Neoplasms

All Conditions

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Antineoplastic Agents

All Drugs and Chemicals

Chlorambucil

Antineoplastic Agents, Alkylating

Alkylating Agents

Eligible patients will be treated with Chlorambucil 6 mg/m2 daily p.o. for 42 consecutive days (weeks 1-6). After restaging, responder patients (complete or partial response) and those with stable disease will receive Chlorambucil 6 mg/m2 daily p.o for 14 consecutive days every 28 days until disease progression or unbearable toxicity, patient refusal or medical decision. Patients' clinical data will be collected pseudo-anonymously and a sequential identification code number will be assigned to each patient enrolled in the study.

Chlorambucil, Oral, 2 Mg

The main objective of this trial is to explore the activity of chlorambucil, an alkylating agent commonly used in chronic lymphocytic leukemia treatment, in metastatic patients, gBRCA, including VUS, or DDR mutated, previously treated with a platinum-containing chemotherapy.

Nowadays, treatment strategies for patients affected by metastatic pancreatic ductal adenocarcinoma (PDAC) are still very scant. Gemcitabine and fluoropyrimidine based chemotherapy regimens are standard I line chemotherapy. Recently, landmark genome-wide studies revealed the existence of a distinct subpopulation of PDAC with highly unstable genomic properties, due to mutations in DNA Damage Repair genes (DDR), in particular BRCA1/2 mutations. Germline mutations cause a deficiency in deoxyribonucleic acid (DNA) damage repair due to inhibition of DNA double-strand breaks repair by the mechanism of homologous recombination. Cancer cells rely on DNA repair to survive the damage induced by genotoxic stress and DNA repair enables cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype. BRCA1/2 abrogation and homologous repair deficiency (HRD) confer sensitivity to DNA damage-inducing drugs, in particular those inflicting cytotoxic DNA crosslinks that interfere with DNA replication. The sensitivity of BRCA1/2-mutated tumors to platinum compounds has been validated in multiple pre-clinical and clinical studies. Nevertheless, similar lesions are induced by DNA-alkylating agents, which include mono-functional (e.g. mitomycin C) or bifunctional alkylators (e.g. chlorambucil). Small molecule inhibitors of poly(ADP-ribose) polymerase (PARP) have been recently developed and they showed an interesting activity and efficacy in breast, ovarian and pancreatic cancer tumors. Although platinum drugs and PARP inhibitors show initially good responses in the clinic, most patients acquire resistance to these drugs. Chlorambucil shows high selective toxicity against human cells and xenograft tumors with compromised BRCA1/2 function. Patients affected by metastatic ductal adenocarcinoma, pretreated with at least one previous platinum-based chemotherapy, will be treated with oral chlorambucil for 42 consecutive days After restaging, responder patients and those with stable disease will receive for 14 consecutive days every 28 days until disease progression (RECIST 1.1 criteria) or unbearable toxicity, patient refusal or medical decision.

Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial)

A Pilot Study of Chlorambucil in Pre-treated Metastatic Pancreatic Adenocarcinoma Patients Bearing a Germ Line BRCA or Other DNA Defects Repair (DDR) Mutations.

Evaluate the proportion of patients who are progression-free defined as progression according to RECIST 1.1 criteria or death. Progression free survival (PFS) is defined as the time between the date of registration and the date of documented radiological PD according to RECIST 1.1 criteria or death from any cause, whichever occurs first, or the date of last follow-up or last available tumour assessment if no further follow-up for disease progression is performed.

Overall survival (OS) is defined as time between the date of registration and the date of death for any cause or the date they were last known to be alive

Radiological response evaluation by using RECIST 1.1 criteria

Biochemical response evaluation by testing Ca19.9 marker

Drug toxicity evaluation by using appropriate SAE report form

Michele Reni

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Niraparib

Aromatase Inhibitors

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Upon meeting all selection criteria, patients enrolled in the study will receive the combination of niraparib orally, once daily, flat- fixed, continuously in 28-day cycles plus aromatase Inhibitors.

Niraparib orally daily beginning on Day 1 and continuing through Day 28 of every 28-day cycle.

