Study Evaluating the Antitumor Activity and Safety of Niraparib as Neoadjuvant Treatment in Participants With Breast Cancer

• ClinicalTrials.gov Identifier: NCT03329937
• Recruitment Status: Completed
• First Posted: November 6, 2017
• Results First Posted: January 12, 2021
• Last Update Posted: January 12, 2021
• Sponsor: Tesaro, Inc.
• Information provided by (Responsible Party): Tesaro, Inc.

Study Description

Brief Summary:

This is an open-label, single-arm pilot study evaluating the antitumor activity and safety of niraparib as neoadjuvant therapy in participants with Human epidermal growth factor receptor 2 (HER2)-negative and breast cancer susceptibility gene mutant (BRCAmut) localized breast cancer (primary tumor >=1 centimeters [cm]). Breast magnetic resonance imaging (MRI), breast ultrasound, and tumor core biopsy will be performed at the screening (Days -28 to -1). Participants will receive niraparib (200 milligrams [mg] orally [PO]) treatment daily for 28 days (Cycle 1) and then will undergo breast ultrasound at the end of Cycle 1 on Day 28. Based on breast ultrasound reports, the participants will either discontinue the study (disease progression) or will continue niraparib treatment (complete response [CR], partial response [PR] or stable disease [SD]) for an additional cycle (Cycle 2). A breast MRI and breast ultrasound will be performed at the end of Cycle 2. Approximately 21 participants will be enrolled in this study and the study duration will be approximately 2 years.

Condition or disease	Intervention/treatment	Phase
Neoplasms, Breast	Drug: Niraparib	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Single-arm Pilot Study Evaluating the Antitumor Activity and Safety of Niraparib as Neoadjuvant Treatment in Localized, HER2-negative, BRCA-mutant Breast Cancer Patients
• Actual Study Start Date: April 12, 2018
• Actual Primary Completion Date: January 2, 2020
• Actual Study Completion Date: March 31, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Participants with HER2-negative and BRCAmut breast cancer; Participants with HER2-negative and BRCAmut localized breast cancer (primary tumor >=1 cm) will receive niraparib (200 mg PO).

Drug: Niraparib; Niraparib is a potent, orally active, highly selective poly adenosine diphosphate ([ADP]-ribose) polymerase 1 (PARP1) and PARP2 inhibitor. It will be supplied as 100 mg capsules and will be administered at starting dose of 200 mg PO daily throughout 28 days for 2 cycles (each cycle is 28 days), with the potential for an additional 4 cycles (maximum total of 6 cycles) at the assigned dose and schedule.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Tumor Response Measured by Breast MRI [ Time Frame: At 2 months ]
   Tumor response measured by breast MRI is defined as >=30 percent (%) reduction of tumor volume from Baseline based on primary lesion after niraparib treatment without any new lesion development. Tumor volume was calculated as (length × width × height × pi [π])/6. Responses were assessed as Clinical complete response (CR): A complete disappearance of all tumor signs in the breast as assessed by imaging test. Clinical partial response (PR): A reduction in the tumor volume of the primary tumor size by >=30% assessed by palpation or imaging test. Clinical stable disease (SD): No significant change in tumor volume during treatment. Clinical progressive disease (cPD): The development of new, previously undetected lesions, or an estimated increase in the size of the primary lesion by greater than 20%. Percentage of participants with tumor response and its 95 percent confidence interval (CI) has been presented. The 95% CI was the binomial exact CI based on Clopper-Pearson method.

Secondary Outcome Measures :

1. Percentage of Participants With Pathological Complete Response (pCR) [ Time Frame: Up to 1 year ]
   pCR is defined as ypT0/Tis ypN0 by receipt of pre-operative chemotherapy (Yes versus No). Following neoadjuvant therapy, pathological staging is recorded using the 'yp' designation. ypT0/Tis ypN0 is the absence of invasive cancer in the breast and axillary nodes. pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0 in the current American Joint Committee on Cancer [AJCC] staging system). Percentage of participants with pCR rate its 95 percent CI has been presented. CI was based on binomial exact CI.
2. Percentage of Participants With Tumor Response as Measured by Breast Ultrasound [ Time Frame: Up to 6 months ]
   Tumor response rate was based on the change in tumor volume as measured by breast ultrasound; a response was considered >=30 percent reduction of tumor volume from Baseline without any new lesion development. Tumor volume was calculated as (length × width × height × π)/6. Percentage of participants with tumor response and its 95 percent CI has been presented. CI was based on binomial exact CI.
3. Percent Change From Baseline in Tumor Volume Measured by Ultrasound [ Time Frame: Baseline and up to 6 months ]
   Percentage change in tumor volume from Baseline was measured using ultrasound. Baseline was defined as the most recent measurement prior to the first administration of niraparib. Tumor volume was calculated as (length × width × height × π)/6. The percentage reduction in tumor volume was set as 99% if the tumor becomes too small to measure at the post-baseline visit. Percent change from Baseline was defined as greatest change in volume, derived from all available cycles of niraparib (range from cycle 2 to 6) and multiplied by 100.
4. Percent Change From Baseline in Tumor Volume Measured by MRI [ Time Frame: Baseline and at 2 months ]
   Percentage change in tumor volume from Baseline after 2 months of niraparib treatment was measured using MRI. Baseline was defined as the most recent measurement prior to the first administration of niraparib. Tumor volume was calculated as (length × width × height × π)/6. The percentage reduction in tumor volume was set as 99% if the tumor becomes too small to measure at the post-baseline visit. Percent change from Baseline was defined as value of post Baseline minus Baseline value and multiplied by 100.
5. Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment Discontinuations and Dose Reductions Due to Adverse Events (AEs) [ Time Frame: Up to 1 year ]
   An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or an important medical event. A TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participants age >= 18 years old.
• Participants with a deleterious or suspected deleterious breast cancer susceptibility gene 1 (BRCA1) or BRCA2 mutation (germline or somatic) may be enrolled into the study based on either local or central laboratory testing of BRCA status.
• Histologically-confirmed HER2-negative localized breast cancer by core biopsy.
• Primary operable, non-metastatic invasive carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. In participants with multifocal and/or multicentric, the largest lesion should be measured. Both unilateral and bilateral breast cancer are allowed.
• Primary tumor size >=1cm.
• Measurable disease by breast ultrasound and MRI.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Adequate organ function defined as:

  1. Absolute neutrophil count (ANC) >=1500 per microliters (/μL).
  2. Platelets >=100,000/μL.
  3. Hemoglobin >=9 grams per deciliter (g/dL).
  4. Serum creatinine <=1.5*upper limit of normal (ULN) or calculated creatinine clearance >=50 milliliters per minute (mL/min) using Cockcroft-Gault equation.
  5. Total bilirubin <=1.5*ULN except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin <=1.5*ULN of the direct bilirubin.
  6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5*ULN.
• Participants must have recovered to Grade 1 toxicity from prior cancer therapy (a participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify for this study).
• Participant able to take oral medications.

• Participant meets the following criteria:

  1. Female participant (of childbearing potential) is not breastfeeding, has a negative serum pregnancy test within 72 hours prior to taking study drug, and agrees to abstain from activities that could result in pregnancy from Screening through 180 days after the last dose of study drug, or is of non-childbearing potential.
  2. Female participant is of non-childbearing potential (other than medical reasons) as defined:

  i) >=45 years of age and has not had menses for >1 year. ii) Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon the screening evaluation.

iii) Has undergone post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented hysterectomy, oophorectomy or tubal ligation must be confirmed in the medical records, otherwise the participant must be willing to use 2 adequate barrier methods throughout the study starting from the screening visit through 180 days after the last dose of study drug. Information must be captured appropriately within the site's source documents.

c) Male participant agrees to use an effective method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

• Able to understand the study procedures and agree to participate in the study by providing written informed consent.

Exclusion Criteria:

• Prior anti-cancer therapies for current malignancy.
• Known evidence of distant metastasis. Staging studies are not required. The decision to pursue staging studies is at the discretion of the treating clinician, based on the participant's clinical and pathological findings consistent with standard guidelines.
• Known hypersensitivity to the components of niraparib components or their formulation excipients.
• Major surgery within 3 weeks of starting the study or participant has not recovered from any effects of any major surgery.
• Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, uncontrolled hypertension, active uncontrolled coagulopathy, bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent.
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study drug, or is not in the best interest of the participant to participate.
• Participant is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study drug or within the 180-day period after the last dose of study drug.
• Immunocompromised participants.
• Known active hepatic disease (Hepatitis B or C).
• Prior treatment with a known PARP inhibitor.
• Other active malignancy that warrants systemic therapy.
• Known history of myelodysplastic syndromes (MDS) or Acute myeloid leukemia (AML).

Contacts and Locations

Locations

United States, Florida

GSK Investigational Site

Fort Myers, Florida, United States, 33908

GSK Investigational Site

Tampa, Florida, United States, 33612

United States, Maryland

GSK Investigational Site

Baltimore, Maryland, United States, 21231

United States, Massachusetts

GSK Investigational Site

Boston, Massachusetts, United States, 02114

United States, Minnesota

GSK Investigational Site

Rochester, Minnesota, United States, 55905

United States, New York

GSK Investigational Site

New York, New York, United States, 10029

United States, Tennessee

GSK Investigational Site

Nashville, Tennessee, United States, 37203

Sponsors and Collaborators

Tesaro, Inc.

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

  Study Documents (Full-Text)

Documents provided by Tesaro, Inc.:

Study Protocol  [PDF] August 1, 2018

Statistical Analysis Plan  [PDF] September 5, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Spring LM, Han H, Liu MC, Hamilton E, Irie H, Santa-Maria CA, Reeves J, Pan P, Shan M, Tang Y, Graham JR, Hazard S, Ellisen LW, Isakoff SJ. Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer. Nat Cancer. 2022 Aug;3(8):927-931. doi: 10.1038/s43018-022-00400-2. Epub 2022 Jul 4. Erratum In: Nat Cancer. 2022 Aug 5;:

• Responsible Party: Tesaro, Inc.
• ClinicalTrials.gov Identifier: NCT03329937
• Other Study ID Numbers: 213355; 3000-01-005 ( Other Identifier: Tesaro )
• First Posted: November 6, 2017
• Results First Posted: January 12, 2021
• Last Update Posted: January 12, 2021
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tesaro, Inc.:

Niraparib; Human epidermal growth factor receptor; Breast cancer; Breast ultrasound; Magnetic resonance imaging

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Niraparib; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents