetic changes in the primary tumour cells with cells from secondary tumour specimens, and with cells from tumour specimens taken if a participant's disease has worsened. The purpose of the latter is to identify possible ways in which the tumour becomes resistant to the study drug.

The purpose of this prospective, single centre, non-randomised, open-label, phase II study will evaluate the activity of dovitinib in the treatment naïve population of patients with advanced RCC.

Background: Prior to the middle of last decade, the only systemic therapy for patients with advanced RCC was immunotherapy (interleukin-2 and interferon-alpha) with limited effectiveness and a multitude of side-effects. Since 2006, there have been 6 targeted therapies that have been FDA-registered for the treatment of advanced RCC; the anti-VEGFR tyrosine kinase inhibitors (sunitinib, sorafenib and pazopanib), the anti-VEGF antibody bevacizumab (with interferon-alpha) and the mTOR inhibitors (everolimus and temsirolimus). These treatments have significantly advanced outcomes for patients with this disease but unfortunately they do not represent cures. The median overall survival for patients treated with a standard first-line therapy (sunitinib) is just over 2 years and the median PFS for subjects receiving this agent is only 11 months. This means that the typical time it takes for subjects to develop resistance to standard first-line tyrosine kinase inhibitor (TKI) treatment, as evidenced by significant tumour growth on imaging, is under 1 year.

Despite the recent rapid advancements in the treatment options for subjects with advanced RCC, there is still an unmet need for more effective therapeutic options for patients with this disease so as to improve survival and make steps towards the ultimate treatment aim for patients with metastatic disease - cure. Available data suggests that dovitinib is a very active agent in metastatic RCC. If it has efficacy in the heavily pre-treated RCC population, one would expect it to be considerably more active when it is moved forward into the first-line setting.

Dovitinib is a broad-targeted receptor Tyrosine Kinase Inhibitor (TKI) primarily active against three receptors that mediate tumour growth and survival: vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR). A distinguishing feature of dovitinib (compared to other anti-VEGFR TKI's) is its FGFR inhibition. Up-regulation of the fibroblast growth factor receptor 1 (FGFR1) pathway has been demonstrated in metastatic RCC and is a postulated mechanism of resistance to anti-VEGFR therapies. This is thought to be one of the reasons why dovitinib has activity in subjects treated with prior anti-VEGFR therapies. If we move the FGFR inhibition forward into the first-line setting (by using dovitinib) we hope to be able prevent or delay the development of resistance acquired through FGFR up-regulation. We hope this may allow subjects to remain on first-line therapy for much longer and in doing so improve survival and outcomes for this group of patients.

Dovitinib has been studied in heavily pre-treated subjects with metastatic RCC, and in these phase I/II studies it looks very active. If it has efficacy in the heavily pre-treated RCC population, it is possible it would be more active when it is moved forward in to the first-line setting.

While we have good prognostic markers to risk-stratify subjects with RCC, there is a lack of predictive markers to guide us as to which patients are best served with each of the different agents available for use. It is therefore imperative that drug development studies in this disease have companion biomarker analysis to identify potentially useful predictive biomarkers for future research. This study also aims to explore (using FISH) the amplification/deletion status of range of genes-of-interest, selected for their relevance to the biology of RCC and the mechanism-of-action of dovitinib. Amplification/deletion of these genes will be further validated using DNA sequencing. The status of these genes-of-interest will be correlated with outcomes of these subjects treated with dovitinib.

The hypothesis of this study is that dovitinib will demonstrate anti-tumour activity when administered to subjects with advanced RCC in the first-line setting and that this activity will correlate with FGFR gene amplification status.

The primary objective is to evaluate the activity of dovitinib in the treatment naïve population of patients with advanced RCC.

Secondary Objectives:

* To determine the gene amplification status for FGFR-1,-2,-3 in this patient population
* To measure the strength of the correlation between measures of clinical efficacy and FGFR gene amplification status
* To further evaluate safety

Exploratory Objectives:

* To assess for amplifications/deletions for genes related to RCC biology in this group of subjects treated with dovitinib.
* To correlate gene amplification status with DNA gene sequence.
* To evaluate differences in tumour gene status between primary and metastatic samples from same subject and again on post-treatment biopsy to elucidate mechanisms of resistance to dovitinib.
* To evaluate effects of dovitinib on bone metastases and pain.

Investigational treatment: Thirty patients from the greater Auckland region will be treated with dovitinib (500 mg p.o. o.d., 5 days on/2 days off) until disease progression, unacceptable toxicity, patient withdrawal or death.

The primary analysis will be performed when 20 progression and/or death events have occurred. No interim efficacy analysis is planned for this study. However, an independent Data Monitoring Committee (DMC) will review data collection (including analysing the adverse event information) and will meet at specified time points during the study.

Visit schedule: Patients will attend clinic visits every 3 weeks while on treatment. Tumour response assessments will occur every 9 weeks until week 54, then every 12 weeks thereafter until disease progression (estimated median time to disease progression = 16 months). Once all patients have completed study treatment, patients will continue to be followed up 3-monthly until approximately 2 months after 20 death events have occurred.

