Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

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

Niraparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patients receive niraparib PO QD on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Following completion of treatment, patients then undergo standard of care surgery.

Niraparib Tosylate Monohydrate

Radical Prostatectomy

Marc Dall'Era

This phase II trial studies how well niraparib, when given before surgery, works in treating patients with high risk prostate cancer that has not spread to other parts of the body (localized) and alterations in deoxyribonucleic acid (DNA) repair pathways. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To assess the impact of neoadjuvant niraparib tosylate monohydrate (niraparib) therapy prior to radical prostatectomy (RP) on pathologic tumor stage, frequency of lymph node metastases and positive margin rates for patients undergoing radical prostatectomy for high-risk, clinically localized prostate cancer with alterations in DNA repair pathways.

SECONDARY OBJECTIVE:

I. To assess 5-year biochemical recurrence in subjects with high-risk prostate cancer and DNA-damage response defects after prostatectomy.

OUTLINE:

Patients receive niraparib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Following completion of treatment, patients then undergo standard of care surgery.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, and then every 6 months for up to 3 years.

Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects

Phase II Trial of PARP Inhibitor Niraparib for Men With High Risk Prostate Cancer and DNA Damage Response Defects

The study will assess the impact of neoadjuvant niraparib therapy prior to radical prostatectomy (RP) on pathologic tumor stage, frequency of lymph node metastases and positive margin rates for patients undergoing radical prostatectomy for high-risk, clinically localized prostate cancer with alterations in deoxyribonucleic acid (DNA) repair pathways. Pathologic complete response (PCR) defined as no tumor identified on hematoxylin and eosin (H\&E) stained sections will be assessed; minimal residual disease (MRD) will be defined as tumor clusters limited to \< 5 mm and confined to prostate gland.

Exact 95% confidence intervals for pRR and other binary outcomes, adjusted for the two-stage design, will be calculated as described by Koyama and Chen. Response rates will be compared between patients with biallelic and monoallelic loss using Fisher's Exact Test.

Median biochemical progression free survival (bPFS) and quartiles (when reached) will be calculated from Kaplan-Meier estimates, and 95% confidence intervals will be calculated using Greenwood's formula.

National Cancer Institute (NCI)

Janssen, LP

Marc Dall'Era, MD

Principal Investigator

Symptoms and General Pathology

Respiratory Tract (Lung and Bronchial) Diseases

Recurrence

Lung Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Talazoparib

Patients receive talazoparib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Vassiliki Papadimitrakopoulou

This phase II trial studies how well talazoparib works in treating patients with homologous recombination repair deficiency (HRRD) positive stage IV squamous cell lung cancer that has come back after previous treatment. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) (confirmed and unconfirmed, complete and partial) with talazoparib (BMN 673) in HRRD Medivation (MDVN)-positive patients.

SECONDARY OBJECTIVES:

I. To evaluate investigator assessed progression-free survival (IA-PFS) and overall survival (OS) associated with therapy in HRRD MDVN-positive patients.

II. To evaluate ORR, IA-PFS, and OS in HRRD Foundation Medicine, Inc. (FMI)-positive patients.

III. To evaluate ORR in HRRD MDVN-negative/HRRD FMI-positive patients. IV. To evaluate the frequency and severity of toxicities associated with talazoparib (BMN 673) in HRRD FMI-positive patients.

TERTIARY OBJECTIVES:

I. To assess if the homologous recombination deficiency (HRD) score is associated with clinical outcomes (response, PFS, OS) in HRRD FMI-positive patients treated with talazoparib (BMN 673).

II. To assess if the level of PARP protein expression determined by immunohistochemistry is associated with clinical outcomes (response, PFS, OS) in HRRD FMI-positive patients treated with talazoparib (BMN 673).

III. To characterize pharmacokinetic properties of talazoparib (BMN 673).

OUTLINE:

Patients receive talazoparib orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and at the end of year 3.

Lung-MAP: Talazoparib in Treating Patients With HRRD Positive Recurrent Stage IV Squamous Cell Lung Cancer

A Phase II Study of Talazoparib (BMN 673) in Patients With Homologous Recombination Repair Deficiency Positive Stage IV Squamous Cell Lung Cancer (Lung-Map Sub-Study)

A logistic regression model will be used as both a continuous variable and categorized as high versus low. A Cox regression model will be used to assess associations with progression free survival and overall survival.

