Clinical Trials /

Nab-paclitaxel and Alpelisib for the Treatment of Anthracycline Refractory Triple Negative Breast Cancer With PIK3CA or PTEN Alterations

NCT04216472

Description:

This phase II trial studies how well nab-paclitaxel and alpelisib works in treating patients with triple negative breast cancer with PIK3CA or PTEN alterations that does not respond to anthracycline chemotherapy (anthrocycline refractory). Drugs used in chemotherapy, such as nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nab-paclitaxel and alpelisib before surgery may help shrink the tumor before surgery.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nab-paclitaxel and Alpelisib for the Treatment of Anthracycline Refractory Triple Negative Breast Cancer With PIK3CA or PTEN Alterations
  • Official Title: A Phase-2, Two-Cohort Trial of Neoadjuvant Nab-Paclitaxel and Alpelisib in Anthracycline Refractory Triple Negative Breast Cancer With PIK3CA or PTEN Alterations

Clinical Trial IDs

  • ORG STUDY ID: 2019-0752
  • SECONDARY ID: NCI-2019-08495
  • SECONDARY ID: 2019-0752
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04216472

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 III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • 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 III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Refractory Breast Carcinoma
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
AlpelisibBYL719, Phosphoinositide 3-kinase Inhibitor BYL719, PiqrayTreatment (alpelisib, nab-paclitaxel)
Nab-paclitaxelABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, Paclitaxel Albumin, paclitaxel albumin-stabilized nanoparticle formulation, protein-bound paclitaxelTreatment (alpelisib, nab-paclitaxel)

Purpose

This phase II trial studies how well nab-paclitaxel and alpelisib works in treating patients with triple negative breast cancer with PIK3CA or PTEN alterations that does not respond to anthracycline chemotherapy (anthrocycline refractory). Drugs used in chemotherapy, such as nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nab-paclitaxel and alpelisib before surgery may help shrink the tumor before surgery.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if alpelisib in combination with nab-paclitaxel in the neoadjuvant setting
      will improve rates of pathologic response (pathological complete response [pCR/RCB-0] or
      minimal residual disease [RCB-I]) from 5% to 20% in patients with chemotherapy insensitive
      triple negative breast cancer (TNBC) with PIK3CA alterations (including PTEN loss). (Cohort
      1) II. To determine if alpelisib in combination with nab-paclitaxel in the neoadjuvant
      setting will improve rates of pathologic response (pCR/RCB-0 or RCB-I) from 5% to 20% in
      patients with chemotherapy insensitive TNBC with PTEN alterations. (Cohort 2)

      SECONDARY OBJECTIVES:

      I. Determine the radiographic response rate for alpelisib in combination with nab-paclitaxel
      as measured by ultrasound and/or magnetic resonance imaging (MRI) (partial response +
      complete clinical response) in chemotherapy insensitive TNBC with PIK3CA (Cohort-1) or PTEN
      (Cohort-2) alterations.

      II. Determine toxicity of alpelisib in combination with nab-paclitaxel given in the
      neoadjuvant setting following anthracycline based therapy.

      III. Determine progression free survival (PFS) at 3 years for patients treated with alpelisib
      in combination with nab-paclitaxel given in the neoadjuvant setting in chemotherapy
      insensitive TNBC with PIK3CA (Cohort-1) or PTEN (Cohort-2) alterations.

      EXPLORATORY OBJECTIVES:

      I. To assess biomarkers of response and resistance to alpelisib and nab-paclitaxel
      combination.

      II. To assess the role of circulating tumor deoxyribonucleic acid (ctDNA) allele fraction in
      predicting response to alpelisib and nab-paclitaxel in early stage TNBC.

      OUTLINE:

      Patients receive alpelisib orally (PO) once daily (QD) on days 1-21, and nab-paclitaxel
      intravenously (IV) over 30 minutes on days 1, 8, and 15. Treatment repeats every 21 days for
      4 cycles in the absence of disease progression or unacceptable toxicity. Patients may then
      undergo surgery to remove the tumor.

      After completion of study treatment, patients are followed up at 30 days, and then
      periodically until up to 3 years after surgery.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (alpelisib, nab-paclitaxel)ExperimentalPatients receive alpelisib PO QD on days 1-21, and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may then undergo surgery to remove the tumor.
  • Alpelisib
  • Nab-paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

          -  Stage I-III breast cancer

          -  Confirmed invasive triple-negative breast cancer defined as estrogen receptor (ER) <
             10%; progesterone receptor (PR) < 10% by immunohistochemistry (IHC) and HER2 negative
             by American Society of Clinical Oncology (ASCO)/(College of American Pathologists) CAP
             guidelines

          -  Activating mutations in PIK3CA (cohort-1), or loss of function alterations in PTEN by
             next generation sequencing (NGS) or IHC (cohort-2) (based on MD Anderson Cancer Center
             [MDACC] Dako 6H2.1 assay)

          -  Fasting plasma glucose (FPG) =< 140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin
             (HbA1c) < 6.4 %

               -  For patients with pre-diabetes (FPG >= 100 mg/dL and/or HbA1c >= 5.7%) at
                  screening, recommend lifestyle changes according to American Diabetes Association
                  (ADA) guidelines. A consultation with a diabetologist is highly recommended

          -  Chemotherapy insensitive disease as defined by ARTEMIS parameters (=< 70 % volumetric
             response after four cycles of anthracycline-based therapy)

