Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Carcinoma

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Antineoplastic Agents

All Drugs and Chemicals

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Cediranib

Enzyme Inhibitors

Protein Kinase Inhibitors

Patients receive olaparib PO BID and cediranib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Joseph W Kim

This randomized phase II trial studies how well olaparib with or without cediranib works in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Cediranib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving olaparib and cediranib may help treat patients with castration-resistant prostate cancer.

PRIMARY OBJECTIVE:

I. To assess the clinical activity of the combination of cediranib and olaparib, as measured by radiographic progression free survival (rPFS), as compared to olaparib monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC).

SECONDARY OBJECTIVES:

I. To assess the clinical activity of the combination of cediranib and olaparib, as measured by prostate-specific antigen (PSA) response rate, radiographic response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1, and overall survival (OS), as compared to olaparib monotherapy in patients with mCRPC.

II. To evaluate association of homologous recombination deoxyribonucleic acid (DNA) repair deficiency (HRD) with the clinical activity of the combination of cediranib and olaparib or olaparib monotherapy, as measured by rPFS, in mCRPC patients.

III. To evaluate the safety the combination of cediranib and olaparib and olaparib monotherapy in patients with metastatic prostate cancer.

EXPLORATORY OBJECTIVES:

I. To characterize genomic alterations by whole exome sequencing in mCRPC patients and correlate that with clinical activity or resistance to olaparib with or without cediranib.

II. To characterize changes in ribonucleic acid (RNA) expression of DNA repair genes, angiogenesis markers, and immune markers, by whole transcriptome sequencing and correlate with clinical activity or resistance to olaparib with or without cediranib.

III. To characterize changes in immune tumor microenvironment in mCRPC patients by profiling expression of co-stimulatory and co-inhibitory molecules and tumor infiltrating lymphocytes, and correlate with clinical activity or resistance to olaparib with or without cediranib.

IV. To identify baseline predictive biomarkers for rPFS or response and to identify on-treatment markers of acquired resistance in men with mCRPC receiving either olaparib plus cediranib or olaparib alone.

V. To explore biomarker signatures that correlate with the clinical activity or resistance to olaparib with or without cediranib, including changes in gene expression or acquired mutations in tumor biopsies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive olaparib orally (PO) twice daily (BID) and cediranib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months.

Testing Two Oral Drugs Combination (Cediranib and Olaparib) Compared to a Single Drug (Olaparib) for Men With Advanced Prostate Cancer

A Randomized Phase 2 Study of Cediranib in Combination With Olaparib Versus Olaparib Alone in Men With Metastatic Castration Resistant Prostate Cancer

The data analysis will be completed using Lasso-based elastic net method.

The two study arms will be compared for radiographic progression free survival with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval, which is based on Greenwood's variance, Thomas and Grunkemeier confidence interval, and the simultaneous confidence bands by Nair and Hall and Wellner, will be reported. In addition, the possible risk factors will be compared for survival with log-rank test.

Will use the rank preserving structure failure time model for the overall survival analysis.

Will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1. The exact 95% confidence interval of objective response rate will be reported based on the binomial distribution. The multivariate data analysis will be completed using the logistic regression model. The adjusted p-value and adjusted 95% confidence interval will also be reported.

Prostate-specific antigen response will be defined by prostate-specific antigen decline from baseline \> 50%, confirmed by a second value at 3-4 weeks later. Prostate-specific antigen response rate analysis will be based on a subset of patients who had prostate-specific antigen progression prior to enrollment. The multivariate data analysis will be completed using the logistic regression model.

Homologous recombination deficiency positive status is defined by presence of homozygous deletion or deleterious mutations in key homologous recombination genes of deoxyribonucleic acid repair genes as analyzed by BROCA-homologous recombination test. The data analysis will be completed using Fisher's exact test. The multivariate data analysis will be completed using the generalized non-linear model.

Will be assessed by whole exome sequencing and transcriptome sequencing. The biomarker data analysis will be completed using Lasso-based elastic net method.

Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (CTCAE version 5.0 will be effective by April 1, 2018). Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percentages and frequencies for categorical parameters, will be presented. Adverse medical events will be tabulated. NCI toxicity grade 3 and grade 4 laboratory abnormalities will be listed and tabled.

National Cancer Institute (NCI)

Rare Diseases

Carcinoma, Neuroendocrine

Carcinoma, Small Cell

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

Lutetium Lu 177 dotatate

Radiopharmaceuticals

Patients receive lutetium Lu 177 dotatate IV over 30 minutes. Cycles repeat Q6W for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gallium Ga 68-dotatate IV during screening then undergo PET/CT scan at baseline and collection of blood throughout the trial.

