Clinical Trials /

Abemaciclib and Niraparib Before Surgery for the Treatment of Hormone Receptor Positive HER2 Negative Breast Cancer

NCT04481113

Description:

This phase I trial tests the side effects and best dose of abemaciclib and niraparib in treating patients with breast cancer that is positive for estrogen or progesterone receptors (hormone receptor positive [HR+]) and HER2 negative. Abemaciclib may stop the growth of tumor cells by blocking certain proteins called cyclin-dependent kinases, which are needed for cell growth. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as niraparib, can keep PARP from working so tumor cells can't repair themselves and grow. Giving abemaciclib and niraparib together before surgery may make the tumor smaller.

Related Conditions:
  • Invasive Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Abemaciclib and Niraparib Before Surgery for the Treatment of Hormone Receptor Positive HER2 Negative Breast Cancer
  • Official Title: A Phase 1 Study of Abemaciclib and Niraparib as Neoadjuvant Therapy in Hormone Receptor Positive (HR+) HER2 Negative (HER2-) Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: STUDY00021243
  • SECONDARY ID: NCI-2020-03813
  • SECONDARY ID: STUDY00021243
  • NCT ID: NCT04481113

Conditions

  • Anatomic Stage I Breast Cancer AJCC v8
  • Anatomic Stage IA Breast Cancer AJCC v8
  • Anatomic Stage IB Breast Cancer AJCC v8
  • Anatomic Stage II Breast Cancer AJCC v8
  • Anatomic Stage IIA Breast Cancer AJCC v8
  • Anatomic Stage IIB Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • HER2 Negative Breast Adenocarcinoma
  • Hormone Receptor Positive Breast Adenocarcinoma
  • Invasive Breast Carcinoma
  • Multifocal Breast Carcinoma
  • Prognostic Stage I Breast Cancer AJCC v8
  • Prognostic Stage IA Breast Cancer AJCC v8
  • Prognostic Stage IB Breast Cancer AJCC v8
  • Prognostic Stage II Breast Cancer AJCC v8
  • Prognostic Stage IIA Breast Cancer AJCC v8
  • Prognostic Stage IIB Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Unilateral Breast Carcinoma

Interventions

DrugSynonymsArms
AbemaciclibLY-2835219, LY2835219, VerzenioTreatment (abemaciclib, niraparib)
Niraparib Tosylate MonohydrateZejulaTreatment (abemaciclib, niraparib)

Purpose

This phase I trial tests the side effects and best dose of abemaciclib and niraparib in treating patients with breast cancer that is positive for estrogen or progesterone receptors (hormone receptor positive [HR+]) and HER2 negative. Abemaciclib may stop the growth of tumor cells by blocking certain proteins called cyclin-dependent kinases, which are needed for cell growth. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as niraparib, can keep PARP from working so tumor cells can't repair themselves and grow. Giving abemaciclib and niraparib together before surgery may make the tumor smaller.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose of the
      combination of abemaciclib and niraparib tosylate monohydrate (niraparib).

      II. To assess safety and tolerability of the combination of abemaciclib and niraparib in
      early stage HR+ breast cancer.

      SECONDARY OBJECTIVES:

      I. To determine clinical response to treatment. II. To determine pathologic response to
      treatment. III. To determine feasibility of combination as determined by no delay to standard
      of care breast surgery.

      EXPLORATORY OBJECTIVE:

      I. To assess occurrence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia
      (AML) malignancy.

      OUTLINE: This is a phase 1 dose-escalation study of abemaciclib in combination with niraparib
      followed by a dose-expansion study.

      Patients receive abemaciclib orally (PO) twice daily (BID) and niraparib PO once daily (QD).
      Treatment repeats every 28 days for up to 2-4 cycles in the absence of disease progression or
      unacceptable toxicity. Patients who complete 4 cycles undergo standard of care mastectomy or
      lumpectomy. Patients demonstrating progressive disease after only 2 cycles are switched to
      receive standard of care chemotherapy prior to undergoing mastectomy or lumpectomy.