Aromatase Inhibitors beginning on Day 1 and continuing through Day 28 of every 28-day cycle.

Antonio Llombart

This study evalues the efficacy -as determined by the clinical benefit rate (CBR)- of niraparib in combination with AIs in unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer patients harboring either gBRCAms or gBRCAwt and HRD.

The planned number of patients is 23.

Investigational product is Niraparib and will be administered daily continuously in 28-day cycles plus aromatase Inhibitors.

Total study duration is 36 months and until 5 years of follow up.

This is a Multicenter, Open-label, Phase II Clinical Trial to Evaluate the Efficacy and Safety of Niraparib plus Aromatase Inhibitors for Hormone Receptor (HR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2)-negative Metastatic Breast Cancers with either Germline BRCA-mutated or Germinal BRCA-wild-type and Homologous Recombination Deficiency (HRD).

The main objetive is to assess the efficacy -as determined by the clinical benefit rate (CBR)- of niraparib in combination with AIs in unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer patients harboring either gBRCAms or gBRCAwt and HRD.

Upon meeting all selection criteria, patients enrolled in the study will receive the combination of niraparib orally (according to baseline criteria described in Table 4), once daily, flat- fixed, continuously in 28-day cycles and AI that must be identical to the last AI-containing regimen.

A total of 23 patients will be recruited as follows:

* Stage I: N=6 patients in the cohort A;
* Stage II: N=8 patients in the cohort A; N=9 patients in the exploratory cohort B

The total duration of the study period is 36 months follow until 5 years of follow up.

Multicenter, open-label, single-arm, two-cohort, Simon's two- stage phase II clinical trial.

Niraparib Plus Aromatase Inhibitors for Luminal-like(HER2-,ER+) and gBRCA or HDR+ Metastatic Breast Cancer (LUZERN)

Multicenter,Open-label,Phase II Clinical Trial to Evaluate the Efficacy and Safety of Niraparib + Aromatase Inhibitors for(HR)+/(HER2)-, MBC With Either Germline BRCA-mutated or Germinal BRCA-wildtype and Homologous Recombination Deficiency

The CBR as best response, defined as the percentage of patients who experience a complete response, partial response or stable disease for at least 24 weeks and assessed by modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria

PFS is defined as the time from the date of the first dose of study treatment until the first documented PD based on RECIST v1.1. or death due to any cause, whichever occurs first based on local investigator's assessment according to RECIST criteria v1.1.

The ORR is defined as the number of patients with CR and PR divided by the number of patients in the analysis set. Tumor response will be defined as best response based on local investigator's assessment according to RECIST criteria v.1.1.

DoR is defined as the time from first documented CR or PR until disease progression or death from any cause, based on local investigator's assessment according to RECIST criteria v1.1.

OS is defined as the time from the date of first dose of study treatment until death by any cause or the last date the patient was known to be alive.

Time to response (TTR) is defined as the time from the date of first dose of study treatment to the first objective tumor response observed for patients who achieved a Complete response (CR) or parcial response (PR).

Safety will be measured by using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.

GlaxoSmithKline

MedSIR

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Ovarian Cancer

Ovarian Epithelial Cancer

Talazoparib

Poly (ADP-ribose) polymerase (PARP) inhibitor; has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in deoxyribonucleic acid (DNA) repair pathways.

BMN 673

Alice P Chen, M.D.

Background:

* The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (DNA) damage repair mechanisms.
* Talazoparib (BMN 673) is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. BMN 673 has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
* BMN 673 is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations.
* This pilot study will evaluate the pharmacodynamic effects of BMN 673 on DNA damage and apoptosis markers in tumor biopsy tissue.

Primary Objective:

-Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.

Secondary Objectives:

* Determine the response rate (Complete Response (CR) + Partial Response (PR) of treatment with BMN 673 in patients with advanced ovarian or primary peritoneal carcinoma and deleterious BRCA mutations.
* Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced breast carcinoma and deleterious BRCA mutations.
* Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced solid tumor (other than breast or ovarian) and deleterious BRCA mutations.

Eligibility:

* Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
* No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
* Age greater than or equal to 18 years of age; Eastern Cooperative Oncology Group (ECOG) performance status less than equal to 2
* Adequate organ function.
* Willingness to undergo tumor biopsies.

Study Design:

* BMN 673 will be administered orally each day in 28-day cycles.
* Dosing will be at the established recommended Phase II dose of 1000 mcg/day each day for

  28 days.
* We plan to accrue a total of 12 evaluable patients per cohort for a total of 36 patients. To allow for some patients who will not be evaluable, the accrual ceiling is 42 patients.
* Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post BMN 673 on day 8. An optional tumor biopsy may also be collected at time of disease progression.

SCHEMA

* BMN 673 is administered orally each day in 28-day cycles
* Tumor biopsies will be performed at baseline (pre-treatment) and 3-6 hrs post dose on cycle 1 day 8. An optional tumor biopsy may also be collected at time of disease progression. Tumor biopsies will be evaluated for protease activated receptor (PAR) levels, DNA damage response markers such as \>=H2A.X Variant Histone (H2AX), cleaved caspase 3, excision repair cross-complementing group 1 (ERCC1), pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM) activation, Checkpoint kinase 1 (chk1) and Checkpoint kinase 2 (chk2)
* Blood samples for circulating tumor cells (CTC) analyses will be collected at baseline (pre-treatment), on cycle 1 day 1(3-6 hours post dose), on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 (3-6 hours post dose)
* Blood samples for pharmacokinetic (PK) analysis will be collected on cycle 1 day 1 pre-dose and 0.5, 1, 2, 3, 4, 6,8, and 24 hours post-dose, on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 pre-dose and 3-6 hours post dose.

Background:

* The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (DNA) damage repair mechanisms.
* Talazoparib (BMN 673) is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. Talazoparib (BMN 673) has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
* Talazoparib (BMN 673) is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations.
* This pilot study will evaluate the pharmacodynamic effects of talazoparib (BMN 673) on DNA damage and apoptosis markers in tumor biopsy tissue.

Primary Objective:

-Determine the pharmacodynamic effect of talazoparib (BMN 673) in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.

Secondary Objectives:

-Determine the response rate (Complete Response (CR) + Partial Response (PR) of treatment with talazoparib (BMN 673) in patients with deleterious BRCA mutations.

Eligibility:

* Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
* No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
* Age greater than or equal to 18 years of age; Eastern Cooperative Oncology Group (ECOG) performance status less than equal to 2
* Adequate organ function.
* Willingness to undergo tumor biopsies.

Study Design:

* Talazoparib (BMN 673) will be administered orally each day in 28-day cycles.
* Dosing will be at the established recommended Phase II dose of 1000 microgram/day each day for 28 days.
* To meet the primary, pharmacodynamic endpoint of the trial, we plan to accrue a total of 12 patients with matched, evaluable baseline and day 8 biopsies. To allow for some patients whose biopsies will not be evaluable (i.e., will contain \<5% tumor content), the accrual ceiling is 24 patients. The number of patients evaluable for objective response, while relevant to the secondary objective of the trial, will not be considered in determining completion of accrual.
* Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post talazoparib (BMN 673) on day 8. One optional tumor biopsy may also be collected either on day 1 (+/- 2 days) of the cycle following any restaging at which a 10-19% increase in tumor volume is observed (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria) if the patient has been on study for at least 4 cycles, or at time of disease progression.

Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Evaluation of drug effect on deoxyribonuclecic acid (DNA) damage response will be performed using immunofluorescence assays to measure the DNA damage repair marker γH2A (the phosphorylated form of histone family member X, H2AX) in the nucleus of tumor cells obtained via core biopsy.

Response will be evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST)1. 1 guidelines; restaging scans will be carried out every 2 cycles. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. And progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.

National Cancer Institute (NCI)

Principal Investigator

Single-agent BMN 673 (talazoparib) dosed orally at 1 mg/day in 28-day cycles. This poly (ADP-ribose) polymerase (PARP) inhibitor has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in deoxyribonucleic acid (DNA) repair pathways.

Talazoparib (BMN 673)

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Alice P. Chen

Percent of Participants Who Achieve a Sustained Progressive Disease (PD) Response, Defined to be at Least 4% Nuclear Area Positive (NAP) γH2AX at the Day 8 Biopsy

Complete Response

Partial Response

Response Rate (Complete Response (CR) + Partial Response (PR) of Treatment With Talazoparib (BMN 673) in Participants With Deleterious Breast Cancer (BRCA) Mutations

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

Overall Study

Olaparib

300 mg olaparib (2×150 mg tablets) twice daily

The rationale of the ROSY-O study is to continue to provide study treatment for patients who have participated in a parent study with olaparib and who are continuing to derive clinical benefit from treatment at the end of such studies, as judged by the Investigator.

ROSY-O is an open label, non-randomised, multicentre,international trial for patients who have completed a parent study using olaparib and who are deriving clinical benefit from continued treatment as judged by the Investigator. Patients will be rolled-over from the parent study and will continue the study indefinitely, until they meet one of the treatment discontinuation criteria

Female subjects with historically diagnosed relapsed high grade serious or high grade endometrioid ovarian cancer; Patients with HER2-ve metastatic breast cancer with germline or somatic BRCA mutations.

Roll Over StudY for Patients Who Have Completed a Previous Oncology Study With Olaparib

Roll Over StudY for Patients Who Have Completed a Previous Oncology Study With Olaparib and Are Judged by the Investigator to Clinically Benefit From Continued Treatment

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Serious adverse events and adverse events of special interest reported until 30 days after the last dose of study drug.

AstraZeneca

Triple Negative Breast Neoplasms

Cystadenocarcinoma, Serous

Fallopian Tube Neoplasms

Cystadenocarcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Fallopian Tube Diseases

Neoplasms, Cystic, Mucinous, and Serous

Fallopian Tube Cancer

Adenocarcinoma of the Appendix

Antirheumatic Agents

Cyclophosphamide

Veliparib

Immunosuppressive Agents

Immunologic Factors

Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.

Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression.

PARP enzymes are critical for maintaining genomic stability by regulating a variety of DNA repair mechanisms. Individuals with deleterious mutations in the BRCA1 or BRCA2 tumor suppressor genes have an increased risk of developing breast and ovarian cancers due to impaired or defective DNA damage repair; these individuals have an increased susceptibility to DNA-damaging agents and PARP inhibitors. Inhibition of PARP inhibits the repair of DNA damage caused by alkylating agents such as cyclophosphamide. Metronomic cyclophosphamide has demonstrated efficacy in several tumor types. The PARP inhibitor ABT-888 has been shown to potentiate the action of cyclophosphamide in xenograft models. This combination is well tolerated in a Phase I study and showing promising activity.

ABT-888

Alice Chen, M.D.

Background:

- The experimental cancer treatment drug ABT-888 (Veliparib) works by preventing deoxyribonucleic acid (DNA) repair in tumor cells. Cyclophosphamide is a cancer treatment drug that works by causing DNA damage in cells, including cancer cells, resulting in cell death. However, because cyclophosphamide has strong and unpleasant side effects, researchers are interested in finding drugs that can be given in combination with cyclophosphamide that will allow a lower dose of cyclophosphamide to be given with similar effects. The combination of ABT-88 and cyclophosphamide may be an effective treatment for some types of cancer, such as certain kinds of breast or ovarian cancer and non-Hodgkin's lymphoma that often do not respond to standard therapies.

Objectives:

- To evaluate the safety and effectiveness of ABT-888 and cyclophosphamide in ovarian and breast cancer and in non-Hodgkin's lymphoma that have not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with (1) (Breast cancer 1/2) BRCA1/2 ovarian cancer, primary peritoneal or ovarian high-grade carcinoma, or fallopian tube cancer; (2) triple-negative breast cancer (not responsive to hormone-related therapy); or (3) low grade non-Hodgkin's lymphoma.