For each patient there will be three separate phases in the study: pre-treatment (screening \& baseline), treatment and follow-up.

Pre-treatment phase (Screening/Baseline): The patient must provide a signed informed consent form (ICF) prior to any study related procedure. A screening period of 28 days is allowed to assess eligibility. Radiologic evaluation (CT of the head, chest, abdomen and pelvis) and baseline tumour measurement using RECIST v1.1 will be performed. Other screening and baseline assessments include ECG \& echocardiogram to assess cardiac function, performance status assessment (ECOG \& WHO), physical examination (including the buccal cavity), height, weight \& vital signs. Laboratory investigations include haematology, chemistry, amylase, lipase, serum lipid profile, coagulation, urinalysis, thyroid function, cardiac enzymes and pregnancy test (if applicable). Disease specific information, general medical information including medical history, concomitant medications, prognostic group according to Heng criteria and demographic data will also be collected.

Treatment phase: This study does not have a fixed treatment duration, as patients will continue therapy until disease progression, intolerable toxicity or withdrawal. Following study inclusion and initiation of study treatment, the patient should visit the site on day 1, 8 and 15 during cycle 1, then day 1 of every subsequent cycle. Patients will have their first dose of study treatment on Day 1, Cycle 1. A study cycle is defined as a period of 21 days.

Tumour response will be evaluated every 3 cycles after registration until week 54, then every 4 cycles until documented disease progression. ECOG performance status will be assessed on day 1 of every cycle. Safety assessments are routinely performed including collection of adverse events (AEs), Serious Adverse Events (SAEs), concomitant medications, vital signs, physical examination, weight, haematological and biochemistry assessments, urinalysis, thyroid function and cardiac enzymes. ECG, amylase, lipase, serum lipids and coagulation will be measured if clinically indicated. An echocardiogram will be performed at weeks 12 and 24, and as clinically indicated. Plasma for storage will be collected on Day 1 of Cycles 1 and 3. Participants with bone metastases will have plasma collected for C-telopeptide testing on day 1 of weeks 1, 2 and 13, and will complete a Quality of Life questionnaire (FACT-BP) at 4 time points: on day 1 of weeks1, 2, 4 and 13.

The End of Treatment (EOT) visit will take place approximately 7 days after the last dose of dovitinib. At this visit the following assessments will be performed and the following data collected: physical examination, ECOG performance status, weight, vital signs, adverse events, concomitant medications, antineoplastic therapies, haematology, biochemistry, amylase and lipase measurements.

Safety follow-up: All patients who discontinue study treatment will have a safety follow-up visit within 30 days of the last dose of dovitinib. Safety assessments will include collection of AEs, SAEs, vital signs, concomitant medications and any new antineoplastic therapies. Patients who progress will be invited to provide an (optional) additional biopsy sample of their tumour, at least 10 days after the last dose of dovitinib, but before any new anticancer therapies are initiated.

Efficacy follow-up: Patients who discontinue the study treatment for reasons other than progression will continue to have radiologic assessments, using the same schedule as for patients who remain on treatment, until documented disease progression.

Survival follow-up: Patients who have discontinued study treatment will be followed-up for survival every 3 months by clinical visits or telephone call until death occurs, the patient is lost to follow-up, or withdraws consent for follow-up for survival. Further treatment will be at the discretion of the investigator.

Statistical Methods: All data will be presented descriptively as means, medians or proportions. Progression free and overall survival from the first dose of dovitinib until disease progression or death will be determined using the method of Kaplan-Meier. The correlation between PFS, OS and baseline biomarker status as well as FGFR gene amplification status will be measured using Spearman's rho. Generalized estimating equations (GEE) for repeated measures will also be used to test the significance of changes in biomarker amplification status relative to baseline. Ordinal logistic regression analysis using a repeated measures structure will be applied to compare bone pain control over the treatment period relative to baseline.

Sample Size Calculation and Expected Duration: The response rate (RR) reported for sunitinib, when studied in a phase III trial versus interferon in the first-line setting was approximately 31%, with a 95%CI ranging from 26 to 36% (Motzer, NEJM 356: 115, 2007). The target sample size in this phase II study is 30, which was based on the assumption that the RR for dovitinib would fall within the range of sunitinib. With such a sample size, the prevalence of dovitinib RR using RECIST 1.1 will be measured with a precision that extends to 15 percentage points, with a 95% probability.

1st-line Activity of Dovitinib and Correlation With Genetic Changes in RCC

Dovitinib In 1st-Line Renal Cell Carcinoma, an Investigation Into Tumour GENe Status and Correlation With Efficacy - 1st Exploratory Study

Proportion of subjects whose tumours have deletion of; VHL, FHIT, PTEN and amplification of; PI3KCA, AKT, MYC, EGFR, PDGFR/CSF-1R, PDGF, imbalance of 1p1q and the correlation of the gene status with clinical outcomes

• Correlation between gene amplification status by FISH and DNA sequence using SequenomTM, OncoCartaTM Panel v 1.0

Discordance in genes-of-interest between and primary and metastatic tumour samples as well as with post-study tumour biopsy (upon progression)

Change in FACT-BP score, CTX levels and opioid usage in subjects with bone metastases. Also assessed at week 13.

Change in FACT-BP score, CTX levels and opioid usage in subjects with bone metastases. Also assessed at week 1.

Description: Subjects will undergo baseline radiology assessment with a CT scan of the chest, abdomen, pelvis and head within 4 weeks of registration. Thereafter subjects will then undergo CT scans of the chest, abdomen and pelvis (where possible using the same technique) every 9 weeks until week 54. From week 54 onward, subjects will undergo CT scans of the chest, abdomen and pelvis every 12 weeks until disease progression. Tumour responses will be evaluated using RECIST 1.1. Confirmation of responses (PR/CR) with repeat CT is not required as the primary end-point is PFS. CT will be the only imaging modality required for subjects on study. The RECIST 1.1 assessments will be done in Auckland by one of the members of the Tumour Response EvAluation Team (TREAT) who have expertise in RECIST reporting.

Assessed every 9 weeks until week 54, then every 12 weeks until disease progression.

Assessed weekly for weeks 1-3, then every 3 weeks until disease progression.

University of Auckland, New Zealand

IGENZ, Ltd., Auckland

Novartis

Auckland District Health Board

Symptoms and General Pathology

Neoplasm Metastasis

Ching-Ting Tan, MD, PhD

Investigate the final diagnosis and treatment result of metastatic cervical carcinoma of unknown primary

Carcinoma of unknown primary (CUP) is defined as biopsy-proven metastasis of an epithelial malignancy in the absence of an identifiable primary site after complete history and physical examination, basic laboratory studies, chest X-ray and additional directed studies indicated by positive findings during the initial work-up. It is characterized by its slow local development and its high metastatic potential.1,2 Patients with CUP represent 4-10% of all new cancer patients.3,4 The presenting sites of metastasis identified pathologically, radiographically or by physical examination were found most frequently in the lymph nodes (37.1%), followed by the liver, bone, lung, pleura/pleural space, brain, peritoneum, adrenal and skin. Of the lymph nodes of metastasis, the supraclavicular cervical area is the leading site (31.3%), followed by the mediastinum, axilla, retroperitonium, and inguina.5 The incidence of metastatic cervical CUP (MCCUP) varies between 2% and 9% of all head and neck cancers.6-8 The level of cervical metastatic involvement may give some clue as to the likely primary site. A submandibular mass (level I) would most commonly be related to a primary in the oral cavity or skin. Level II nodes, including the jugulodigastric node, may point to a primary in the oral cavity, oropharynx, or supraglottic larynx. Tumours of the nasopharynx generally spread to level II or the posterior triangle, as well as retropharyngeal nodes. Middle and lower jugular nodes (levels III and IV) are more likely related to a laryngeal or hypopharyngeal cancer. Metastatic disease restricted to the supraclavicular region is often due to an infraclavicular primary site.9 The prognosis is different according to the involved lymph node level and possible primary site. Modern cancer management relies heavily on recognition of the primary tumor; thus the absence of a primary site poses major diagnostic and therapeutic problems. The patient benefits from identification of the initial tumor site because postoperative irradiation ports may be reduced and because surveillance for recurrence may be improved.10 In order to identify the likely primary site of MCCUP and compare the prognoses of known and unknown primary groups, we report the results according to the different levels of metastatic cervical lymph nodes.

The Final Diagnosis and Treatment Result of Metastatic Cervical Carcinoma of Unknown Primary

National Taiwan University Hospital

Patients will receive SABR in a single-fraction regiment treatment with one single dose of radiation therapy per lesion. Patients may be treated for up to a total of ten lesions. Each lesion will be treated in one fraction.

Single-fraction of stereotactic ablative body radiation (SABR) therapy will be delivered with an integrated magnetic resonance imaging (MRI)-guided radiotherapy delivery system (ViewRay MRIdian Linac). The prescription dose is dependent on the anatomic location of the lesion and based on previously published safety data.

Stereotactic ablative body radiation therapy

Michael Chuong, MD

This is a multi-site single arm feasibility study of single-fraction Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) for primary or metastatic carcinoma involving the lung, liver, adrenal gland, abdominal/pelvic lymph node, pancreas, and/or kidney. Stereotactic ablative body radiation therapy (SABR) is a highly-focused radiation treatment that gives an intense dose of radiation concentrated on a tumor, while limiting the dose to the surrounding organs.

Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) in One Fraction

A Feasibility Study of Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) in One Fraction for Inoperable Primary or Metastatic Carcinoma (SMART ONE)

Number of SABRs that meet the following criteria:

1. Successful completed for each lesion within 3 days of intended treatment
2. Successful completion of treatment to each lesion within 90 minutes from the patient entering the treatment room until treatment completion
3. Image guidance verification of treatment delivery within 5 mm of the planned delivery

Number of patients that meet the following criteria:

1. No greater than 4 of 30 patients experience grade 3 or higher acute toxicity within 90 days of completing SABR
2. No grade 5 toxicity is attributed to SABR

Change in one-year local control will be assessed according to RECIST 1.1 criteria and will be estimated using the Kaplan-Meier method along with the corresponding 95% confidence interval from the time of study treatment.