A logistic regression model will be used to evaluate if HRD score (as both a continuous variable and categorized as high versus low) and PARP protein expression levels are associated with response. Similarly, a Cox regression model will be used to assess associations with progression free survival and overall survival.

The percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment with talazoparib per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Analysis was performed using a more restricted definition of homologous recombination repair deficiency (HRRD)-positivity (Medivation \[MDVN\] criteria; defined by alterations in ATM/ATR/BRCA1/BRCA2/PALB2 genes). With 40 HRRD subset positive patients, overall response rate can be estimated within 13% with 95% confidence.

From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration or death due to any cause. Participants last known to be alive without report of progression were censored at date of last disease assessment.

Analysis was performed using a more restricted definition of homologous recombination repair deficiency (HRRD)-positivity (Medivation \[MDVN\] criteria; defined by alterations in ATM/ATR/BRCA1/BRCA2/PALB2 genes).

From date of sub-study registration to date of death due to any cause. Participants last known to be alive were censored at date of last contact.

Analysis was performed using a more restricted definition of homologous recombination repair deficiency (HRRD)-positivity (Medivation \[MDVN\] criteria; defined by alterations in ATM/ATR/BRCA1/BRCA2/PALB2 genes).

The percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment with talazoparib per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Analysis was performed using a broader definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc. \[FMI\] criteria; defined by alterations in ATM/ATR/BARD1/BRCA1/BRCA2/BRIP1/CHEK1/CHEK2/FANCA/FANCC/FANCD2/FANCF/FANCM/NBN(NBS1)/PALB2/RAD51/RAD51B(RAD51L1)/RAD54L/RPA1 genes).

From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration or death due to any cause. Participants last known to be alive without report of progression were censored at date of last disease assessment.

Analysis was performed using a broader definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc. \[FMI\] criteria; defined by alterations in ATM/ATR/BARD1/BRCA1/BRCA2/BRIP1/CHEK1/CHEK2/FANCA/FANCC/FANCD2/FANCF/FANCM/NBN(NBS1)/PALB2/RAD51/RAD51B(RAD51L1)/RAD54L/RPA1 genes).

From date of sub-study registration to date of death due to any cause. Participants last known to be alive were censored at date of last contact.

Analysis was performed using a broad definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc. \[FMI\] criteria; defined by alterations in ATM/ATR/BARD1/BRCA1/BRCA2/BRIP1/CHEK1/CHEK2/FANCA/FANCC/FANCD2/FANCF/FANCM/NBN(NBS1)/PALB2/RAD51/RAD51B(RAD51L1)/RAD54L/RPA1 genes).

From date of documentation of response (complete or partial) to date of first documentation of progression assessed by local review or symptomatic deterioration or death due to any cause among participants who achieve a complete or partial response.

The percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment with talazoparib per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Analysis was performed on participants that meet a broader definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc.) but not the stricter definition set by MDVN.

\[FMI\] criteria; defined by alterations in ATM/ATR/BARD1/BRCA1/BRCA2/BRIP1/CHEK1/CHEK2/FANCA/FANCC/FANCD2/FANCF/FANCM/NBN(NBS1)/PALB2/RAD51/RAD51B(RAD51L1)/RAD54L/RPA1 genes).

Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.

SWOG Cancer Research Network

47 participants that were eligible and received protocol therapy were assessed for AEs

Participants receive talazoparib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Measure Description: Participants were graded according to the Zubrod Performance Status Scale.

0 - Fully active, able to carry out on all pre-disease performance without restriction.

1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light housework, office work.

Performance status

Number of prior lines of therapy for stage IV disease

Current smoker

Recent smoker

Former smoker

Never smoker

Smoking status

Lung Committee Statistician

Participants that meet the MDVN criteria for homologous recombination repair deficiency (HRRD)

Overall Response Rate Assessed by Response Evaluation Criteria in Solid Tumors 1.1 in HRRD-positive (MDVN) Participants

Eligible participants that meet the MDVN criteria for homologous recombination repair deficiency (HRRD)

Investigator-assessed Progression-free Survival (IA-PFS) in HRRD-positive (MDVN) Participants

Overall Survival (OS) in HRRD-positive (MDVN) Participants

All eligible participants that meet a broad definition of homologous recombination repair deficiency (HRRD) -positivity (Foundation Medicine Inc. \[FMI\] criteria).

Overall Response Rate Assessed by Response Evaluation Criteria in Solid Tumors 1.1 in HRRD-positive (FMI) Participants

All eligible participants that meet the FMI criteria for homologous recombination repair deficiency (HRRD)

Investigator-assessed Progression Free Survival (IA-PFS) FEP in HRRD-positive (FMI) Participants

Overall Survival (OS) in HRRD-positive (FMI) Participants

Duration of Response in HRRD-positive (FMI) Participants

All eligible participants that meet a broad definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc. \[FMI\] criteria), but do not meet the more restrictive MDVN criteria for HRRD positivity.

Overall Response Rate Assessed by Response Evaluation Criteria in Solid Tumors 1.1 in HRRD-negative Per MDVN But HRRD-positive Per FMI Participants

Alanine aminotransferase increased

Anemia

Aspartate aminotransferase increased

Dehydration

Dyspnea

Fatigue

Generalized muscle weakness

Hypertension

Hypoalbuminemia

Hyponatremia

Hypotension

Hypoxia

Lung infection

Lymphocyte count decreased

Nausea

Neutrophil count decreased

Platelet count decreased

Respiratory failure

Sepsis

Vomiting

White blood cell decreased

Wound infection

Participants who received at least one dose of talazoparib treatment.

Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs

Homologous Recombination Deficiency (HRD) Immunohistochemistry Score

PARP Protein Expression Levels Assessed by Immunohistochemistry

Overall Study

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Olaparib

After the screening procedures confirm eligibility to participate in the research study:

* Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart.
* Tumor measurement q6 weeks x 24 weeks, then q 12 weeks

After the screening procedures confirm eligibility to participate in the research study:

* Olaparib: Each study treatment cycle lasts 21 days (3 weeks), taking 2 times per day, 12 hours apart.
* Tumor measurements q6 weeks x 24 weeks, then q 12 weeks

olaparib tablets bid daily continuously on a 21 day cycle until progression, intolerable toxicity, consent withdrawn, patient noncompliance or death.

Nadine Tung, MD

This research study is for patients with metastatic breast cancer.

* Metastatic means that the cancer has spread beyond the breast. In addition, through genetic testing of the blood or tumor, an altered gene has been found that suggests the tumor may not be able to repair its genetic material (DNA) when it becomes damaged.
* This aspect of the cancer may cause it to be more sensitive - that is, more effectively killed by certain types of drugs such as the study agent being evaluated in this trial, Olaparib.

  * Olaparib is a type of drug known as a PARP inhibitor. Some types of breast cancer and ovarian cancer share some basic features that make them sensitive to similar treatments. Information from those other research studies suggests that this drug may help to treat metastatic breast cancer.

    * This study will evaluate whether olaparib is effective in breast cancer patients whose tumor has a mutation in one of the other genes that function with BRCA1 and BRCA2 to repair damaged DNA .This mutation may have been inherited from a parent, or may have developed only in the tumor.
    * This study will also evaluate whether olaparib is effective in breast cancer patients whose tumor has a mutation in BRCA1 or BRCA2 that was acquired by the tumor, but not inherited.

* This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the study drug, Olaparib, is being studied for use in this setting and the research doctors are trying to learn more about it-the side effects it may cause and if the drug is effective in treating this type of cancer.
* What is a DNA repair gene mutation?

  -- In order to survive, all cells, even cancer cells, must be able to repair their genetic material (DNA) when it gets damaged. A mutation is an alteration or change in a gene- either inherited from a parent or acquired over time- that prevents the gene from working properly. Faulty genes (or genes that carry a mutation) have been linked to increased risk of hereditary breast and ovarian cancer.
* What is Olaparib?

