Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Antineoplastic Agents

All Drugs and Chemicals

Docetaxel

Hormones

No Prior treatment for prostate cancer with cytotoxic chemotherapy (adjuvant or neoadjuvant chemotherapy is acceptable if completed \>2 years prior to study)

* Must have evidence of radiographic metastatic disease
* Must have been treated with a docetaxel-based chemotherapy regimen for HRPC with a minimum of 2 cycles with either PSA or RECIST defined radiographic progression during or witin 60 days of completeing docetaxel based chemotheraph or be intolerant of docetaxel-based chemotherapy
* No more than three prior chemotherapies regimens for HRPC

IPI-504 at 400mg/m2, IV, 2 times a week for 2 weeks with 10 days off treatment. Twenty-one (21) day cycle

IPI-504

William Oh, MD

To determine:

* Anti-tumor activity of IPI-504 in 2 groups of subjects with hormone resistant prostate cancer.
* Group A - subjects who have not previously received chemotherapy
* Group B - sujects who have received prior chemotherapy or could not tolerate chemotherapy.
* Clinical response will be determined by PSA and radiological response

IPI-504 is a novel, water-soluble analog of 17-AAG and a potent inhibitor of Hsp90. Hsp90's role in the cell is to control the proper folding, function, and viability of various "client" proteins. Many of these client proteins (such as AKT, Her-2, Bcr-Abl, PDGFR-α, and c-Kit) are oncoproteins or important cell signaling proteins. Inhibition of HSP-90 leads to the proteasomal degradation of these proteins.

In patients with HRPC,there are several proteins that are important in the progression of HRPC, including AR, AKT and Her-2. All of these are client proteins of Hsp90 and in response to Hsp90 inhibition are degraded by their proteasome. Preclinical studies have shown that Hsp90 inhibition causes a dose dependent degradation of these client proteins and growth inhibition of prostate cancer in xenograft tumors.

A Phase 2 Study to Investigate the Clinical Activity of IPI-504 in Patients With Hormone-resistant Prostate Cancer

A Phase 2 Open-Label Study to Investigate the Pharmacodynamics and Clinical Activity of IPI-504 in Patients With Castration-Resistant Prostate Cancer Stratified by Prior Chemotherapy

Infinity Pharmaceuticals, Inc.

Endothelin A Receptor Antagonists

Tubulin Modulators

Antimitotic Agents

placebo oral tablet once daily + docetaxel intravenous infusion every 3 weeks

ZD4054 10 mg oral tablet once daily + docetaxel intravenous infusion every 3 weeks

intravenous infusion given every three weeks

ZD4054

Placebo

Karim Fizazi, MD, PhD

Judd W Moul, MD, FACS

Enthuse M1C is a large phase III clinical trial studying the safety and efficacy of ZD4054 (Zibotentan) in combination with docetaxel (Taxotere) in patients with metastatic hormone resistant prostate cancer (HRPC).

This clinical trial will test if the Endothelin A Receptor Antagonist ZD4054 (Zibotentan) can further improve survival compared with docetaxel alone.

ZD4054 (Zibotentan) is a new type of agent, which is thought to slow tumour growth and spread by blocking Endothelin A receptor activity. This trial will look at the effects of ZD4054 (Zibotentan) in hormone resistant prostate cancer patients with bone metastases compared with docetaxel.

All patients participating in this clinical trial will receive docetaxel chemotherapy, which is a commonly used chemotherapy to treat prostate cancer in addition to other existing prostate cancer therapies.

Half the patients will receive ZD4054 (Zibotentan), and half the patients will receive placebo in addition to docetaxel and other prostate cancer therapy. By participating in this trial there is a 50% chance that patients will receive an agent that may further slow the progression of the tumour.

No patients will be deprived of standard prostate cancer therapy.

A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) and Docetaxel in Metastatic Hormone Resistant Prostate Cancer

A Phase III, Randomised, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of 10 mg ZD4054 (Zibotentan) in Combination With Docetaxel in Comparison With Docetaxel in Patients With Metastatic Hormone-resistant Prostate Cancer

Median time (in months) from randomisation until death using the Kaplan-Meier method.

Median time (in months) from randomisation until clinical progression of disease using the Kaplan-Meier method. Progression is defined, using RECIST, as a measurable increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline

Median time (in months) from randomisation until occurrence of a skeletal related event using the Kaplan-Meier method, where skeletal related event is defined as the first occurrence of a pathological fracture, a vertebral compression fracture not related to trauma, prophylactic surgery or radiation for impending fracture or spinal cord compression, or a spinal cord compression.

Median time (in months) from randomisation until first PSA value \>50% higher than baseline of at least 5ng/ml seen in at least 2 consecutive PSA values at least 2 weeks apart using the Kaplan-Meier method.

Median time (in months) from randomisation until date of first assessment of increased pain using the Kaplan-Meier method, where increased pain event is defined as the first of a patient requiring opiate medication for duration of ≥1 week for pain due to prostate cancer metastasis, pain due to metastasis that has an increase in the worst pain item of the Brief Pain Inventory (BPI) from baseline to a minimum score of 5 with no decrease in analgesic use, or pain due to metastasis requiring radionuclide therapy, radiation therapy or surgery.

Number of patients with a pain response, defined as a decrease in brief pain inventory questionnaire (BPI) of at least 2 points from baseline or a decrease in opiate use of 25% from baseline.

Median time (in months) from randomisation until deterioration of Health Related Quality of Life using the Kaplan-Meier method, where deterioration is defined as a change from baseline of less than or equal to -6 points in Total FACT-P score maintained for 2 consecutive visits.

PSA response defined as \>50% decrease in serum PSA values from baseline seen in at least 2 consecutive PSA values at least 2 weeks apart.

AstraZeneca

XD4054 10 mg oral tablet once daily + docetaxel intravenous infusion every 3 weeks

ZD4054 + Docetaxel

Placebo + Docetaxel

Total

overall

Age Continuous

Sex: Female, Male

Gerard Lynch

Overall Survival

Progression Free Survival

Incidence of Skeletal Related Events

Time to Prostate-specific Antigen (PSA) Progression

Time to Pain Progression

The Pain Response Analysis Set includes patients who were either receiving opiates at baseline (randomisation) or with a baseline BPI score ≥2.

Pain Response

Health Related Quality of Life

PSA Response

Overall Study

Symptoms and General Pathology

Neoplasm Metastasis

Pain

Matching Placebo, oral tablets once daily

Martin Gleave, MD, FRCSC, FACS

Joel B Nelson, MD

Enthuse M1 is a large phase III clinical trial studying the safety and efficacy of ZD4054 (Zibotentan) in patients with hormone resistant prostate cancer and bone metastases.

* This clinical trial will test if the Endothelin A Receptor Antagonist ZD4054 (Zibotentan) can improve survival compared with placebo.
* ZD4054(Zibotentan) is a new type of agent, which is thought to slow tumour growth and spread by blocking Endothelin A receptor activity. This trial will look at the effects of ZD4054 (Zibotentan) in hormone resistant prostate cancer patients with bone metastases.
* All patients participating in this clinical trial will receive existing standard prostate cancer treatments in addition to trial therapy.
* Half the patients will receive ZD4054 (Zibotentan), and half the patients will receive placebo in addition to standard prostate cancer therapy. By participating in this trial there is a 50% chance that patients will receive an agent that may slow the progression of the tumour.
* No patients will be deprived of standard prostate cancer therapy.

A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Hormone Resistant Prostate Cancer With Bone Metastases

A Phase III Trial to Test the Efficacy of ZD4054(Zibotentan), an Endothelin A Receptor Antagonist, Versus Placebo in Patients With Hormone Resistant Prostate Cancer (HRPC) and Bone Metastasis Who Are Pain Free and Mildly Symptomatic.

Median time (in months) from randomisation until death using the Kaplan-Meier method

Median time (in months) from randomisation until clinical progression of disease, where progression is defined, using RECIST, as a measurable increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline, using the Kaplan-Meier method

Median time (in months) from randomisation until use of opiates for disease-related symptoms for a duration ≥1 week using the Kaplan-Meier method

Median time (in months) from randomisation until occurrence of a skeletal related event, where skeletal related event is defined as the first occurrence of a pathological fracture, a vertebral compression fracture not related to trauma, prophylactic surgery or radiation for impending fracture or spinal cord compression, or a spinal cord compression, using the Kaplan-Meier method.

Median time (in months) from randomisation to appearance of ≥4 new bone lesions using the Kaplan-Meier method

Median time (in months) from randomisation until deterioration of Health related Quality of Life using the Kaplan-Meier method, where deterioration is defined as a change from baseline of less than or equal to -6 points in Total FACT-P score maintained for 2 consecutive visits.

Median time (in months) from randomisation to first PSA value \>50% higher than baseline of at least 5ng/ml seen in at least 2 consecutive PSA values at least 2 weeks apart using the Kaplan-Meier method.

