Patient case: 38-year-old male with Liposarcoma. Genetic variant: CDK4 Amplification. Other conditions: GERD.

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

Summary: 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, and preliminary efficacy in 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 approx 27 patients evaluable for response to define the recommended Phase II dose (RP2D).
  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

Eligibility: Inclusion:
  Postmenopausal women >= 18 WHO/ECOG perf. status 0-1 Histologically or cytologically proven diagnosis of breast cancer with evidence of locally advanced or metastatic disease not amendable to resection or radiation ER+ and HER2 negative Parts A: Must be eligible for fulvestrant. A maximum of 3 prior lines of chemotherapy are allowed Parts B and C: Postmenopausal with locally advanced or metastatic ER+ breast cancer and refractory to aromatase inhibitors (AIs), 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.
  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
  Exclusion:
  Prior chemotherapy, biological or radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents, or any investigational drug or corticosteroids within 14 days Prior radiotherapy to >= 25% of bone marrow regardless of when it was received Unresolved toxicity from prior therapy > CTCAE grade 1 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 Exposure to sensitive or narrow therapeutic range substrates of the drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K within the appropriate wash-out period (a minimum of 5 x reported elimination half-life) before the first dose of study treatment Previous treatment with AZD2014, AZD8055 or other mTORC1/2 inhibitor, Part C: Prior treatment with fulvestrant, or everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway Prior treatment with CDK4/6, or everolimus or any PI3K-mTOR pathway 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 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.
  Any evidence of severe or uncontrolled systemic disease as judged by the Investigator.
  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.
  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 Abnormal ECHO or MUGA at baseline (LVEF <50%) 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 Any clinically important abnormality in rhythm, conduction, or morphology of resting ECG, e.g. complete left bundle branch block, third degree heart block.
  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.
  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.
  Part A Only: Individual cohorts may have specific baseline ANC ranges for patients to be enrolled within the limits of the above exclusion. These sub-groups are defined as follows
  -  Low ANC Patients: ANC between 1.5 x 10^9/L and 3.0 x 10^9/L
  -  High ANC Patients: ANC between 3.0 x 10^9/L and above Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis.
  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.
  History of hypersensitivity to active or inactive excipients of AZD2014, palbociclib or fulvestrant, or drugs with a similar chemical structures Patients with Diabetes Type I or uncontrolled Type II 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.
  Prior hematopoietic stem cell or bone marrow transplant Patients receiving regular coumadin therapy (LMW heparin is allowed) Known coagulation abnormalities 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.

Relevance to patient case: not relevant