Number of participants with one-year overall survival will be estimated using the Kaplan-Meier method along with the corresponding 95% confidence interval from the time of study treatment.

Proportion of participants with a change in acute and late toxicity results who experience acute grade 3 or higher toxicity attributable to SABR will be determined along with the corresponding 95% confidence interval. For patients receiving SABR to multiple lesions, acute toxicity will be determined from the date of the initiation of SABR.

Patient-reported quality of life will be determined using the FACT-G survey instrument. Fact-G is a 27-item questionnaire that covers four HR-QOL sub-domains: physical, social, emotional, and function well being. Each question will be scored from a scale from 0 (not at all) to 4 (very much) using a manual scoring template in which some items are reverse.

Viewray Inc.

Baptist Health South Florida

Respiratory Tract (Lung and Bronchial) Diseases

Nervous System Diseases

Small Cell Lung Carcinoma

Lung Neoplasms

Brain Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Neoplastic Processes

Carcinoma, Bronchogenic

Bronchial Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Small Cell Lung Cancer

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

temozolomide oral 150mg/m2 d1-5/28d for 12 cycles

prophylaxis cranial radiotherapy,25-30Gy/10Fra

temozolomide

prophylaxis cranial radiotherapy

Haihong Yang, MD

Haihng Yang, MD

Haihong Yang, Dr.

Hailing Yang, MD

To investigate the response of temozolomide versus prophylactic cranial radiotherapy in preventing brain metastases in completed or partial remission limited small cell lung cancer patients.

We'd like to investigate the 2-year incidence rate of brain metastases in completed or partial remission limited small cell lung cancer patients who received temozolomide only for 12 months or 25-30Gy prophylactic cranial radiotherapy in preventing brain metastases.

Temozolomide in Preventing Brain Metastases in Small Cell Lung Cancer

Radiation Versus Temozolomide in Preventing Brain Metastases in Limited Stage Small Cell Lung Cancer

Guangzhou Medical University

Associate Chief Physician

Blood and Lymph Conditions

Immune System Diseases

Sarcoma

Lymphoma

Soft Tissue Sarcoma

Lymphosarcoma

Antibodies

Antibodies, Monoclonal

Vaccines

Immunoglobulins

Day 1: KLH + anti-OX40; Day 3: anti-OX40; Day 4: anti-OX40; Day 29: Tetanus vaccine

Day 1: Tetanus vaccine + anti-OX40; Day 3: anti-OX40; Day 5: anti-OX40; Day 29: KLH

Cohort 1 anti-OX40

Cohort 2 anti-OX40

Cohort 3 anti-OX40

Tetanus toxoid vaccine 0.5ml (5 LF/ml tetanus toxoid)on Day 29

Tetanus Day 29

Tetanus toxoid vaccine 0.5ml (5 LF/ml tetanus toxoid)on Day 1.

Tetanus Day 1

1 mg KLH in 1 cc diluent subcutaneously on Day 1.

KLH Day 1

1 mg KLC in 1 cc diluent by subcutaneous injection on Day 29.

KLH Day 29

Brendan Curti, MD

This study is designed to determine the safety and highest tolerated dose of anti-OX40 in patients with advanced cancer.

This study will evaluate the safety and determine the maximal tolerated dose of anti-OX40; evaluated the immune response to the study treatment; measure the pharmacokinetics of anti-OX40; monitor tumor regression, and identify the most biologically active dose of anti-OX40 to induce antigen-specific responses to a variety of immunogens.

Phase 1 Study of Anti-OX40 in Patients With Advanced Cancer

Phase 1 Trial of a Monoclonal Antibody to OX40 in Patients With Advanced Cancer.

A dose limiting toxicity is defined as any grade \>=3 hematologic (except lymphopenia) or non-hematologic toxicity (except hypothyroidism or vitiligo) that, in the opinion of the investigator is considered at lease possibly related to the study treatment. If DLT is observed in greater than two patient in any cohort, then the previous cohort will be the maximal tolerated dose.

Blood tests and leukapheresis product will be collected to determine the response to three types of reporter antigens: (1) new antigen (keyhole limpet hemocyanin (KLH)), (2) recall protein antigen (tetanus), and (3) viral antigen (cytomegalovirus (CMV)). Changes in the number of antigens will be used to determine immune response.

Providence Health & Services

Tomotherapy

Robert Pearcey, MD

Radiation treatment is often used to treat cancer that has spread to the abdomen. It can be very effective at relieving symptoms such as pain, but the radiotherapy itself can cause side-effects such as cramping and diarrhea. This study will investigate whether it is possible to reduce the unwanted side-effects of radiotherapy with a new technology called "helical tomotherapy". Tomotherapy is a new way to deliver radiation in a much more accurate fashion than is currently done, and with less radiation being delivered to normal tissues around the tumor. This study will involve the treatment of 20 patients, who have a spread of their cancer within the abdomen and pelvis, using helical tomotherapy. The dose and energy of radiation will be the same as is currently used - only the delivery system is different. The purpose is to assure that tomotherapy is a safe way to deliver radiation treatment and to investigate whether it will reduce the toxicity of radiation treatment in these patients. Patients will be treated in groups of three until all 20 have been treated. The toxicity of treatment will be measured with a questionnaire for each one. If any unexpected severe treatment complications occur, further accrual will stop.