Median time (in months) from randomisation to first assessment of an increased pain event, where increased pain event is defined as the first of a patient requiring opiate medication for duration of ≥1 week for pain due to prostate cancer metastasis, pain due to metastasis that has an increase in the worst pain item of the Brief Pain Inventory (BPI) from baseline to a minimum score of 5 with no decrease in analgesic use, or pain due to metastasis requiring radionuclide therapy, radiation therapy or surgery.

Median time (in months) from randomisation to first administration of any chemotherapy using the Kaplan-Meier method

Overall

Age, Continuous

Time to Use of Opiates

Bone Metastases Formation

Time to Initiation of Chemotherapy

Pharmacokinetic Characteristics of ZD4054

Rare Diseases

Kennedy Disease

Amino Acids

Androgens

Dasatinib

Androgen Antagonists

Nilutamide

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Hormone Antagonists

Tyrosine

Nilutamide 150mg orally each day for 28 days per cycle. After first progression, Nilutamide 150mg orally each day in combination with Dasatinib 100mg orally each day for 28 days per cycle.

Dasatinib 100mg orally daily x 28 days per cycle. After first progression, Dasatinib 100mg orally each day in combination with Nilutamide 150mg orally each day for 28 days per cycle.

Daniel George, MD

This is a phase II multi-center study to determine the clinical impact of using a patient-specific genomic expression signature of androgen receptor (AR) activity to determine therapy for patients with castration-resistant metastatic prostate cancer (CRPC). After patient eligibility is determined, the genomic signature will be applied to fresh frozen tissue harvested from a metastatic lesion during image-guided biopsy. After assessing for androgen receptor activity, the investigators will select patients for either continued androgen manipulation with nilutamide (high AR activity) or targeted therapy with dasatinib (low AR activity). Once patients develop a first progression on either arm, patients will receive combination therapy with dasatinib and nilutamide. The primary aim is to estimate the median progression free survival in men with CRPC treated according to tumor AR activity. The investigators hypothesize that by treating men based upon AR activity, median progression free survival (PFS) will improve from a historical median of 3.0 months to 6.0 months.

Prostate cancer is the most commonly diagnosed non-cutaneous malignancy of men in the United States and remains the second leading cause of cancer-related mortality among men. Novel approaches are necessary to personalize and improve treatment. The androgen receptor (AR) plays a critical role in the normal development and function of the prostate and promotes growth in most prostate cancers. Most patients with advanced prostate cancer have cancer that will initially respond to androgen-targeting therapy (focusing on decreasing the circulating levels of testosterone which is the primary source of ligand for the AR receptor). However, castrate resistance usually develops within 18 to 24 months and the median survival of men with castration resistant prostate cancer (CRPC) ranges between 12 to 18 months. Current options are limited including: secondary hormonal manipulations, radiopharmaceuticals, and chemotherapy and only docetaxel, a taxane that targets microtubules, has been proven to prolong survival.

Importantly, it has become clear that for some patients with CRPC, the prostate tumors remain dependent on AR activity. This has been supported by studies demonstrating different genetic and metabolic mechanisms by which prostate cancer cells maintain AR activity despite low levels of circulating androgen. An assay detecting AR activity that more comprehensively reflects the variety of mechanisms by which AR activity is preserved has the potential to accurately differentiate between men who have tumors still dependent on AR activity from those that are truly independent of AR activity. The identification of patients with continued AR activity has the potential to improve response to secondary hormonal manipulations; men with tumors having low levels of AR activity are likely to require alternative approaches.

We have developed a transcriptional "signature" for AR activity with the goal of identifying the true status of AR in tumors of men with CRPC. After validating the AR signature on in vitro and human prostate samples to ensure that it accurately and reproducibly detects AR activity, we applied the AR signature to several independent datasets to determine the distribution of CRPC tumors with preserved AR activity. Interestingly, there is consistent heterogeneity with respect to predicted AR activity. While overall AR activity decreases in CRPC, there is a subgroup of patients with persistently elevated AR activity. In tumors with low AR activity, we observed that the probability of AR activity was negatively correlated with predicted SRC activity in localized prostate cancer and CRPC.

Patients with persistently high AR activity will be treated with nilutamide, an approved oral agent used in metastatic CRPC to target the AR. Patients with tumors having low AR activity will be treated with dasatinib (an oral drug known to target the SRC family kinases). As there is compelling pre-clinical evidence of interactions between the SRC pathway and AR signaling, patients failing either single agent treatment will be treated with the combination of nilutamide and dasatinib and followed again for progression.

Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer

A Phase II Trial of Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer

PFS is the interval from start of monotherapy until first disease progression or death, whichever occurred first.

Tumor response was based on Response Criteria in Solid Tumors (RECIST). Complete response (CR) is defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Tumor response is based on Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Bristol-Myers Squibb

Duke University

High Androgen Receptor (AR) activity of \>= 0.50

Nilutamide: Nilutamide 150mg orally each day for 28 days per cycle. After first progression, Nilutamide 150mg orally each day in combination with Dasatinib 100mg orally each day for 28 days per cycle.

Arm 1=High AR Nilutamide

Low Androgen Receptor (AR) activity of \< 0.50

Dasatinib: Dasatinib 100mg orally daily x 28 days per cycle. After first progression, Dasatinib 100mg orally each day in combination with Nilutamide 150mg orally each day for 28 days per cycle.

Arm 2= Low AR Dasatinib

Combination Nilutamide and Dasatinib

Age, Categorical

Race (NIH/OMB)

United States

Region of Enrollment

64 consented but 7 screen failures, so 57 enrolled. 2 never assigned to rx (withdrew consent, clinically unstable), 33 assigned by AR activity (15 high AR to nilutamide, 18 low AR to dasatinib) and 22 QC technical failures (received dasatinib). 14 of 15 high AR and 17 of 18 low AR began protocol treatment. Analyses include the 31 treated patients.

Dr. Daniel George

Progression Free Survival (PFS)

14 subjects began treatment; 13 with response documentation are included in the calculation; 1 subject was omitted because response documentation was not provided.

Overall Response Rate of Men With High AR Activity

Of the 17 subjects treated, 15 had response documentation and are included in the calculation. Two were omitted (1 because response documentation was not provided; 1 ended treatment after 2 weeks for toxicity prior to repeat scans).

Overall Response Rate of Men With Low AR Activity

Monotherapy

Etoposide

Carboplatin

Etoposide phosphate

Carboplatin AUC4 on day 1 repeated every 3 weeks for a maximum of 6 cycles

Etoposide 100 mg/m2 on day 1, day 2 and day 3 repeated every 3 weeks for a maximum of 6 cycles

FLECHON Aude, MD

The aim of our study is to assess the efficacy and toxicity of a chemotherapy regimen combining carboplatin and etoposide in patients with metastatic hormone-resistant prostate cancer and neuro-endocrine differentiation. Eligible patients are treated with the combination of carboplatin AUC4 on day 1 and etoposide 100 mg/m2 on day 1, day 2 and day 3 repeated every 3 weeks for a maximum of 6 cycles. Efficacy endpoints include Prostate Specific Antigen (PSA) and neuro-endocrine marker response (defined as a 50% or greater decrease from baseline serum values), objective response rate (according to RECIST criteria), and toxicity.

Neuro-endocrine differentiation is observed in the evolution of hormone-resistant prostate cancer. The aim of our study is to assess the efficacy and toxicity of a chemotherapy regimen combining carboplatin and etoposide in patients with metastatic hormone-resistant prostate cancer and neuro-endocrine differentiation. To be eligible, patients must have either circulating neuro-endocrine markers (Chromogranin A: CgA, Neuron Specific Enolase: NSE)and/or visceral metastases. Eligible patients are treated with the combination of carboplatin AUC4 administered on day 1 and etoposide 100 mg/m2 given on day 1, day 2 and day 3 and repeated every 3 weeks for a maximum of 6 cycles. The primary objective of the study is to assess objective response to the carboplatin - etoposide combination (according to RECIST criteria for lesions and defined as a 50% or greater decrease from baseline serum values for PSA and neuro-endocrine markers). Secondary objectives include evaluation of toxicity, duration of response, progression-free-survival and overall survival.

Carboplatin-Etoposide Combination in Hormone-Resistant Prostate Cancers

Phase II Multicenter Study Evaluating the Efficacy of Carboplatin-Etoposide Combination in Hormone-resistant Prostate Cancers With Neuroendocrine Differentiation.

Centre Leon Berard

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Prednisone

Prednisolone

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Estramustine

Glucocorticoids

Antineoplastic Agents, Hormonal

Antineoplastic Agents, Alkylating

Alkylating Agents

weekly docetaxel (35mg/m\&) plus prednisone 10mg a day associated with estramustine form day 1to 5 and 8 to 12

35mg/m² on day 2 and 9 (21days in a cycle)

docetaxel

140mg caps x3 bid from day 1to 5 and day 8 to 12 of each cycle

estramustine

prednisone

Jean-Pascal Machiels, MD PHD

Joseph Kerger, MD

we propose to randomize patients with hormone resistant prostate cancer between docetaxel/estramustine/prednisone and docetaxel/prednisone in a phase II study. The principal endpoint will be the efficacy in term of PSA response.

