Clinical Trials /

Study of AZD2014 and Palbociclib in Patients With Estrogen Receptor Positive (ER+) Metastatic Breast Cancer

NCT02599714

Description:

This dose finding/extension study was designed originally to consist of three parts: Part A was intended to identify the MTD of the AZD2014/ palbociclib combination on a background of fulvestrant (referred to as the triplet) in postmenopausal women with locally advanced/ metastatic estrogen receptor positive (ER+) breast cancer. Part B was to further characterize safety, tolerability, PK, and preliminary efficacy in single-arm dose expansion groups. Part C was to be a Phase 2, randomized, double-blind, extension comparing the triplet and doublet combinations. Part C was deleted from the protocol and was not performed.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Study of AZD2014 and <span class="go-doc-concept go-doc-intervention">Palbociclib</span> in Patients With Estrogen Receptor Positive (ER+) Metastatic Breast Cancer

Title

  • Brief Title: Study of AZD2014 and Palbociclib in Patients With Estrogen Receptor Positive (ER+) Metastatic Breast Cancer
  • Official Title: A Phase I/II Multicenter Study of the Combination of AZD2014 and Palbociclib on a Background of Hormonal Therapy in Patients With Locally Advanced/Metastatic Estrogen Receptor Positive Breast Cancer Comprising a Safety, Pharmacokinetic and Preliminary Efficacy Evaluation Followed by a Randomised, Double-Blind, Placebo-controlled, Parallel Group Extension
  • Clinical Trial IDs

    NCT ID: NCT02599714

    ORG ID: D2270C00020

    NCI ID: BRE 253

    Trial Conditions

    Advanced and Metastatic Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    AZD2014 Triplet Combination
    Placebo to match AZD2014 Placebo Doublet Combination
    palbociclib Ibrance, PD-0332991 Triplet Combination, Doublet Combination
    fulvestrant Faslodex Triplet Combination, Doublet Combination
    Placebo to match palbociclib Placebo Triplet Combination

    Trial Purpose

    This dose finding/extension study consists of three parts: Part A will identify the MTD of
    the AZD2014/palbociclib combination on a background of fulvestrant (referred to as the
    triplet) in postmenopausal women with locally advanced/metastatic estrogen receptor positive
    (ER+) breast cancer. Part B will further characterize safety, tolerability, PK, drug-drug
    interaction and preliminary efficacy in 3 single-arm dose expansion groups. Part C will
    investigate the efficacy of the triplet combination in a double-blind, placebo-controlled,
    stratified, parallel group extension.

    Detailed Description

    This is a Phase I/II international, multicenter study of the combination of AZD2014 and
    palbociclib on a background of 500 mg fulvestrant (referred to as the triplet) in
    postmenopausal women with locally advanced/metastatic estrogen receptor positive (ER+)
    breast cancer. The study consists of three parts:

    Part A is a Phase I triplet-dose finding investigation in 3-6 patients per cohort to
    determine the maximum tolerated dose (MTD) of the triplet.

    Part B will comprise Phase I single arm expansions in 3 sub-parts:

    Part B1 will be single arm expansion(s) in 9-15 patients evaluable for response to define
    the recommended Phase II dose (RP2D).

    Part B2 will be a single arm expansion of the B1 dose in 25 additional patients to give a
    total of 40 patients evaluable for response at the dose under investigation. Part B2 will
    only be opened if indicated by emerging data.

    Part B3 will be single arm drug-drug interaction (DDI) investigation in additional cohort(s)
    of approximately 9 patients. Part B3 will only be opened if indicated by emerging data.

    Part C will investigate the efficacy of the triplet combination at the RP2D in a randomized,
    double-blind, placebo-controlled, stratified, parallel group extension. Part C will include
    ER+, locally advanced and/or metastatic breast cancer patients who have progressed following
    prior non-steroidal aromatase inhibitor (NSAI) endocrine therapy. Patients in Part C will be
    randomized to receive either the triplet combination (AZD2014 + palbociclib + fulvestrant)
    or the doublet (matching AZD2014 placebo + palbociclib + fulvestrant). Patients will be
    stratified according to hormone sensitivity, presence of visceral metastases, and prior CDK
    inhibitor treatment. Part C will be opened if indicated by emerging data

    Trial Arms

    Name Type Description Interventions
    Triplet Combination Experimental The experimental arm will be comprised of AZD2014 + palbociclib + fulvestrant. AZD2014, palbociclib, fulvestrant, Placebo to match palbociclib
    Doublet Combination Active Comparator The comparator will be comprised of Matching AZD2014 placebo + palbociclib + fulvestrant. (Part C Only) Placebo to match AZD2014, palbociclib, fulvestrant

    Eligibility Criteria

    Inclusion:

    1. Postmenopausal women >= 18

    2. WHO/ECOG perf. status 0-1

    3. Histologically or cytologically proven diagnosis of breast cancer with evidence of
    locally advanced or metastatic disease not amendable to resection or radiation

    4. ER+

    5. HER2 negative

    6. Parts A & B: Must be eligible for fulvestrant. A maximum of 3 prior lines of
    chemotherapy are allowed

    7. Part C: Postmenopausal with locally advanced or metastatic ER+ breast cancer and
    refractory to non steroidal aromatase inhibitors (NSAIs), defined as: disease
    recurrence while on, or within 12 months of end of adjuvant treatment with letrozole,
    anastrazole, or exemestane; or disease progression while on, or within one month of
    end of letrozole, anastrazole, or exemestane, or exemestane treatment for locally
    advanced or metastatic breast cancer.