Design:

* Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will be divided into two groups with different treatment subgroups.
* Group 1: Participants who have BRCA-positive ovarian cancer, primary peritoneal or ovarian high-grade serous carcinoma, or fallopian tube cancer
* Participants will receive either the combination of ABT-888 and cyclophosphamide, or cyclophosphamide alone.
* Participants will take the study drug by mouth once a day for 21-day cycles of treatment, and will keep a diary to record drug doses and any side effects.
* Participants will have clinic visits with blood and urine tests, imaging studies, and other examinations on days 1, 2, 7, and 14 of cycle 1, and on the first day of all other cycles.
* Group 2: Participants who have triple-negative breast cancer or non-Hodgkin's lymphoma
* Participants will receive either the combination of ABT-888 and cyclophosphamide, or cyclophosphamide alone.
* Participants will take the study drug by mouth once a day for 21-day cycles of treatment, and will keep a diary to record drug doses and any side effects.
* Participants will have clinic visits with blood and urine tests, imaging studies, and other examinations on days 1, 2, 7, and 14 of cycle 1, and on the first day of all other cycles.
* Participants receiving only cyclophosphamide who show signs of disease progression after tumor imaging studies can receive the combination of ABT-888 with cyclophosphamide.
* Treatment will continue as long as participants tolerate the drugs and the disease does not progress.

Background:

* The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of DNA repair mechanisms.
* Individuals with deleterious mutations in the BRCA1 or BRCA2 tumor suppressor genes have an increased risk of developing breast and ovarian cancers due to impaired or defective DNA damage repair; these individuals have an increased susceptibility to DNA-damaging agents and PARP inhibitors. Inhibition of PARP inhibits the repair of DNA damage caused by alkylating agents such as cyclophosphamide.
* Metronomic cyclophosphamide has demonstrated efficacy in several tumor types. The PARP inhibitor ABT-888 has been shown to potentiate the action of cyclophosphamide in xenograft models. This combination is well tolerated in a Phase I study and showing promising activity.

Objectives:

* Compare the response rate (complete response (CR) + partial response (PR)) of the combination of ABT-888 with metronomic oral cyclophosphamide to the response rate (CR+PR) of metronomic oral cyclophosphamide in patients with deleterious BRCA mutations and refractory ovarian cancer or patients with primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube cancer.
* Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral cyclophosphamide to the response rate (CR+PR) of single-agent oral cyclophosphamide in patients with triple-negative metastatic breast cancer, stratified for deleterious BRCA mutation.
* Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral cyclophosphamide to the response rate (CR+PR) of single-agent metronomic oral cyclophosphamide in patients with refractory low-grade lymphomas.

Secondary Objectives:

- Determine PAR levels in tumor biopsies, evaluate in archival tissue whether patients tumors have mutations in genes involved in DNA damage repair (e.g., BRCA/Fanconi anemia/protein 53 (p53)), perform exploratory gene expression profiling to correlate PARP messenger ribonucleic acid (mRNA) levels or BRCA mutation status with response to therapy, count circulating tumor cells (CTCs), and determine H2AX levels in CTCs and tumor biopsies (National Cancer Institute (NCI) clinical center only).

Eligibility:

-Adults with refractory BRCA-positive ovarian cancer, primary peritoneal or ovarian high-grade serous carcinoma, fallopian tube cancer, triple-negative breast cancer, or low-grade lymphoid malignancies (non-Hodgkin's lymphoma) whose disease has progressed following at least one line of therapy.

Study Design:

* This is a randomized, multi-histology Phase II trial with patients enrolled into 3 cohorts: BRCA-positive ovarian cancer or primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube cancer (A); triple-negative breast cancer (B); or low grade non-Hodgkin's lymphoma (C). Patients in cohort A will be randomized to the combination of ABT-888 with metronomic oral cyclophosphamide or metronomic oral cyclophosphamide alone. Patients in cohort B will be randomized to the combination of ABT-888 with metronomic oral cyclophosphamide or metronomic oral cyclophosphamide alone. Patients in cohort C will be randomized to the combination of ABT-888 with metronomic oral cyclophosphamide or metronomic oral cyclophosphamide alone.
* Cyclophosphamide (50 mg) and ABT-888 (60 mg) will be administered orally once a day, continuously in 21-day cycles.