The addition of estramustine to other chemotherapeutic agents that affect microtubule function may improve their efficacy15, 16, 17, 18. A phase III trial compared vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer. They showed that the association of estramustine and vinblastine was superior to vinblastine alone for time to progression, PSA response and survival (Hudes et al., ASCO 2002). In addition, Berry et al. found that estramustine/paclitaxel improved PSA response rate but not overall survival compared with paclitaxel alone (Berry et al. ASCO2001).

Similar association has been studied with docetaxel. In a phase I trial combining docetaxel and estramustine19, 53% of patients reported a decrease in narcotic use and 63% experienced a PSA response. In another phase I trial, a reduction in PSA of 50% or more was observed in 14 of 17 patients (82%)20. In a phase II trial involving 35 patients, a PSA response was reported in 74% of the patients and objective response in 4 out of 7 patients with measurable disease21. Median survival 22 months in this last study. These studies as well as other support the combination of estramustine and docetaxel in the treatment of HRPC22, 23.

Recently, Oudard et al. competed a phase II randomized study comparing mitoxantrone/prednisone versus docetaxel/estramustine prednisone24. Docetaxel was given either weekly or every 3 weeks. Association of docetaxel/estramustine was found superior to mitoxantrone in term of PSA response, (67-63% versus 18%), clinical benefit (79-56% versus 41%) and survival (19.2 months versus 11.6 months). In addition, toxicities of these regimens were manageable and predictable. In this study, patients received 2 mgr of coumadin to prevent thromboembolic event due to estramustine and only 7 % of the patients had thrombosis. Other grade III \& IV toxicities of the estramustine/docetaxel combination included neutropenia (37% in the 3-week regimen and 0 % in the weekly regimen) nausea/vomiting (2% in the 3-week regimen and 0 % in the weekly regimen), diarrhea (7% in the 3-week regimen and 0 % in the weekly regimen). No febrile neutropenia was observed.

Although these data support a role for chemotherapy combinations, such as estramustine and docetaxel, in the treatment of HRPC, further studies are needed to determine the relative contribution of estramustine to the efficacy of docetaxel/estramustine regimen. In this context, we propose to randomize patients with hormone resistant prostate cancer between docetaxel/estramustine/prednisone and docetaxel/prednisone in a phase II study. The principal endpoint will be the efficacy in term of PSA response. We chose to use the weekly regimen as described by Oudard since the toxicity of this regimen is well described and is easily manageable in our experience.

Safety and Efficacy Study of of Docetaxel vs Docetaxel Estramustine in Hormone Refractory Prostatic Cancer

Randomized Phase Ii Trial Of Weekly Docetaxel, Estramustine And Prednisone Versus Docetaxel And Prednisone In Patient With Hormone-Resistant Prostate Cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase 2 Study to Investigate the Clinical Activity of IPI-504 in Patients With Hormone-resistant Prostate Cancer	NCT00564928	Prostate Cancer Prostatic Neopl... Cancer of the P...	IPI-504	18 Years -	Infinity Pharmaceuticals, Inc.
A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) and Docetaxel in Metastatic Hormone Resistant Prostate Cancer	NCT00617669	Prostate Cancer	Docetaxel ZD4054 Placebo	18 Years -	AstraZeneca
A Phase 2 Study to Investigate the Clinical Activity of IPI-504 in Patients With Hormone-resistant Prostate Cancer	NCT00564928	Prostate Cancer Prostatic Neopl... Cancer of the P...	IPI-504	18 Years -	Infinity Pharmaceuticals, Inc.
A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Hormone Resistant Prostate Cancer With Bone Metastases	NCT00554229	Prostate Cancer	ZD4054 Placebo	18 Years -	AstraZeneca
A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Hormone Resistant Prostate Cancer With Bone Metastases	NCT00554229	Prostate Cancer	ZD4054 Placebo	18 Years -	AstraZeneca
Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer	NCT00918385	Prostate Cancer	Nilutamide Dasatinib	18 Years -	Duke University
Carboplatin-Etoposide Combination in Hormone-Resistant Prostate Cancers	NCT00973882	Prostate Cancer	Carboplatin Etoposide	18 Years -	Centre Leon Berard
A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Hormone Resistant Prostate Cancer With Bone Metastases	NCT00554229	Prostate Cancer	ZD4054 Placebo	18 Years -	AstraZeneca
Safety and Efficacy Study of of Docetaxel vs Docetaxel Estramustine in Hormone Refractory Prostatic Cancer	NCT00541281	Hormone Resista... Metastatic Pros...	docetaxel estramustine prednisone	18 Years -	Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Spots Global Cancer Trial Database for hormone resistant prostate cancer