    8. Parts A, B3, and C: At least 1 lesion (measurable or non measurable) that can be
    accurately assessed at baseline with CT or MRI and which is suitable for accurate
    repeated measurement

    9. Parts B1 & B2: At least 1 lesion (measurable or non measurable), not previously
    irradiated and not biopsied during screening that can be accurately assessed at
    baseline as >= 10 mm in longest diameter (except lymph nodes which must have short
    axis >= 15 mm) with CT or MRI and which is suitable for accurate repeated measurement

    Exclusion:

    1. Prior chemotherapy, biological or radiation therapy, androgens, thalidomide,
    immunotherapy, other anticancer agents, or any investigational drug or
    corticosteroids within 14 days

    2. Prior radiotherapy to >= 25% of bone marrow regardless of when it was received

    3. Unresolved toxicity from prior therapy > CTCAE grade 1

    4. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5, CYP2C8, Pgp (MDR1)
    or BCRP if taken within the stated washout period prior to start of treatment

    5. Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising
    enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6, or other drug transporters Pgp (MDR1), BCRP,
    OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period for each drug
    (>= 5 elimination half-life).

    6. Previous treatment with AZD2014, AZD8055 or other mTORC1/2 inhibitor, fulvestrant, or
    everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR
    pathway

    7. Major surgery or significant trauma within 4 weeks or anticipated need for major
    surgery during the study, or minor surgery within 2 weeks of study entry

    8. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or
    leptomeningeal disease, as indicated by clinical symptoms, cerebral edema, and/or
    progressive growth. History of CNS metastases or cord compression are eligible if
    they have been definitively treated (e.g. radiotherapy, stereotactic surgery) and are
    clinically stable, off anticonvulsants and steroids for at least 4 weeks. Not
    eligible if they have spinal cord compression and/or brain metastases unless they are
    asymptomatic or treated and stable off steroids for at least 4 weeks.

    9. Any evidence of severe or uncontrolled systemic disease as judged by the
    Investigator.

    10. Any other malignancy within 3 years prior to study treatment, except for adequately
    treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.

    11. Any of the following currently or within 12 months: coronary/peripheral artery bypass
    graft, angioplasty, vascular stent, MI, angina, CHF (NYHA Grade >=2), ventricular
    arrhythmias requiring continuous therapy, supraventricular arrhythmias including
    atrial fibrillation, symptomatic pulmonary embolism, haemorrhagic or thrombotic
    stroke, including TIA or any other CNS bleeding

    12. Abnormal ECHO or MUGA at baseline (LVEF <50%)

    13. Mean resting QTc > 470 msec, family or personal history of long or short QT syndrome,
    Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12
    months

    14. Any clinically important abnormality in rhythm, conduction, or morphology of resting
    ECG, e.g. complete left bundle branch block, third degree heart block.

    15. Concomitant medications known to prolong QT, or with factors that increase the risk
    of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia,
    congenital long QT syndrome, family history of long QT syndrome, family history of
    unexplained sudden death under age 40.

    16. Inadequate bone marrow reserve or organ function as demonstrated by any of the
    following: ANC <1.5 x 109/L, platelets <100x109/L, haemoglobin <90g/L, ALT >2.5 x ULN
    or >5 x ULN in the presence of liver metastases, total bilirubin >1.5 x ULN or >3 x
    ULN in patients with Gilbert's Syndrome, serum creatinine >1.5 x ULN concurrent with
    creatinine clearance <= 50 mL/min.

    17. Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi
    Syndrome or renal tubular acidosis.

    18. Refractory nausea and vomiting, chronic GI diseases, inability to swallow the
    product, or previous significant bowel resection that would preclude adequate
    absorption of AZD2014 or palbociclib.

    19. History of hypersensitivity to active or inactive excipients of AZD2014, palbociclib
    or fulvestrant, or drugs with a similar chemical structures

    20. Patients with Diabetes Type I or uncontrolled Type II

    21. Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of
    life-threatening complications in the short term including patients with massive
    uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis,
    and over 50% of liver involvement in metastases.

    22. Prior hematopoietic stem cell or bone marrow transplant

    23. Patients receiving regular coumadin therapy (LMW heparin is allowed)

    24. Known coagulation abnormalities

    25. Erythropoietin, G-CSF, and GM-CSF are not allowed within 2 weeks prior to study. The
    primary prophylactic use of G-CSF is not permitted but it may be used to treat
    treatment-emergent neutropenia.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 130 Years

    Eligible Gender: Female

    Primary Outcome Measures

    In Parts A, B1 and B2: Number of adverse events experienced by patients

    In Part B3: Maximum concentration of drug in the body (Cmax) to assess drug interaction

    In Part B3: Exposure to the drug for the triplet and the doublet combination through measurement of AUC (Area Under the Curve) to assess drug interaction

    In Part C: Measurement of Progression Free Survival (PFS)

    Secondary Outcome Measures

    In Parts B3 and C: Measure the incidence of adverse events

    Parts A, B1, B2, and B3: Measurement of Progression Free Survival (PFS)

    All Study Parts: Measurement of Best Objective Response (BOR)

    All Study Parts: Measurement of Objective Response Rate (ORR)

    All Study Parts: Measurement of Duration of Response (DoR)

    Parts B1, B2 and C: Overall Survival (OS) assessed through survival assessment

    Parts A and B2: Plasma concentrations (Cmax) of AZD2014 and palbociclib following single dose

    Parts A, B1, B2 and B3: Plasma concentrations (Cmax) of AZD2014 and palbociclib following multiple doses

    Part C: Change from baseline in biomarker H-score

    Part C: Measure change from baseline in EORTC QLQ-C30 Questionnaire

    Trial Keywords

    AZD2014, Palbociclib, Fulvestrant, Hormonal Therapy, Estrogen, Receptor, Positive, Locally-Advanced, Metastatic, Breast Cancer