Radiotherapy is an effective treatment for treating metastatic disease. When used to treat disease in the lower abdomen or pelvis, however, it is frequently associated with gastrointestinal toxicity. The most common symptoms of radiation enteritis are diarrhea, bloating, and abdominal cramping. They are caused by irritation and inflammation of the bowel mucosa, and although the pathophysiology is poorly understood, it is thought to be due in part to malabsorption of bile salts and lactose, imbalances in bacterial flora, disturbances in motility. The true incidence of clinically significant enteritis is not well known and probably underestimated, because the majority of patients with symptoms do not seek medical advice, but is approximately 80% in patients receiving pelvic radiotherapy for gynecologic and rectal tumors. Different approaches have been taken to try to minimize acute small and large bowel toxicity from radiotherapy. Medical management with opioid derivatives, such as loperamide, is often effective for mild cases. Other medications, which try to inhibit the biochemical pathways leading to symptomatic gastroenteritis, have undergone clinical testing with some success. The other approach to minimizing toxicity is to minimize the volume and/or dose of radiation delivered to the small bowel. Simple mechanical devices, such as the "belly board" or a mesh sling, have had some success. With new techniques in intensity-modulated radiotherapy, it may be possible to avoid much of the bowel, or significantly reduce the dose delivered to the bowel, without mechanical intervention or compromising tumour doses. The aim of this trial is to test whether a new and highly sophisticated form of intensity modulated radiotherapy called helical tomotherapy can safely be used to deliver radiotherapy to the abdomen and pelvis. It will also establish whether this treatment modality will allow a reduction in the radiation dose to normal structures and the incidence of radiation-induced bowel injury. Helical tomotherapy is a new form of radiation treatment delivery which will be introduced at the Cross Cancer Institute in late 2001 or early 2002. Unlike standard radiotherapy, in which treatment is delivered through one or a few separate beams, helical tomotherapy delivers treatment with a rotating, intensity-modulated fan beam. The patient is translated through the ring of the gantry while the beam is rotated around, so that the treatment beam forms a helical shape in a similar manner to that of computed tomography (CT) scans. The ring gantry provides a stable platform to perform tomographic verification of both setup and delivered dose. Helical tomotherapy is similar to the NOMOS PeacockTM system currently in clinical use. The PeacockTM system also uses an intensity-modulated fan beam, but because it is an attachment to a standard C-arm linear accelerator, it delivers treatment by a "translate then rotate" method rather than a continuous spiral delivery. Because of the complete freedom of helical tomotherapy to deliver treatment from all angles around the patient and with intensity modulation and inverse treatment planning, it is possible to treat highly complex and irregular target volumes while giving a low radiation dose to surrounding normal structures. This study, along with a parallel study involving the treatment of bone metastases, will involve the first patients to be treated with helical tomotherapy at the Cross Cancer Institute. It will be an important first step in understanding the processes and capabilities of helical tomotherapy in delivering accurate image-guided therapy. It is designed to provide the framework for the next generation of clinical trials using helical tomotherapy in the adjuvant and radical setting. The objectives of the study are as follows:

* To assess whether is is feasible to deliver daily fractionated radiotherapy with helical tomotherapy;
* To assess the acute toxicity associated with the treatment of pelvic and abdominal metastases with helical tomotherapy;
* To test the accuracy of the daily setup verification process inherent in the helical tomotherapy system;
* To perform in vivo dosimetry, where possible;
* To analyze the dose distributions possible with helical tomotherapy planning, and compare to plans obtained using conventional linear accelerator systems.

To accomplish these objectives, the investigators will recruit 20 patients for treatment with helical tomotherapy. Patients with solid malignancy of any primary site with proven or suspected metastatic disease involving the abdomen, pelvis, or bones of the lumbar spine or pelvis will be eligible, provided they are over 18 years of age; signed informed consent is obtained; and there are no contraindications for radiotherapy. The investigators will select patients for enrollment who have a high likelihood (\>50%) of suffering from grade 2 or higher acute GI toxicity if standard radiotherapy techniques were used. Treatment will be delivered with the helical tomotherapy system, with the dose plan designed to treat the target volume to a homogeneous dose, while minimizing dose to normal structures including the small bowel. The first 10 patients will be treated with a dose of 2500 cGy in 10 fractions, and the second cohort of 10 patients to 3000 cGy in 10 fractions. The slightly lower than normal dose used for the first cohort is designed to provide an extra margin of safety.