          -  Residual primary tumor size of at least 1.0 cm by imaging (ultrasound or MRI) or
             evidence of lymph node involvement by imaging (ultrasound or MRI) after
             anthracycline-based neoadjuvant chemotherapy (NACT)

          -  Received at least one dose of an anthracycline-based NACT. Patients are eligible if
             therapy was discontinued due to disease progression or therapy intolerance

          -  Prior to participation on ARTEMIS trial (2014-0185) multigated acquisition scan (MUGA)
             or echocardiogram showing left ventricular ejection fraction (LVEF) >= 50%

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

          -  Platelets >= 100 x 10^9 /L

          -  Hemoglobin (Hb) > 9 g/dL

          -  Fasting serum amylase =< 2 x upper limit of normal (ULN)

          -  Fasting serum lipase =< ULN

          -  Total serum bilirubin =< 1.5 mg/dL

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN or
             total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients
             with well documented Gilbert's syndrome

          -  Serum creatinine =< 1.5 x ULN or and/or creatinine clearance > 50% lower limit of
             normal (LLN)

          -  Signed informed consent obtained prior to any screening procedures

          -  Patients must have at least 2 and no more than 5 weeks between anthracycline-based
             therapy and start of treatment with alpelisib and nab-paclitaxel

          -  Patients must have resolution of toxic effect(s) of the most recent prior chemotherapy
             to grade 1 or less (except alopecia)

          -  Women of childbearing potential (WCBP) must have a negative pregnancy test within 3
             days prior to the first dose of study treatment. WCBP (defined as all women
             physiologically capable of becoming pregnant) must use highly effective methods of
             contraception during the study and 12 weeks after. Highly effective contraception
             methods include a combination of any two of the following:

               -  Placement of an intrauterine device (IUD) or intrauterine system (IUS)

               -  Barrier methods of contraception: condom or occlusive cap (diaphragm or
                  cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

               -  Total abstinence

               -  Male/ female sterilization

        Exclusion Criteria:

          -  Pregnant or lactating women

          -  Patient has a known hypersensitivity to alpelisib or any of its excipients

          -  Patients with clinically manifest diabetes mellitus (DM) or documented steroid induced
             DM

          -  Presence of distant metastatic disease (loco-regional nodal involvement of the
             ipsilateral axillary, internal mammary and/or supraclavicular nodes is not considered
             distant metastatic disease

          -  Prior radiation therapy of the primary breast carcinoma or axillary lymph nodes

          -  Patient is concurrently using other anti-cancer therapy

          -  Patients with an established diagnosis of diabetes mellitus type II or uncontrolled
             type II based on fasting plasma glucose or HbA1c

          -  Patients with a history of non-compliance to medical regimens or who are considered
             potentially unreliable or will not be able to complete the entire study

          -  Known impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of alpelisib

          -  Male patients whose sexual partner(s) are WCBP who are not willing to use adequate
             contraception, during the study and for 4 weeks after the end of treatment

          -  Patients with > grade 1 peripheral neuropathy

          -  Patients being treated with drugs recognized as being strong inhibitors or inducers of
             the isoenzyme CYP3A within the last 5 days prior to study entry

          -  Serious concurrent illness or clinically-relevant active infection, including, but not
             limited to the following:

               -  Known active hepatitis B or C

               -  Known human immunodeficiency virus (HIV) infection

               -  Varicella-zoster virus (shingles)

               -  Cytomegalovirus infection

               -  Any other known concurrent infectious disease, requiring IV antibiotics within 2
                  weeks of study enrollment

          -  Clinically- significant cardiac disease:

               -  Recent myocardial infarction (< 6 months prior to day 1)

               -  Unstable angina pectoris

               -  Uncontrolled congestive heart failure (New York Heart Association > class II)

               -  Uncontrolled hypertension

               -  Prior history of hypertensive crisis or hypertensive encephalopathy

               -  Uncontrolled cardiac arrhythmias

               -  Clinically-significant vascular disease (e.g. aortic aneurysm dissecting
                  aneurysm)

               -  Severe aortic stenosis

               -  Clinically significant peripheral vascular disease

               -  Friderica's Corrected QT interval (QTcF) > 470 for females and > 450 for males

          -  History of neurological conditions that would confound assessment of
             treatment-emergent neuropathy

          -  History of hemorrhagic or ischemic stroke within the last 6 months

          -  Patient with severe liver impairment (Child Pugh score B/C) or cirrhotic liver disease

          -  Patient has documented history of pneumonitis/interstitial lung disease

          -  History of acute pancreatitis within 1 year of screening or past medical history of
             chronic pancreatitis

          -  Patients who have a history of another primary malignancy, with the exceptions of:
             non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from
             which the patient has been disease free for 3 years

          -  History or evidence of thrombotic or hemorrhagic disorders within 6 months before
             first study treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of pathological complete response (pCR/RCB-0)
Time Frame:Up to 30 days
Safety Issue:
Description:Will be assessed by the alpelisib in combination with nab-paclitaxel in the neoadjuvant setting will improve rates.

Secondary Outcome Measures

Measure:Radiographic response rate (partial response + complete clinical response)
Time Frame:Up to 30 days
Safety Issue:
Description:Will be assessed by the radiographic response rate for alpelisib in combination with nab-paclitaxel
Measure:Incidence of adverse events
Time Frame:Up to 30 days
Safety Issue:
Description:Evaluated by Common Terminology Criteria for Adverse Events version 5.
Measure:Progression free survival
Time Frame:Up to 30 days
Safety Issue:
Description:Will be estimated using Kaplan-Meier method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 31, 2019