Phase II ABT-888 With Cyclophosphamide

Phase II Randomized Trial of ABT-888 in Combination With Metronomic Oral Cyclophosphamide in Refractory BRCA-Positive Ovarian, Primary Peritoneal, Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, or Triple-Negative Breast Cancer

Data are being shared with this CT.gov report and two peer-reviewed publications. There is no plan to share individual patient results.

Complete response (CR) + partial response (PR)) of the combination of ABT-888 with metronomic oral cyclophosphamide to the response rate (CR+PR) of metronomic oral cyclophosphamide in patients with deleterious BRCA mutations and refractory ovarian cancer or patients with primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube cancer. CR + PR was determined by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm). Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Time to progression for each participant for the initial intervention.

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

PAR levels (in pg/μg protein) were assessed in peripheral blood mononuclear cells (PBMCs) by immunoassay to assess poly (ADP-ribose) polymerase (PARP) activity. Significant inhibition of PARP activity is associated with 50% or greater reduction in PAR levels.

Number of CTCs (evaluable defined as ≥ 6 CTCs) were measured in whole blood during the course of treatment to determine drug-induced deoxyribonucleic acid damage in tumor cells.

Gene expression profiling was performed in archival tumor tissue for a panel of 211 genes using deoxyribonucleic acid (DNA) array to determine deleterious mutations (i.e. nonsynonymous mutations at coding regions) of genes. Sequences were mapped to human genome reference hg19. Variants were identified with VarScan, annotated with AVIA, and masked to the exonic or exonic:splicing regions of the 211 interrogated DNA repair genes, with nonsynonymous/frameshift/stop-gain/stop-loss variants that have a population frequency of 1% or less in either 1000G (2014_04) or the ExomeSequencingProject (ESP6500si_all) with a minimum variant frequency of 10% and at least 20 reads. Lastly, variants were manually inspected for known platform and mapping errors.

Adverse events were categorized by treatment (initial vs. crossover treatment arms) rather than indication as this was how we analyzed the data.

BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide

Oral cyclophosphamide 50mg by mouth (PO) for 21 days.

BRCA-positive Ovarian Cancer: Cyclophosphamide Alone

BRCA-positive Ovarian Cancer: Crossover

Triple-negative Breast Cancer: Cyclophosphamide & ABT-888

Triple-negative Breast Cancer: Cyclophosphamide Alone

Triple-negative Breast Cancer: Crossover

Non-Hodgkin's: ABT-888 + Cyclophosphamide

Non-Hodgkin's: Cyclophosphamide Alone

Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO).

Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide

Total

Canada

Dr. Alice Chen

Percentage of Participants With an Overall Response Rate

Progression Free Survival

BRCA-positive Ovarian Cancer: ABT-888 & Cyclophosphamide

Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth on a continuous schedule.

Non-Hodgkin's: ABT-888 & Cyclophosphamide

Number of Participants With Adverse Events

Patients with PBMCs data pre- and post-drug administration, and with PAR levels above the lower limit of quantitation (LLOQ) of 23 pg/μg protein were analyzed.

Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline

Patients with sufficient CTC counts (defined as ≥6 total CTCs) pre- and post-drug administration were analyzed.

Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood

Patients with sufficient tumor content in archival tissue (defined as ≥70% tumor after macrodissection) were analyzed for genetic alterations in DNA repair genes by whole-exome sequencing.

Number of Participants With Deleterious Mutations in DNA Repair Genes

First Intervention

Disease Progression/Crossover

This study aims to answer very important questions regarding the prevalence of somatic and germline mutations (sBRCAm and gBRCAm) in a population of newly diagnosed ovarian cancer patients from Latin America. These answers may be extremely helpful in the counseling for genetic risk and treatment approach in these populations and will aid in making treatment decisions in the future

FLABRA is a cross-sectional, multi-center, epidemiological observational study designed to evaluate the prevalence of BRCA mutations in newly diagnosed ovarian cancer patients across understudied ethnic groups in Latin America. Secondary objectives of the study are to evaluate the prevalence of sBRCAm versus gBRCAm in newly diagnosed ovarian cancer patients and to describe current ovarian cancer counselling and treatment approach patterns at front line setting across Latin America.

In the Screening Visit, consecutive eligible patients who have been newly diagnosed with ovarian cancer within the last 120 days will be invited to participate. After having provided consent, patients will be asked to provide ethnicity and cancer family history information. Patients will self-identify to one or more of the defined broad ethnic groups (Native American, Afro-Caribbean, Caucasian) based on self-reported ancestry information. Archived tumor blocks or twenty 10-µm sections from eligible patients will be requested from the local pathology lab and used for BRCA mutations testing.

Patient medical records will be reviewed for data relevant to the ovarian cancer diagnosis, including basic demographics, medical history, and treatment history.

During the Devolution Visit, results of the tumor BRCA test will be communicated to the patient, and information about counselling approach and treatment plan will be recorded in the medical chart. This Devolution Visit will be the last visit for this study for the cases of non-mutated patients. For patients for whom a BRCA mutation have been identified in tumor, additional test in blood looking for the specific point mutation found in tumor will be performed to investigate if these patients harbor a germline BRCA mutation. For these patients a further visit will be organised to communicate results to the patient and data regarding germline test results will be recorded in the medical chart of the patient.

Archived tumor blocks or twenty 10-µm sections from eligible patients will be requested from the local pathology lab and used for BRCA mutations testing.

FLABRA: Frontline Approach for BRCA Testing in OC Treatment naïve Population. A LATIN AMERICA Epidemiologic Study

Frontline Approach for BRCA Testing in OC Treatment naïve Population. A LATIN AMERICA Epidemiologic Study

FLABRA is a cross-sectional, multi-center, epidemiological observational study designed to evaluate the prevalence of BRCA mutations in newly diagnosed ovarian cancer patients across understudied ethnic groups in Latin America

To estimate the prevalence of gBRCAm in newly diagnosed ovarian cancer patients who have a BRCA mutation identified in the tumor sample, in LATAM population, and by ethnic sub-groups

To describe all professionals participating in this process, and time for the approach

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial)	NCT04692740	Pancreatic Duct...	Chlorambucil, O...	18 Years -	IRCCS San Raffaele
Niraparib Plus Aromatase Inhibitors for Luminal-like(HER2-,ER+) and gBRCA or HDR+ Metastatic Breast Cancer (LUZERN)	NCT04240106	Breast Cancer Breast Cancer M...	Niraparib Aromatase Inhib...	18 Years -	MedSIR
Niraparib Plus Aromatase Inhibitors for Luminal-like(HER2-,ER+) and gBRCA or HDR+ Metastatic Breast Cancer (LUZERN)	NCT04240106	Breast Cancer Breast Cancer M...	Niraparib Aromatase Inhib...	18 Years -	MedSIR
Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial)	NCT04692740	Pancreatic Duct...	Chlorambucil, O...	18 Years -	IRCCS San Raffaele
Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations	NCT01989546	Advanced Ovaria... Primary Periton... Advanced Breast... Advanced Solid ...	BMN 673	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations	NCT01989546	Advanced Ovaria... Primary Periton... Advanced Breast... Advanced Solid ...	BMN 673	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Roll Over StudY for Patients Who Have Completed a Previous Oncology Study With Olaparib	NCT04421963	Ovarian Cancer Breast Cancer	Olaparib	18 Years - 99 Years	AstraZeneca
Phase II ABT-888 With Cyclophosphamide	NCT01306032	Ovarian Cancer Primary Periton... Serous Carcinom... Triple-Negative... Fallopian Tube ...	ABT-888 Cyclophosphamid...	18 Years -	National Institutes of Health Clinical Center (CC)
FLABRA: Frontline Approach for BRCA Testing in OC Treatment naïve Population. A LATIN AMERICA Epidemiologic Study	NCT02984423	Ovarian Cancer		-	AstraZeneca
Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations	NCT01989546	Advanced Ovaria... Primary Periton... Advanced Breast... Advanced Solid ...	BMN 673	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial)	NCT04692740	Pancreatic Duct...	Chlorambucil, O...	18 Years -	IRCCS San Raffaele

Spots Global Cancer Trial Database for brca mutations