Clinical Trials /

Study of AZD9833 Alone or in Combination With Palbociclib in Women With Advanced Breast Cancer

NCT03616587

Description:

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

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of AZD9833 Alone or in Combination With Palbociclib in Women With Advanced Breast Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: D8530C00001
  • SECONDARY ID: 2018-000667-92
  • SECONDARY ID: 138396
  • NCT ID: NCT03616587

Conditions

  • ER+ HER2- Advanced Breast Cancer

Interventions

DrugSynonymsArms
AZD9833AZD9833 monotherapy dose escalation
AZD9833 with palbociclibAZD9833 with palbociclib dose escalation
AZD9833AZD9833 monotherapy dose expansion
AZD9833 with palbociclibAZD9833 with palbociclib dose expansion

Purpose

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

Detailed Description

      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).
    

Trial Arms

NameTypeDescriptionInterventions
AZD9833 monotherapy dose escalationExperimental
  • AZD9833
AZD9833 monotherapy dose expansionExperimental
  • AZD9833
AZD9833 with palbociclib dose escalationExperimental
  • AZD9833 with palbociclib
AZD9833 with palbociclib dose expansionExperimental
  • AZD9833 with palbociclib

Eligibility Criteria

        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
             offered.

          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.

        Exclusion criteria

          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
             alopecia.

          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
                  attack.

               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
             palbociclib.

         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
             requirements.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:The number of subjects with dose-limiting toxicity, as defined in the protocol.
Time Frame:Minimum observation period 28 days on treatment.
Safety Issue:
Description:Dose-limiting toxicity as described in the protocol that is not related to disease progression, intercurrent illness or concomitant medications and that, despite optimal therapeutic intervention, meets protocol-defined criteria.

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:Weeks 8, 16 and 24 and then every 12 weeks (weeks 36, 48 and 60) until the end of the study (approximately 1 year).
Safety Issue:
Description:Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
Measure:Duration of Response
Time Frame:Weeks 8, 16 and 24 and then every 12 weeks (weeks 36, 48 and 60) until the end of the study (approximately 1 year).
Safety Issue:
Description:Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
Measure:Clinical benefit rate at 24 weeks
Time Frame:Up to 24 weeks
Safety Issue:
Description:Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
Measure:Percentage Change in Tumour Size
Time Frame:Weeks 8, 16 and 24 and then every 12 weeks (weeks 36, 48 and 60) until the end of the study (approximately 1 year).
Safety Issue:
Description:Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
Measure:Progression Free Survival
Time Frame:Weeks 8, 16 and 24 and then every 12 weeks (weeks 36, 48 and 60) until the end of the study (approximately 1 year).
Safety Issue:
Description:Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
Measure:Maximum Observed Plasma Concentration (Cmax) of AZD9833 alone or in combination with Palbociclib
Time Frame:At predefined intervals throughout the AZD9833 treatment period (approximately 16 weeks )
Safety Issue:
Description:Blood samples will be collected to assess plasma concentrations of AZD9833 alone or in combination with Palbociclib at a series of timepoints to derive Cmax
Measure:Time to observed Cmax (Tmax) for AZD9833 alone or in combination with Palbociclib
Time Frame:At predefined intervals throughout the AZD9833 treatment period (approximately 16 weeks )
Safety Issue:
Description:Blood samples will be collected to assess plasma concentrations of AZD9833 alone or in combination with Palbociclib at a series of timepoints to derive Tmax
Measure:Area under the plasma concentration-time curve (AUC) for AZD9833 alone or in combination with Palbociclib
Time Frame:At predefined intervals throughout the AZD9833 treatment period (approximately 16 weeks )
Safety Issue:
Description:Blood samples will be collected to assess plasma concentrations of AZD9833 alone or in combination with Palbociclib at a series of timepoints to derive AUC
Measure:Renal clearance (CLR) for AZD9833
Time Frame:At predefined intervals throughout the AZD9833 treatment period (approximately 16 weeks )
Safety Issue:
Description:Urine samples will be collected to assess urine concentrations of AZD9833 at a series of timepoints to derive renal clearance

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Breast Cancer
  • Phase 1
  • Safety
  • Tolerability
  • Pharmacokinetics
  • ER Positive
  • HER2 Negative
  • Advanced Breast Cancer

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