Biospecimen Collection

Computed Tomography

Gallium Ga 68-DOTATATE

Lutetium Lu 177 Dotatate

Positron Emission Tomography

Site Public Contact

Jacek Pinski

Mamta Parikh

Maha H. Hussain

Zin W. Myint

John M. Floberg

Michael A. Carducci

Michael McCormack

Edmund Folefac

John M Floberg

This phase II trial studies how well lutetium Lu 177 dotatate works in treating patients with prostate cancer with neuroendocrine differentiation that has spread to other places in the body (metastatic). Neuroendocrine differentiation refers to cells that have traits of both hormone-producing endocrine cells and nerve cells. These cells release hormones into the blood in response to a signal from the nervous system. Hormones are biological substances that circulate through the bloodstream to control the activity of other organs or cells in the body. Lutetium Lu 177-dotate is a radioactive drug. It binds to a protein called somatostatin receptor, which is found on some neuroendocrine tumor cells. Lutetium Lu 177-dotatate builds up in these cells and gives off radiation that may kill them. It is a type of radioconjugate and a type of somatostatin analog. Treatment with Lutetium Lu 177 dotatate may shrink the tumor in a way that can be measured in patients with metastatic prostate cancer with neuroendocrine differentiation.

PRIMARY OBJECTIVE:

I. Evaluate the objective response rate for patients treated with lutetium Lu 177 dotatate using Prostate Cancer Working Group (PCWG) 3 criteria.

SECONDAY OBJECTIVES:

I. Evaluate the 6-month radiographic progression-free survival of neuroendocrine-differentiated prostate cancer treated with lutetium Lu 177 dotatate.

II. Determine if the change in fludeoxyglucose (FDG)-positron emission tomography (PET) signal from pre-treatment to after 2 doses of lutetium Lu 177 dotatate correlates with objective response rate.

EXPLORATORY OBJECTIVES:

I. Evaluate the potential to perform patient-specific dosimetry of lutetium Lu 177 dotatate using gamma imaging to predict treatment response and renal toxicity.

II. Perform gene expression analysis of circulating tumor cells to identify pre-treatment biomarkers of response and signatures of resistance at the time of progression.

OUTLINE:

Patients receive lutetium Lu 177 dotatate intravenously (IV) over 30 minutes. Cycles repeat every 6 weeks (Q6W) for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gallium Ga 68-dotatate IV during screening then undergo positron emission tomography (PET)/computed tomography (CT) scan at baseline and collection of blood throughout the trial.

Patients are followed up at 6 weeks after last dose lutetium Lu 177 dotatate and then every 3 months for 2 years after removal from study or until death, whichever occurs first.

Testing the Safety and Effectiveness of Radiation-based Treatment (Lutetium Lu 177 Dotatate) for Metastatic Prostate Cancer That Has Neuroendocrine Cells

A Phase II Study of Lutetium Lu 177 Dotatate in Metastatic Prostate Cancer With Neuroendocrine Differentiation

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will be summarized using descriptive statistics. Expression levels of candidate markers will be correlated with radiographic time to progression using univariate Cox proportional hazard regression analysis. The Benjamini-Hochberg false discovery rate method will be utilized to control the false discovery rate when evaluating the markers. Machine learning methods will be used to identify signatures of resistance at the time of progression.

Descriptive analyses will be conducted to evaluate the potential to perform patient-specific dosimetry of lutetium Lu 177 dotatate using gamma imaging to predict treatment response and renal toxicity. Imaging outcome parameters will be summarized in terms of means, medians, standard deviations and ranges, stratified by assessment time point (24, 96, and 192 hours post-injection), stratified by response (PD, SD versus CR, PR) and toxicity type/grade.

The objective response rate according to Prostate Cancer Working Group (PCWG) 3 criteria will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). ORR will be reported along with the corresponding two-sided 95% confidence interval. The confidence interval will be adjusted for the two-stage design structure. This analysis will be based on the intent-to-treat population.

Will be determined by PCWG3 criteria. Specifically, progression/response will be determined via RECIST 1.1 criteria using diagnostic computed tomography (CT) scans of the chest/abdomen/pelvis to analyze progressive disease (PD), stable disease (SD), complete response (CR), partial response (PR), and toxicity type/grade. Progression and response will also be assessed by fludeoxyglucose positron emission tomography (18F-FDG PET).

Will be assessed with Quantitative Total Extensible Imaging (QTxI).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing Two Oral Drugs Combination (Cediranib and Olaparib) Compared to a Single Drug (Olaparib) for Men With Advanced Prostate Cancer	NCT02893917	Advanced Prosta... Castration-Resi... Metastatic Pros... Metastatic Pros... Prostate Adenoc... Stage IV Prosta...	Cediranib Olaparib	18 Years -	National Cancer Institute (NCI)
Testing the Safety and Effectiveness of Radiation-based Treatment (Lutetium Lu 177 Dotatate) for Metastatic Prostate Cancer That Has Neuroendocrine Cells	NCT05691465	Metastatic Pros... Metastatic Pros... Metastatic Pros... Stage IV Prosta...	Biospecimen Col... Computed Tomogr... Gallium Ga 68-D... Lutetium Lu 177... Positron Emissi...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for metastatic prostate adenocarcinoma with neuroendocrine differentiation