      Patients are followed up at 30 days after date of surgery, every 3 months for the first 6
      months, every 6 months for 2 years, then annually for up to 5 years from date of surgery.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (abemaciclib, niraparib)ExperimentalPatients receive abemaciclib PO BID and niraparib PO QD. Treatment repeats every 28 days for up to 2-4 cycles in the absence of disease progression or unacceptable toxicity. Patients who complete 4 cycles undergo standard of care mastectomy or lumpectomy. Patients demonstrating progressive disease after only 2 cycles are switched to receive standard of care chemotherapy prior to undergoing mastectomy or lumpectomy.
  • Abemaciclib
  • Niraparib Tosylate Monohydrate

Eligibility Criteria

        Inclusion Criteria:

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Females (regardless of menopausal status), or males of all races and ethnic groups

          -  Biopsy proven estrogen receptor (ER) and/or progesterone receptor (PR) positive as
             defined as ER >= 1% and/or PR >= 1% by immunohistochemistry according to American
             Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
             for hormone receptor testing

          -  HER2 non-amplified per 2018 ASCO/CAP guidelines, defined as:

               -  Immunohistochemistry (IHC) score 0/1+, or

               -  IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to
                  CEP17 < 2.0, and if reported, average HER2 gene copy number < 4 signals/cells; or

               -  ISH non-amplified with a ratio of HER2 to CEP17 < 2.0, and if reported, average
                  HER2 gene copy number < 4 signals/cells

          -  Clinical T1-T3, any N, M0 invasive breast cancer, by American Joint Committee on
             Cancer (AJCC) 8th edition clinical staging with the goal being curative intent surgery
             to completely excise involved tumor in the breast and the draining lymph nodes

          -  Individuals with unilateral, multi-focal breast cancer (defined as more than one
             lesion of invasive breast cancer in the same breast separated from the dominant breast
             lesion by less than 5 cm of radiologically normal breast tissue) are eligible

          -  Participants must be planned for neoadjuvant chemotherapy

          -  Except for allowable endocrine therapy up to 4 weeks prior to study enrollment,
             participants must not have received prior anti-cancer therapy for the treatment of
             their breast cancer

          -  Participant must have disease that is amenable to biopsy, and agree to provide the
             required research biopsies at baseline, and 2 months after initiating study therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

          -  The participant is able to swallow oral medications

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

          -  Platelets >= 100 x 10^9/L

          -  Hemoglobin >= 9 g/dL

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN). Participants with Gilbert's
             syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal
             limits are permitted

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN

          -  If a participant is a cancer survivor, they have undergone potentially curative
             therapy for all prior malignancies, with no evidence of recurrence > 5 years

          -  Female participants of childbearing potential (FOCBP) must have a negative serum or
             urine pregnancy test (per institutional standards) within 7 days prior to the start of
             study drugs

          -  FOCBP must agree to use highly-effective method(s) of contraception during the study
             and for 6 months after the last dose of study drugs

          -  FOCBP are those who have not been surgically sterilized or have not been free from
             menses for > 1 year without an alternative medical cause

          -  Male participants must agree to use an adequate method of contraception starting with
             the first dose of study therapy through at least 3 months after the last dose of study
             drugs

          -  Participant must agree to not donate blood during the study or for 90 days after the
             last dose of study treatment

          -  Participant receiving corticosteroids may continue as long as their dose is stable for
             least 4 weeks prior to initiating protocol therapy

          -  Participant must agree to not breastfeed during the study or for 30 days after the
             last dose of study treatment

        Exclusion Criteria:

          -  Prior history of malignancy within 5 years except for successfully treated cervical
             carcinoma in situ, lobular carcinoma in situ of the breast, or non-melanoma skin
             cancer

          -  Inflammatory breast cancer defined as clinically significant erythema of the breast
             and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau
             d'orange without erythema) is not eligible

          -  Participants that have undergone surgical axillary staging procedure prior to study
             entry

               -  Fine needle aspiration (FNA) or core needle biopsy of axillary node is permitted

          -  Bilateral breast cancer, provided tumors exhibit similar biomarkers (grade, ER/PR,
             HER2)

          -  Clinical or radiographic evidence of metastatic disease

               -  Isolated ipsilateral supraclavicular node involvement is permitted

               -  A prior history of ductal breast carcinoma in situ (DCIS) treated with
                  contralateral mastectomy and not receiving endocrine therapy is eligible

          -  Breast implants are contraindicated only if the implant precludes the required
             research biopsies or interferes with palpating the breast lesion

          -  Prior treatment for this cancer including surgery, radiation therapy, chemotherapy,
             biotherapy, hormonal therapy or investigational agent prior to study entry

               -  Participants may have received up to 4 weeks of endocrine therapy prior to
                  enrollment on trial