Statistical Considerations: With the doses of radiation used in the current study, the risk of grade 4-5 toxicity using standard treatment techniques is very low. The investigators will, therefore, use observed grade 4-5 acute toxicity as an early stopping rule to monitor the safety of helical tomotherapy. Patients will be accrued onto treatment sequentially, with no more than 3 patients on treatment or within 1 week of completing treatment at any time. If a patient develops a grade 4 toxicity during or shortly after treatment, further accrual will be suspended until such time as the cause of the severe treatment toxicity can be established, and it is determined that treatment to subsequent patients can proceed safely. If a second severe toxicity is observed the trial will close to accrual. For the purposes of the study the risk of grade 4-5 radiation enteritis (using standard radiotherapy techniques) is assumed to be 2% or less. Thus the probability of stopping accrual before trial completion is 0.16 if there is no reduction in toxicity rate with helical tomotherapy (according to binomial probabilities). If the true rate is 1% then the probability of rejecting treatment is 0.01. The acute side effects of treatment will be monitored with the use of a patient symptom questionnaire and physician assessment with history and physical examination. These will be performed pre-treatment, weekly during treatment, and at 1 and 4 weeks post treatment. A secondary endpoint of the study is to test the setup verification process of the helical tomotherapy system. It is designed to automatically detect whether patients are set up accurately for treatment, and to adjust the treatment for day-to-day changes in patient position. For the first 10 patients, the investigators will compare the tomotherapy-derived setup error to the error manually computed by studying the CT image sets. If the computer derived setup error is accurate when compared to the manual evaluation (within 5 mm for at least 80% of measurements), then the automated setup verification process will be utilized for the second cohort of 10 patients. It is estimated that this study will take 3-6 months to complete.

Helical Tomotherapy as a Radiotherapy Technique for Treating Pelvic and Abdominal Metastases

Alberta Health services

Skin and Connective Tissue Diseases

Breast Neoplasms

Triple Negative Breast Neoplasms

Antirheumatic Agents

Anti-Infective Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Immunomodulating Agents

Immunosuppressive Agents

Immunologic Factors

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Non-myeloablative, lymphocyte depleting preparative regimen, followed by KK-LC-1 TCR T cells plus aldesleukin at escalating doses

dose of 720,000 IU/kg (based on total body weight) as an intravenous bolus over a 15 minute period beginning within 24 hours of cell infusion and continuing for up to four days (maximum 12 doses).

IL-2 (Aldesleukin)

30 mg/kg IV infusion over 1 hour (+ 10 min) Once daily x 2 doses (Days -6 and -5)

KK-LC-1 TCR

25 mg/m2 IV infusion over 30 minutes (+ 10 min) To be administered following completion of cyclophosphamide. Once daily x 5 doses (Days -6, -5, -4, -3, -2)

Monica E Epstein, R.N.

Scott M Norberg, D.O.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Researchers have found a new way to treat cancer using T cell therapy. The therapy used in this study is T Cell Receptor (TCR) Gene Therapy Targeting KK-LC-1, a cancer germline antigen that is expressed by certain cancers. This therapy is a type of treatment in which a participant s T cells (a type of immune system white blood cell) are changed in the laboratory to attack cancer cells and given back to the participant. This treatment might help people with KK-LC-1 positive cancers which may include gastric, breast, cervical, lung and other epithelial Cancers. Epithelial cancers are cancers that begin in the cells that line an organ.

Objective:

The purpose of this study is to determine the safety of different doses of KK-LC-1 TCR T cells plus aldesleukin to treat metastatic or refractory/recurrent KK-LC-1 positive cancers.

Eligibility:

Adults aged 18 and older with metastatic or refractory/recurrent KK-LC-1 positive epithelial cancer.

Design:

Participants will be screened with HLA typing (a blood test needed for eligibility) and KK-LC-1 testing of the cancer tumor (to determine if the cancer is KK-LC-1 positive). A new biopsy may be needed if tumor from an outside location is not available for KK-LC-1 testing. Eligible participants will come to the NIH campus to have a screening evaluation which will include physical exam, review of medical history and current medications, blood and heart tests, imaging (X-ray, CT scan, MRI or PET scan), and evaluation of participant s veins that are used for drawing blood.

If the participant is eligible for the study based on the screening evaluation, they will have a baseline evaluation prior to receiving the experimental treatment which may include additional laboratory or imaging tests.

Participants will have a large IV catheter inserted into a vein to undergo a procedure called leukapheresis. Leukapheresis is the removal of the blood by a machine to collect specific white blood cells. The remaining blood is returned to the body. This procedure is needed to collect the cells that will be modified to target the cancer. The cells are grown in the lab and given back to the participant through an injection into the participant's tumor. It takes 11-15 days to grow the cells.

While the cells are growing, the participant will be admitted to the hospital about one week

before the cell infusion to receive 2 types of chemotherapy through an IV catheter over 5 days. The main purpose of the chemotherapy is to make the cells more effective in fighting the cancer tumors. The cells will be given 1-2 days after the last dose of chemotherapy. Within 24 hours after the cell infusion, participants will be given a cell growth factor called aldesleukin through an IV for up to 4 days. Aldesleukin is thought to help the cells live longer in the participant s body. Participants will recover in the hospital until they are well enough to go home, which is usually about 7-12 days after the cell infusion or last dose of aldesleukin.

Participants will have a follow-up visit at approximately 40 days after the date of cell infusion. This visit will be to evaluate the safety of the cell therapy and the response of the cancer to the treatment which will include physical examination, lab tests, and imaging studies. If a participant has stable disease or their cancer has responded to the treatment, they will be seen again at 12 weeks post cell infusion, every 3 months x 3 visits, and then every 6 months x 5 years. If a participant s cancer progresses after this therapy, they will be return to their home doctor for further management.

After receiving cell therapy, participants will be followed on a long-term gene therapy protocol. Participants will have blood drawn periodically to test if the cells have grown or changed. These blood tests will take place immediately before the cells, and then at 3, 6, and 12 months for the first year and possibly annually thereafter based on the results. These tests can be drawn locally and sent to the NIH. After a participant is off the study, they will be contacted by telephone or mailed questionnaire for a total of 15 years after cell therapy....

Background:

KK-LC-1 is a cancer germline (CG) antigen with expression restricted to germ cells (which lack MHC class I expression) in adults and epithelial cancers including lung, breast and gastric.

This limited expression pattern makes it an ideal target for T Cell Receptor (TCR) gene therapy.

TCR T cell therapy targeting CG antigens has been shown to induce objective responses without autoimmunity or off-target toxicity in participants with melanoma, synovial sarcoma and cervical cancer

T cells genetically engineered with a TCR targeting KK-LC-1 display specific reactivity against HLA-A01:01, KK-LC-1 target cells.

KK-LC-1 TCR T cells can mediate tumor regression in pre-clinical mouse models of cancer

Objective:

To determine the maximally tolerated dose of KK-LC-1 TCR T cells plus aldesleukin for the treatment of metastatic KK-LC-1 positive epithelial cancers.

Eligibility:

Participants greater than or equal to 18 years old with metastatic or refractory/recurrent KK-LC-1 positive epithelial cancer.

Prior first line systemic therapy is required unless the participant declines standard treatment.

Participants must be HLA-A-01:01-positive.

Design:

This is a phase I clinical trial that will test the safety and efficacy of escalating doses of KK-LC-1 TCR T cells.

Participants will receive a non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine followed by a single infusion of KK-LC-1 TCR T cells and high-dose aldesleukin.

Re-treatment will be allowed for a small number of subjects

T Cell Receptor Gene Therapy Targeting KK-LC-1 for Gastric, Breast, Cervical, Lung and Other KK-LC-1 Positive Epithelial Cancers

A Phase I Trial of T Cell Receptor Gene Therapy Targeting KK-LC-1 for Gastric, Breast, Cervical, Lung and Other KK-LC-1 Positive Epithelial Cancers

.IPD recorded in the medical record will be shared with intramural investigators upon request.

The fraction of patients who experience a DLT will be identified at a given dose level, with information reported about the number and grade of each type of DLT identified.

National Cancer Institute (NCI)

Endometrial Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Hormones

Sirolimus

Anastrozole

Aromatase Inhibitors

Temsirolimus

MTOR Inhibitors

Antineoplastic Agents, Hormonal

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Following inclusion, patients will be randomized (2:1) to receive Arm A : AZD2014 + anastrozole Arm B : anastrozole alone

Mode of Action Selective and specific mTOR kinase inhibitor targeting both mTORC1 and mTORC2 complexes.

Route of Administration Oral

Dosage regimen 125mg BID with intermittent schedule (2 days of treatment followed by 5 days off (500mg/week))

Duration of treatment Until the patient experiences unacceptable toxicity, disease progression and/or treatment is discontinued per patient or investigator request.

AZD2014

Therapeutic Class Aromatase inhibitor

Mode of Action Potent and highly selective non-steroidal aromatase inhibitor.

Route of Administration Oral

Dosage regimen

1 mg tablet once a day

Duration of treatment Patients may continue treatment with anastrozole until the patient experiences unacceptable toxicity, disease progression and/or treatment is discontinued per patient or investigator request.

Pierre-Etienne HEUDEL, MD

The investigators hypothesize that the dual inhibition of mTORC1/mTORC2 by AZD2014 combined with inhibition of aromatase enzyme by anastrozole will act synergistically and may be an interesting therapeutic option for endometrial cancer with a manageable toxicity profile.

The investigators proposal is to conduct a multicenter, 2-step, randomized, Phase I/II trial to evaluate the safety and efficacy of a combination treatment associating anastrozole to AZD2014 in advanced endometrial cancer patients.

The study is divided in 2 steps :

* A safety run-in phase aiming to evaluate the safety of the proposed combination AZD2014 + anastrozole (Arm A) versus anastrozole alone (Arm B). No dose escalation is scheduled (doses are based on maximum tolerated dose (MTD) defined for AZD2014 and the summary of product characteristics (SPC) of anastrozole). However, dose de-escalation for AZD2014 will be applied in case of toxicity.
* A two-stage randomized Phase II part aiming to evaluate the clinical benefit of the AZD2014 + anastrozole (Arm A) combination therapy versus anastrozole (Arm B).

TREATMENT PLAN :

Following randomisation patients will receive Arm A : AZD2014 plus anastrozole or Arm B: anastrozole alone AZD2014 will be administered with an intermittent schedule i.e. 125 mg bis in die (BID) intermittent with 2 days on followed by 5 days off per week for a total weekly dose of 500 mg/week (250mg D1 and D2, 5 days off) Anastrozole will be administered at the standard dose defined in the SPC i.e. 1mg/d, per os, continuously.

Both treatment will be administered until progressive disease (PD), unacceptable toxicity or willingness to stop.

STATISTICS :

A total of 72 patients will be randomized in the study.

Safety run-in Phase on the first 9 patients randomized - As no dose escalation will be performed, the safety will be evaluated following the treatment and 8-week follow-up of the first 6 patients by the experimental association AZD2014+anastrozole (experimental arm). By similarity to a classic 3+3 design, based on binomial probabilities, there is a 90% probability of observing one or more patients with a toxicity event, if that event occurs in at least 32% of the target population. Assuming a 2:1 randomization ratio, a total of 9 patients (Arm A - Experimental: 6 patients, Arm B - Control: 3 patients) will be enrolled in this safety run-in phase and will be included in the evaluation of Phase II part.

Phase II The sample size calculation was based on a Simon optimal two-stage design, with a minimum success (8-week non progression) rate considered of interest p1=60% and an uninteresting rate p0=40%. Assuming a type I error alpha of 0.05 and 80% power, 46 evaluable patients are needed in the experimental arm to reject the null hypothesis H0: p≤p0 versus the alternative hypothesis H1: p ≥ p1 in a unilateral situation (16 patients in Stage I and 30 additional patients in Stage II).

With a 2:1 randomization and based on the assumption that 5% of the patients may be non-evaluable, a total of 72 patients will be included in the study : 48 patients in Arm A - experimental and 24 patients in Arm B - control).

DATA ENTRY, DATA MANAGEMENT AND STUDY MONITORING All the data concerning the patients will be recorded in the electronic case report form (eCRF) throughout the study. serious adverse event (SAE) reporting will be also paper-based by e-mail and/or Fax.

The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local law requirements.

Hormone Receptor Positive endometrIal Carcinoma Treated by Dual mTORC1/mTORC2 Inhibitor and Anastrozole (VICTORIA)

A Multicentric, Randomized, Non Comparative, Open-label Phase I/II Evaluating AZD2014 (Dual Mammalian Target of Rapamycin Complex 1/2 (mTORC1/mTORC2) Inhibitor) in Combination With Anastrozole Versus Anastrozole Alone in the Treatment of Metastatic Hormone Receptor-positive Endometrial Adenocarcinoma

Severe toxicities defined as

* Any grade ≥ 4 treatment related toxicity
* Any grade≥ 3 treatment related toxicity lasting more than 7 days

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
1st-line Activity of Dovitinib and Correlation With Genetic Changes in RCC	NCT01791387	Clear Cell Rena...	Dovitinib	18 Years -	Auckland District Health Board
The Final Diagnosis and Treatment Result of Metastatic Cervical Carcinoma of Unknown Primary	NCT00302588	Metastasis Cerv...		20 Years - 75 Years	National Taiwan University Hospital
Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) in One Fraction	NCT04939246	Metastatic Carc...	Stereotactic ab...	18 Years -	Baptist Health South Florida
Temozolomide in Preventing Brain Metastases in Small Cell Lung Cancer	NCT02605811	Small Cell Lung... Metastatic Carc...	temozolomide prophylaxis cra...	18 Years - 75 Years	Guangzhou Medical University
Temozolomide in Preventing Brain Metastases in Small Cell Lung Cancer	NCT02605811	Small Cell Lung... Metastatic Carc...	temozolomide prophylaxis cra...	18 Years - 75 Years	Guangzhou Medical University
Phase 1 Study of Anti-OX40 in Patients With Advanced Cancer	NCT01644968	Advanced Cancer	Cohort 1 anti-O... Cohort 2 anti-O... Cohort 3 anti-O... Tetanus Day 29 Tetanus Day 1 KLH Day 1 KLH Day 29	18 Years -	Providence Health & Services
Helical Tomotherapy as a Radiotherapy Technique for Treating Pelvic and Abdominal Metastases	NCT00129051	Neoplasm Metast... Carcinoma	Tomotherapy	18 Years -	AHS Cancer Control Alberta
T Cell Receptor Gene Therapy Targeting KK-LC-1 for Gastric, Breast, Cervical, Lung and Other KK-LC-1 Positive Epithelial Cancers	NCT05035407	Kita-kyushu Lun...	IL-2 (Aldesleuk... Cyclophosphamid... KK-LC-1 TCR Fludarabine	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Hormone Receptor Positive endometrIal Carcinoma Treated by Dual mTORC1/mTORC2 Inhibitor and Anastrozole (VICTORIA)	NCT02730923	Endometrial Car... Metastatic Carc... Hormone Recepto...	AZD2014 Anastrozole	18 Years -	Centre Leon Berard
Gut Microbiome in Fecal Samples From Patients With Metastatic Cancer Undergoing Chemotherapy or Immunotherapy	NCT02960282	Metastatic Carc... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Biospecimen Col... Laboratory Biom...	18 Years -	University of Southern California
Radiation Stent Versus Self-expanding Metallic Stents (SEMS) for Palliative Treatment of Malignant Biliary Stricture	NCT01320241	Cholangiocellul... Pancreatic Canc... Gallbladder Can... Metastatic Carc...	self-expandable... self-expandable...	18 Years - 80 Years	Southeast University, China

Spots Global Cancer Trial Database for metastatic carcinoma