A Phase 1 Dose Escalation and Expansion Study of AZD9833 Alone or in Combination with
Palbociclib in Women with ER Positive, HER2 Negative Advanced Breast Cancer
This is a first-in-human study of AZD9833 monotherapy (Parts A and B) and AZD9833 in
combination with palbociclib (Parts C and D) in women with ER Positive HER2 Negative advanced
breast cancer that is not amenable to treatment with curative intent. Parts A and C of the
study allow for an escalation of AZD9833 dose alone (Part A) or in combination with
palbociclib (Part C). In Parts B and D of the study, eligible subjects will be randomised to
receive selected doses of AZD9833 alone (Part B) or in combination with palbociclib (Part D).
1. Signed written informed consent.
2. >= 18 years.
3. Any menopausal status:
1. Pre-menopausal women must have commenced treatment with an LHRH agonist at least
4 weeks prior to starting IMP (AZD9833 and/or palbociclib) and must be willing to
continue to receive LHRH agonist therapy for the duration of the trial.
2. Post-menopausal defined according to standard criteria in the protocol.
4. Histological and cytological confirmation of adenocarcinoma of the breast.
5. Documented positive oestrogen receptor status of primary or metastatic tumour tissue,
according to the local laboratory parameters. HER-2 negative.
6. Metastatic disease or locoregionally recurrent disease not amenable to treatment with
curative intent and, where available, standard-of-care therapies have been received or
7. Metastatic or locoregionally recurrent disease and radiological or objective evidence
of progression on or after the last systemic therapy prior to starting IMP.
8. Prior chemotherapy, endocrine therapy and other therapy in the advanced setting is
restricted as follows:
1. No more than 2 lines of chemotherapy for advanced disease.
2. Recurrence or progression on at least one line of endocrine therapy.
3. There is no limit on the number of lines of prior endocrine therapies.
4. Prior treatment with CDK4/6 inhibitors is permitted.
9. Women of childbearing potential must agree to use a highly effective contraceptive
measure, must not be breast feeding, and must have a negative pregnancy test prior to
the start of dosing.
10. At least one lesion (measurable and/or non-measurable, as per Response Evaluation
Criteria in Solid Tumours version 1.1 [RECIST 1.1] that can be accurately assessed at
baseline and is suitable for repeated assessment by computed tomography (CT), magnetic
resonance imaging (MRI), or plain X-ray; or clinical examination. Blastic-only lesions
in bone are not considered assessable.
11. Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance
status 0 to 1, with no deterioration over the previous 2 weeks and a minimum life
expectancy of 12 weeks.
1. Intervention with any of the following:
1. Any cytotoxic chemotherapy, investigational agents or other anti-cancer drugs for
the treatment of advanced breast cancer from a previous treatment regimen or
clinical study within 14 days of the first dose of IMP.
2. Medications or herbal supplements known to be strong inhibitors/inducers of
cytochrome P450 3A4/5 (CYP3A4/5) and sensitive cytochrome P450 2B6 (CYP2B6)
substrates or inability to stop use within a suitable washout period prior to
receiving the first dose of AZD9833.
3. Drugs that are known to prolong QT and have a known risk of Torsades de Pointes.
4. Radiotherapy with a limited field of radiation for palliation within one week of
the first dose of IMP, radiotherapy to more than 30% of the bone marrow or a wide
field of radiation within 4 weeks of the first dose of IMP.
5. Major surgical procedure or significant traumatic injury, as judged by the
investigator, within 4 weeks of the first dose of IMP, or an anticipated need for
major surgery during the study.
2. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) Grade 1 at the time of starting IMP, with the exception of
3. Presence of life-threatening metastatic visceral disease.
4. Evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the investigator's opinion makes
it undesirable for the patient to participate in the trial or which would jeopardise
compliance with the protocol, or active infection* including hepatitis B, hepatitis C,
and human immunodeficiency virus (HIV).
*Active viral infection is defined as requiring antiviral therapy. Screening for
chronic conditions is not required.
5. Any of the following cardiac criteria:
1. Mean resting QT interval corrected by Fridericia's formula (QTcF) >470 msec
obtained from a triplicate electrocardiogram (ECG).
2. Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECG (eg, complete left bundle branch block, second- and third-degree
heart block), or clinically significant sinus pause. Patients with controlled
atrial fibrillation can be enrolled.
3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as symptomatic heart failure, hypokalaemia, congenital long QT
syndrome, immediate family history of long QT syndrome, or unexplained sudden
death at <40 years of age. Hypertrophic cardiomyopathy and clinically significant
stenotic valve disease.
4. Experience of any of the following procedures or conditions in the preceding 6
months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
infarction, unstable angina pectoris, congestive heart failure New York Heart
Association (NYHA) Grade ≥2, cerebrovascular accident, or transient ischaemic
5. Uncontrolled hypertension. Hypertensive patients may be eligible but blood
pressure must be adequately controlled at baseline. Patients may be re-screened
regarding the blood pressure requirement.
6. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
1. Absolute neutrophil count (ANC) <1.5 × 109/L.
2. Platelet count <100 × 109/L.
3. Haemoglobin <90 g/L.
4. Alanine aminotransferase (ALT) >2.5 × the upper limit of normal (ULN).
5. Aspartate aminotransferase (AST) >2.5 × ULN.
6. Total bilirubin (TBL) >1.5 × ULN or >3 × ULN in the presence of documented
Gilbert's Syndrome (unconjugated hyperbilirubinaemia).
7. Glomerular filtration rate (GFR) <50 mL/min.
7. Involvement in the planning and conduct of the study (applies to AstraZeneca staff or
staff at the study site).
8. Refractory nausea and vomiting, uncontrolled chronic gastrointestinal (GI) diseases,
inability to swallow the formulated product, or previous significant bowel resection
that would preclude adequate absorption of AZD9833 and palbociclib.
9. History of hypersensitivity to active or inactive excipients of AZD9833 or drugs with
a similar chemical structure or class to AZD9833.
For subjects in Parts C and D: History of hypersensitivity to active or inactive
excipients of palbociclib or drugs with a similar chemical structure or class to
10. 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