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BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT02379247
Recruitment Status : Active, not recruiting
First Posted : March 4, 2015
Last Update Posted : November 6, 2020
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Priyanka Sharma, University of Kansas Medical Center

Brief Summary:
Investigate the use of BYL719 as combination therapy with Nab-Paclitaxel in locally recurrent or metastatic HER-2 negative breast cancer.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: BYL719 Drug: Nab-paclitaxel Phase 1 Phase 2

Detailed Description:

Breast cancer is the most common cancer and the second leading cause of cancer related death in American women. Despite recent improvement in the treatment of breast cancer, 40,000 women still die each year in the US as a result of breast cancer. Chemotherapy (usually consisting of sequential single agent) remains the backbone of treatment for patients with HER-2 negative metastatic breast cancer. A majority of patients show an initial response to treatment, but all eventually show disease progression.

The purpose of this study is to determine the highest dose of BYL719 combined with Nab-Paclitaxel that results in no serious side effects. The safety and effectiveness of BYL719 combined with Nab-Paclitaxel to treat patients with HER-2 negative breast cancer will be assessed, along with the determination of how long this drug combination will keep the disease from getting worse.

The study will be done in two parts:

Part 1 will determine the highest dose of BYL719 that is safe and tolerable to take in combination with Nab-Paclitaxel. Part 1 will be completed before Part 2 begins.

Part 2 will investigate taking BYL719 (at the dose determined in Part 1) + Nab-Paclitaxel is safe and effective for patients with HER-2 negative breast cancer.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of BYL719 and Nab-Paclitaxel in Subjects With Locally Recurrent or Metastatic HER-2 Negative Breast Cancer
Actual Study Start Date : February 2015
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Paclitaxel

Arm Intervention/treatment
Experimental: Co-hort 1 BYL719 (250mg)+Nab-paclitaxel

BYL719: 250mg daily on day 1-28

Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day)

Drug: BYL719
Oral PI3K inhibitor
Other Name: PI3K inhibitor

Drug: Nab-paclitaxel
IV taxane
Other Name: Taxane

Experimental: Co-hort 2 BYL719 (300mg)+Nab-paclitaxel

BYL719: 300mg by mouth daily on day 1-28 of each 28 day cycle

Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day)

Drug: BYL719
Oral PI3K inhibitor
Other Name: PI3K inhibitor

Drug: Nab-paclitaxel
IV taxane
Other Name: Taxane

Experimental: Co-hort 3 BYL719 (350mg)+Nab-paclitaxel

BYL719: 350mg by mouth daily on day 1-28 of each 28 day cycle

Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day)

Drug: BYL719
Oral PI3K inhibitor
Other Name: PI3K inhibitor

Drug: Nab-paclitaxel
IV taxane
Other Name: Taxane

Experimental: BYL719 Dose Expansion

BYL719: MTD from Phase I by mouth daily on day 1-28 of each 28 day cycle

Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day)

Drug: BYL719
Oral PI3K inhibitor
Other Name: PI3K inhibitor

Drug: Nab-paclitaxel
IV taxane
Other Name: Taxane




Primary Outcome Measures :
  1. Phase I: Recommended Phase II Dose of BYL719 + Nab-paclitaxel to be used in combination to treat advanced HER-2 negative breast cancer [ Time Frame: 12 months ]
    Phase I Dose escalation

  2. Phase II: Overall Response Rate of subjects treated at the recommended phase II dose [ Time Frame: 24 months ]
    Phase II Dose expansion


Secondary Outcome Measures :
  1. Clinical Benefit Rate at 16 weeks of study treatment based on subjects having complete response, partial response or stabile disease at the recommended phase II dose [ Time Frame: 24 months ]
    Determine Clinical Benefit Rate

  2. Pharmacokinetics - Nab paclitaxel plasma concentration vs time profile when given with BYL [ Time Frame: 12 months ]
    Determination of pharmacokinetics of BYL719 when combined with Nab-paclitaxel

  3. Pharmacokinetics - BYL plasma concentration vs time profile when given with Nab paclitaxel [ Time Frame: 12 months ]
    Determination of pharmacokinetics of Nab-paclitaxel when combined with BYL719

  4. Progression-Free Survival and Overall Survival [ Time Frame: 36 months ]
    Determine progression free survival and overall survival


Other Outcome Measures:
  1. Correlation of PI3K aberrations with clinical response [ Time Frame: 24 months ]
    Investigate the correlation of PI3K aberrations with clinical response



Information from the National Library of Medicine

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

Inclusion Criteria:

  • HER-2 negative breast cancer that is either stage III disease not amenable to curative therapy or stage IV
  • Have measurable disease of ≥ 2 cm by conventional measurement or ≥ 1 cm on spiral CT
  • Prior chemotherapy for metastatic disease is allowed. No limitations to number of prior chemotherapies. Prior taxanes (except Nab-Paclitaxel) is allowed if it has been ≥ 6 months since prior taxane. NOTE: For subjects who are, or who have previously received, endocrine therapy for breast cancer, the treating investigator will decide how many days should pass between the last dose of endocrine therapy and the first dose of study treatment.
  • All patients should have received at least one line of chemotherapy in either the advanced or adjuvant setting and hormonal therapy (where appropriate)
  • ECOG Performance status ≥ 2
  • Subject is able to swallow and retain oral medicines
  • Laboratory values as follows:

    • Absolute neutrophil count ≥ 1500/uL
    • Platelets 100,000/uL (no transfusion ≤ 2 weeks)
    • Hemoglobin > 9 g/dL (may be reached by transfusion)
    • Total bilirubin within normal range or ≤ 1.5X IULN if liver metastases
    • Total bilirubin ≤ 3.0X IULN with direct bilirubin within normal range in subjects with Gilbert's Syndrome
    • AST(SGOT)/ALT(SPGT) ≤ 2.5X IULN or ≤ 5X IULN if liver metastases
    • Serum creatinine ≤ 1.5X IULN
    • INR ≤ 1.5
    • Fasting plasma glucose ≤ 140 mg/dL or 7.8 mmol/L
    • HBA1c ≤ 8%
    • Potassium, calcium (corrected for serum albumin) & magnesium within IULN
  • IV bisphosphate and denosumab for bony metastatic disease will be allowed
  • Radiation to bony metastases is allowed ≥ 14 days before starting study treatment
  • Subjects with previously treated brain metastases who are free of CNS symptoms and > 3 months from treatment are eligible
  • Subjects should be > 2 weeks from last chemotherapy for breast cancer AND be recovered to Grade 1 from related side effects

NOTE: Subjects who have had previous treatment with Nab-Paclitaxel will NOT be excluded if given in the adjuvant or neoadjuvant setting Only in the metastatic setting, will subjects previously treated with Nab-Paclitaxel be excluded from this trial.

  • Women of child bearing potential and their partners must use contraception prior to study entry, continuing for 90 days after treatment

Exclusion Criteria:

  • Other medical or psychiatric disorder placing the subject at undue risk for treatment complications
  • Subject is pregnant or nursing
  • Subject has been treated with Nab-Paclitaxel NOTE: Subjects who have had previous treatment with Nab-Paclitaxel will NOT be excluded if given in the adjuvant or neoadjuvant setting.

NOTE: Only in the metastatic setting, will subjects previously treated with Nab-Paclitaxel be excluded from this trial.

  • Subject has inflammatory breast cancer
  • Subject has a known hypersensitivity to Nab-Paclitaxel or BYL719
  • Subject has a concurrent malignancy or malignancy within 3 years, except for basal/squamous cell carcinoma, non-melanoma skin cancer or curatively resected cervical cancer
  • Subject has diabetes mellitus or steroid-induced diabetes mellitus
  • Subject has impaired gastrointestinal function or disease altering the absorption of study drugs
  • Subject is classified into Child-Pugh class C
  • Subject has a known history of HIV infection (testing not mandatory)
  • Subject has an active and uncontrolled infection
  • Subject has symptomatic/untreated CNS disease
  • Subject has ≥ Grade 2 peripheral neuropathy
  • Subject has active or history of cardiac disease including:

    • Unstable angina within 6 months before study entry
    • Symptomatic peritonitis
    • Documented heart attack within 6 months before study entry
    • History of congestive heart failure (New York Heart Association functional classification III-IV)
    • Documented cardiomyopathy
    • Left Ventricular Ejection Fraction (LVEF) < 50% measured by Multiple Gated Acquisition (MUGA) scan or echocardiogram (ECHO)
    • Subject has any of the following cardiac abnormalities
  • Ventricular arrhythmias except benign premature contractions
  • Other arrhythmias requiring a pacemaker or not controlled with medicine
  • Conduction abnormality requiring a pacemaker
  • Subject has a QTcF > 480 msec on the screening ECG
  • Subject must continue to take a drug that causes ECG abnormalities or induces Torsades de Pointes
  • Subject had major surgery within 14 days before starting study drug or has not recovered from major side effects
  • Subject is taking or has taken systemic corticosteroids ≤ 2 weeks prior to starting study drug or have not fully recovered from side effects
  • Subject is taking drugs known to be inhibitors or inducers of CYP3A.
  • Subject is taking warfarin or other coumarin-derived anti-coagulant. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
  • Patient has received previous treatment with a PI3K inhibitor. Exceptions may be made for subjects who discontinued treatment with a previous PI3K inhibitor for reasons other than toxicity or progression and as long as it has been > 12 months since discontinuation of the previous PI3K inhibitor. This exception will require prior approval from the study PI.
  • Subjects having participated in a clinical trial within 30 days prior enrollment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02379247


Locations
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United States, Kansas
University of Kansas Cancer Center
Kansas City, Kansas, United States, 66205
University of Kansas Cancer Center - Overland Park
Overland Park, Kansas, United States, 66210
United States, Missouri
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, United States, 64064
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Priyanka Sharma
Novartis Pharmaceuticals
Investigators
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Principal Investigator: Priyanka Sharma, MD University of Kansas Medical Center
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Responsible Party: Priyanka Sharma, Medical Doctor, University of Kansas Medical Center
ClinicalTrials.gov Identifier: NCT02379247    
Other Study ID Numbers: CBYL719XUS06T
First Posted: March 4, 2015    Key Record Dates
Last Update Posted: November 6, 2020
Last Verified: November 2020
Keywords provided by Priyanka Sharma, University of Kansas Medical Center:
HER-2 Negative
Metastatic Breast Cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action