          -  Participants with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

          -  Contraindication to undergoing breast and/or axillary lymph node biopsy

          -  Contraindication to undergoing surgical resection

          -  Prior therapy with a PARP inhibitor

          -  Prior therapy with a CDK 4/6 inhibitor

          -  The patient has active systemic bacterial infection (requiring intravenous [IV]
             antibiotics at time of initiating study treatment), fungal infection, or detectable
             viral infection (such as known human immunodeficiency virus positivity or with known
             active hepatitis B or C [e.g., hepatitis B surface antigen positive]. Screening is not
             required for enrollment

          -  The patient has serious and/or uncontrolled preexisting medical condition(s) that, in
             the judgment of the investigator, would preclude participation in this study (for
             example, interstitial lung disease, severe dyspnea at rest or requiring oxygen
             therapy, severe renal impairment [e.g. estimated creatinine clearance < 30ml/min],
             history of major surgical resection involving the stomach or small bowel, or
             preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition
             resulting in baseline grade 2 or higher diarrhea)

          -  Known history of pneumonitis or interstitial lung disease (ILD)

          -  Known history of deep vein thrombosis (DVT) or pulmonary embolism (PE)

          -  Participant must not have received a transfusion (platelets or red blood cells) =< 4
             weeks prior to initiating protocol therapy. Exceptions may be made at the discretion
             of the investigator for the treatment of clinical complications such as bleeding. In
             these cases, protocol therapy may start >= 7 days after transfusion

          -  Participant must not have received colony stimulating factors (e.g., granulocyte
             colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
             recombinant erythropoietin) within 4 weeks prior initiating protocol therapy

          -  The patient has a personal history of any of the following conditions: syncope of
             cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
             not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
             cardiac arrest

          -  Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
             cardiac conditions, as judged by the investigator (e.g., unstable ischemia,
             uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's Correction
             Formula (QTcF) prolongation > 500 ms, electrolyte disturbances, etc.), or participants
             with congenital long QT syndrome

          -  Uncontrolled hypertension, or hypertension that cannot otherwise be clinically managed
             before initiating study therapy

          -  Psychiatric illness/social situations, or any condition that, in the opinion of the
             investigator, would: interfere with evaluation of study treatment or interpretation of
             participant safety or study results, or substantially increase risk of incurring
             adverse events (AEs), or compromise the ability of the patient to give written
             informed consent

          -  Participant must not have had major surgery =< 3 weeks prior to initiating protocol
             therapy and participant must have recovered from any surgical effects

          -  Hypersensitivity to any study agent, or its excipients, when administered alone

          -  Females who are pregnant or lactating

          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose limiting toxicities (DLTs) for the proposed combination
Time Frame:First dose of study agents to end of cycle 1 for dose-determining phase (each cycle is 28 days)
Safety Issue:
Description:Dose-limiting toxicities will specifically be reported for the DLT evaluation period using the MTD-evaluable population.

Secondary Outcome Measures

Measure:Overall objective response rate (ORR)
Time Frame:From the date of first dose of study agents to 30 days post-surgery (up to 5 months)
Safety Issue:
Description:Overall response will be summarized descriptively. ORR will be estimated with 95% confidence interval (CI). The CI will be calculated based on the exact method for binomial distributions.
Measure:Clinical benefit rate (CBR)
Time Frame:From date of dose of study agents to 30 days post-surgery (up to 5 months)
Safety Issue:
Description:An estimate of CBR will be measured and reported with 95% exact CI. Participants who achieve a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months on the current protocol will be qualified as deriving benefit from therapy and will count towards the CBR measurement.
Measure:Rate of pathological complete response (pCR)
Time Frame:At time of surgical resection (up to 4 months)
Safety Issue:
Description:pCR will be tabulated as proportions and analyzed descriptively. Rate of delay to breast surgery will be summarized descriptively
Measure:Rate of residual cancer burden (RCB) 0-1
Time Frame:At time of surgical resection (up to 4 months)
Safety Issue:
Description:RCB will be tabulated as proportions and analyzed descriptively. Rate of delay to breast surgery will be summarized descriptively
Measure:Rate of delay to breast surgery
Time Frame:From date of last dose of study drug to date of surgery (up to 4 months)
Safety Issue:
Description:Defined as proportion of participants with time-to-surgery > 90 days following completion of study therapy due to study-treatment related toxicity.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Last Updated

March 30, 2021