  * Olaparib is a drug that may stop cancer cells from growing. Olaparib is a PARP inhibitor which means that it blocks an enzyme (proteins that help chemical reactions in the body occur) in cells called PARP. PARP helps repair DNA when it becomes damaged. It has been shown that the tumors in individuals who have inherited or acquired a mutation in the BRCA1 or BRCA2 genes are often sensitive to killing by PARP inhibitors.
  * In normal cells and many other tumors, repair of damage to the DNA requires pathways of genes that work with BRCA1 and BRCA2. Therefore, when a drug that inhibits PARP from working is given to people with a BRCA mutation, or a defect in another gene that works with BRCA1 and BRCA2, both ways of repairing damaged DNA no longer work. The combined effect of knocking out both DNA repair mechanisms is so severe that the cancer cells could die. This might stop the growth of type of breast cancer, but this is not known.
  * The FDA (U.S. Food and Drug Administration) has approved Olaparib for use in advanced ovarian cancer with a BRCA1 or BRCA2 mutation. Olaparib is not approved for breast cancer.

Olaparib In Metastatic Breast Cancer

A Phase 2 Study of Olaparib Monotherapy in Metastatic Breast Cancer Patients With Germline or Somatic Mutations in DNA Repair Genes (Olaparib Expanded)

RECIST 1.1 criteria will be reported with a two-sided 90% confidence interval using the method from Atkinson and Brown to account for the two-stage design

Reported with 90% binomial exact confidence intervals.

Treatment-related toxicities will be summarized within and across Cohorts by maximum grade and by term using CTCAE v4.0 and reported with 90% binomial exact confidence intervals.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects	NCT04030559	ATM Gene Mutati... BRCA1 Gene Muta... BRCA2 Gene Muta... BRIP1 Gene Muta... CDK12 Gene Muta... CHEK1 Gene Muta... CHEK2 Gene Muta... DNA Damage Resp... DNA Repair Gene... FANCA Gene Muta... FANCD2 Gene Mut... FANCL Gene Muta... GEN1 Gene Mutat... NBN Gene Mutati... Prostate Carcin... RAD51 Gene Muta... RAD51C Gene Mut...	Niraparib Niraparib Tosyl... Radical Prostat...	18 Years -	University of California, Davis
Lung-MAP: Talazoparib in Treating Patients With HRRD Positive Recurrent Stage IV Squamous Cell Lung Cancer	NCT03377556	ATM Gene Mutati... ATR Gene Mutati... BARD1 Gene Muta... BRCA1 Gene Muta... BRCA2 Gene Muta... BRIP1 Gene Muta... CHEK1 Gene Muta... CHEK2 Gene Muta... FANCA Gene Muta... FANCC Gene Muta... FANCD2 Gene Mut... FANCF Gene Muta... FANCM Gene Muta... NBN Gene Mutati... PALB2 Gene Muta... RAD51 Gene Muta... RAD51B Gene Mut... RAD54L Gene Mut... Recurrent Squam... RPA1 Gene Mutat... Stage IV Squamo...	Laboratory Biom... Pharmacological... Talazoparib	-	SWOG Cancer Research Network
Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects	NCT04030559	ATM Gene Mutati... BRCA1 Gene Muta... BRCA2 Gene Muta... BRIP1 Gene Muta... CDK12 Gene Muta... CHEK1 Gene Muta... CHEK2 Gene Muta... DNA Damage Resp... DNA Repair Gene... FANCA Gene Muta... FANCD2 Gene Mut... FANCL Gene Muta... GEN1 Gene Mutat... NBN Gene Mutati... Prostate Carcin... RAD51 Gene Muta... RAD51C Gene Mut...	Niraparib Niraparib Tosyl... Radical Prostat...	18 Years -	University of California, Davis
Olaparib In Metastatic Breast Cancer	NCT03344965	Metastatic Brea... Invasive Breast... Somatic Mutatio... Somatic Mutatio... CHEK2 Gene Muta... ATM Gene Mutati... PALB2 Gene Muta... RAD51 Gene Muta... BRIP1 Gene Muta... NBN Gene Mutati...	Olaparib	18 Years -	Beth Israel Deaconess Medical Center

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