Clinical Trials /

A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety and Efficacy of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer

NCT02561832

Description:

This is an open-label study to assess the safety, tolerability and efficacy of olaparib in combination with carboplatin. There are two parts in this study: Part A, a dose escalation in patients with advanced Human Epidermal Growth Factor 2 (HER-2) negative breast cancer and Part B, a dose expansion in the neoadjuvant treatment of HER-2 negative breast cancer patients with germline Breast Cancer Susceptibility Gene (BRCA)1/2 mutations.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety and Efficacy of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer
  • Official Title: A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety, Tolerability and Efficacy of Olaparib in Combination With Carboplatin: Part A: Dose Escalation of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer; Followed by Part B: an Expansion Phase of Olaparib in Combination With Carboplatin in the Neoadjuvant Treatment of HER-2 Negative Breast Cancer Patients With Germline BRCA1/2 Mutations

Clinical Trial IDs

  • ORG STUDY ID: D081EC00001
  • NCT ID: NCT02561832

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
OlaparibArm 1
CarboplatinArm 1
AnthracyclineArm 1
CyclophosphamideArm 1

Purpose

This is an open-label study to assess the safety, tolerability and efficacy of olaparib in combination with carboplatin. There are two parts in this study: Part A, a dose escalation in patients with advanced Human Epidermal Growth Factor 2 (HER-2) negative breast cancer and Part B, a dose expansion in the neoadjuvant treatment of HER-2 negative breast cancer patients with germline Breast Cancer Susceptibility Gene (BRCA)1/2 mutations.

Detailed Description

      In Part A up to 36 evaluable patients with advanced breast cancer will be enrolled across 6
      cohorts. The total number of patients will depend on the number of dose escalations necessary
      to enable a decision to be made on the recommended dose to take forward into Part B of the
      study.

      The planned dose escalation will start with cohort 1, where patients will receive carboplatin
      (AUC5) on day 1 of cycle 1, and will start dosing with olaparib tablets at the dose of 50 mg
      twice daily (bd) on day 4 until day 19 of cycle 1 inclusive (a total of 16 days per cycle).
      Patients will receive carboplatin on day 1 of each 3 weeks cycle in combination with olaparib
      for a total of 4 cycles. Provided that there are no safety concerns after assessment of 6
      evaluable patients in the first cohort, patients in subsequent cohorts may be dosed following
      Safety Review Committee (SRC) approval. Dose escalation scheme may be adjusted during the
      study on the basis of emerging safety, efficacy and pharmacokinetic data. Those patients in
      Part A who tolerate the combination up to and including cycle 4 may remain on treatment,
      either continuing with the combination, with carboplatin alone at the same AUC or with
      olaparib alone at the dose of 300 mg bd, if in the opinion of the treating Investigator, a
      patient is deemed to be deriving clinical benefit from treatment. In these cases, a patient
      may remain on treatment until progression, unacceptable toxicity or until other
      discontinuation criteria are met. Beyond cycle 4, patients will undergo assessments in line
      with the clinical protocol. Once the maximum tolerated dose (MTD) and/or recommended dose
      (RD) has been defined in Part A, a dose expansion phase, Part B will begin and this will
      include up to 21 patients with HER2 negative breast cancer, with a deleterious or suspected
      deleterious germlineBRCA1/2 (gBRCA1/2) mutation, who are deemed eligible for neoadjuvant
      therapy.

      Part B will explore the safety, tolerability and efficacy of the combination of olaparib and
      carboplatin in terms of pathological complete response (pCR) rate. Neoadjuvant systemic
      therapy will consist of the following anti-cancer drugs for a total of 8 cycles of treatment:

        -  The first 4 cycles (cycle 1 to cycle 4: 12 weeks) will be based on combination of
           olaparib, at the defined RD and schedule from Part A, with carboplatin. It is expected
           that a cycle of treatment would be 3 weeks.

        -  Another 4 cycles (cycle 5 to cycle 8) will be based on a combination of an anthracycline
           and cyclophosphamide (AC). The choice of the AC regimen will be up to local Investigator
           following international guidelines (National Comprehensive Cancer Network (NCCN),
           European Society for Medical Oncology (ESMO), and St Gallen).

      The tumour response will be assessed through careful clinical examination and also with
      radiological examinations between cycle 4 and 5 and at the end of neoadjuvant part, before
      surgery. Additionally, tumour biopsy will be performed within 7 days before cycle 5 day 1,
      after completion of carboplatin and olaparib combination therapy and early pathological
      response assessed by local pathologist. Curative-intent surgery should be performed following
      completion of neoadjuvant treatment in all patients, 3 to 5 weeks after day 1 of the last
      cycle of neoadjuvant treatment.

      A decision has been made to stop recruitment after Part A cohort 2, and to not start Part B
      of the study. The protocol has been amended to define that the collection of clinical data
      will stop once the final patient from cohort 2 of Part A has completed 4 cycles or all
      patients from cohort 2 of Part A discontinue prior to end of cycle 4 to enable data analysis
      and reporting. The database would close at this time point, however AstraZeneca commits to
      providing study treatment to ongoing patients that continue to receive clinical benefit, in
      Investigator's judgment. Patients who remain on study treatment after this time point will be
      monitored according to routine clinical practice as defined by the Investigator and no
      clinical data will be collected, other than SAEs and drug dispensing/accountability.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalPart A: ascending doses of olaparib in combination with carboplatin will be administered to investigate safety and tolerability and to define the MTD and/or RD for part B. Patients will be treated with this combination up to cycle 4, after cycle 4 they can continue with combination or monotherapy (carboplatin or olaparib). Cohorts will be started sequentially, based on SRC recommendation. Part B will start after MTD/RD identification in part A. Patients will receive olaparib and carboplatin combination for first 4 cycles (21 days per cycle), at the dose, frequency and schedule recommended from Part A. This will be followed by another 4 cycles of standard cancer therapy consisting of anthracycline and cyclophosphamide regimen. Total of 8 treatment cycles will be given before final surgery
  • Olaparib
  • Carboplatin
  • Anthracycline
  • Cyclophosphamide

Eligibility Criteria

        Inclusion criteria

          -  Male or female aged ≥18 years

          -  Normal organ and bone marrow function, measured within 28 days prior to administration
             of study treatment

          -  Eastern Cooperative Oncology Group performance status of 0-1

          -  Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential.

        Additional for patients participating in Part A only

          -  Advanced or metastatic breast cancer that is HER-2 negative (HR positive or HR
             negative)

          -  Between 0 and 2 lines of prior cytotoxic chemotherapy. Additional for patients
             participating in Part B only

          -  Patients with operable breast adenocarcinoma and no evidence of metastatic disease are
             allowed.

          -  Patient must meet at least one of the following criteria: Clinical primary tumour size
             defined as T2 or above, clinical or patho-histological evidence of regional lymph
             nodes involvement (N+), grade 2-3 disease

          -  Availability of formalin fixed, paraffin embedded tumour sample from diagnostic
             biopsies (Not Applicable for patients at sites in Israel)

          -  Histological confirmation of HER-2 negative breast cancer

          -  Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or
             suspected deleterious

          -  Eligible for neo-adjuvant chemotherapy, but have not yet received neoadjuvant
             chemotherapy for breast cancer (chemo-naive) Exclusion criteria

          -  Exposure to an investigational product within 30 days or 5 half-lives (whichever is
             the longer) prior to enrolment

          -  Prior use of Poly ADP Ribose Polymerase (PARP) inhibitors

          -  Patients with a known hypersensitivity to olaparib or carboplatin

          -  Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal
             agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator.
             Patient must have discontinued use of such agents 3 weeks prior to beginning study
             treatment. Luteinising hormone-Releasing hormone (LHRH) analogues are allowed for all
             patients in Part A.

          -  Concomitant use of known potent Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers

          -  Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) grade ≥2
             and neuropathy CTCAE > grade 1) caused by previous cancer therapy, excluding alopecia
             - Patient with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with
             features suggestive of MDS/AML

          -  Patient must have recovered from any effects of any major surgery

          -  Patient considered at poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled seizures or active
             uncontrolled infection

          -  Patient with known active Hepatitis B or C, or Human immunodeficiency virus (HIV)

          -  Other malignancy within the last 5 years (few exceptions apply). Additional for
             patients participating in Part A only

          -  Prior chemotherapy within 3 weeks of study entry

          -  Other anti-cancer therapy (eg, targeted biotherapy of hormonal agents) within 3 weeks
             of study entry

          -  Radiation therapy within 4 weeks or radionuclide treatment within 6 weeks of treatment
             start

          -  Prior use of platinum compound in the advanced or metastatic setting. Previous
             exposure to platinum compounds is allowed only if they were used in early adjuvant or
             neoadjuvant setting with relapse occurring >6 months after the last platinum
             administration and if there is no residual toxicity

          -  Patient with a history of treated Central Nervous System (CNS) metastases are
             eligible, provided they meet certain protocol-specified criteria.

        Additional for patients participating in Part B only

          -  Prior treatment (local or systemic) of their breast tumour. Sentinel lymph node biopsy
             is considered as diagnostic procedure and therefore is authorized before neoadjuvant
             treatment in part B

          -  Patients with inflammatory breast cancer or patients with inoperable locally advanced
             breast cancer (including T4 lesions) at the time of enrolment.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: Numbers of adverse events (AEs) and serious AEs, vital signs for blood pressure and pulse, and body temperature, ECGs, Physical exams and laboratory parameters which including Biochemistry, Coagulation, Haematology and Urinalysis.
Time Frame:The time frame for determining the safety outcome measures is non-specific. E.g. If a patient has toxicity, the duration may be less that 12 weeks, otherwise, the duration may be longer than 9 months (=12 weeks +6 months).
Safety Issue:
Description:To investigate the safety and tolerability of olaparib tablets in combination with carboplatin in patients with advanced breast cancer, and to define a dose and schedule for further clinical evaluation.

Secondary Outcome Measures

Measure:Part A: Objective response rate (ORR)
Time Frame:The time frame for the length of participation in Part A, and for determining of ORR, is non-specific. Eg. If a patient has toxicity the duration may be less that 12 weeks, otherwise, the duration may be longer than 9 months (=12 weeks + 6 months).
Safety Issue:
Description:To obtain a preliminary assessment of the anti-tumour activity of olaparib in combination with carboplatin in patients with advanced breast cancer. ORR will be assessed for metastatic patients with measurable disease. Tumour response will be evaluated using Response Evaluation Criteria in Solid Tumours (RECIST) V1.1.
Measure:Part B: Objective response rate (ORR)
Time Frame:The time frame for determining the ORR outcome in Part B is up to 6 months (approx) from the start of treatment in part B.
Safety Issue:
Description:To assess ORR prior to surgery during the neoadjuvant phase in Part B. Clinical Response to olaparib carboplatin combination and to further chemotherapy regimens will be assessed by radiographic evaluation of tumour (Magnetic resonance imaging (MRI) and mammogram). Tumour response will be evaluated using RECIST V1.1.
Measure:Part A: Time to treatment failure (TTF) preliminary assessment of the anti-tumour activity of olaparib in combination with carboplatin in patients with advanced breast cancer
Time Frame:The time frame for the length of participation in Part A, and for determining TTF, is non-specific. Eg. If a patient has toxicity the duration may be less that 12 weeks, otherwise, the duration may be longer than 9 months (=12 weeks + 6 months).
Safety Issue:
Description:TTF will be defined as the time from start of the treatment (day 1, cycle 1) until the discontinuation of the two drugs assessed (carboplatin and olaparib), whichever occurs last, for any reason including but not limited to death, progression, toxicity or add-on of new anti-cancer therapy.
Measure:Part B: pCR2 (Pathological Complete Response)
Time Frame:The time frame for determining the pCR2 outcome is up to 6 months (approx) from the start of treatment in part B.
Safety Issue:
Description:pCR2 is defined as the absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy.
Measure:Part B: Numbers of adverse events (AEs) and serious AEs, vital signs for blood pressure and pulse, and body temperature, ECGs, Physical exams and laboratory parameters which including Biochemistry, Coagulation, Haematology and Urinalysis.
Time Frame:The time frame for determining the safety outcome data is up to 7 months (approx) (=6 months + 30 days) from the start of treatment in part B.
Safety Issue:
Description:To assess the safety and tolerability of olaparib in combination with carboplatin as part of neoadjuvant treatment
Measure:Part B: RCB (Residual Cancer Burden)
Time Frame:The time frame for determining the RCB outcome is up to 6 months (approx) from the start of treatment in part B.
Safety Issue:
Description:RCB will be calculated using the following parameters: The largest 2 dimensions (mms) of the residual tumour bed in the breast (largest tumour bed if multicentric disease) Submission of the entire largest cross-sectional area of the residual tumour bed for histologic mapping, with specific identification of those slides in the pathology report Histological assessment of the percentage of the tumour bed area that contains carcinoma Histological estimate of the percentage of the carcinoma in the tumour bed that is in situ The number of positive (metastatic) lymph nodes The largest diameter (mm) of the largest nodal metastasis
Measure:Part A and part B: Pharmacokinetic (PK) parameters of Maximum Plasma Concentration (Cmax) of Carboplatin
Time Frame:The time frame for determining the Cmax PK parameter in part A is approx within 4 weeks (C2D1) from the start of treatment in part A. The time frame for determining the Cmax PK parameter in part B is within 24 hours of the start of treatment in part B.
Safety Issue:
Description:To determine the Pharmacokinetic (PK) parameters of Cmax of free carboplatin in plasma. For part B, PK sampling will be performed on subset of patients only (6 patients).
Measure:Part A and part B: Pharmacokinetic (PK) parameters Time of Maximum Plasma Concentration (tmax) of Carboplatin
Time Frame:The time frame for determining the tmax PK parameter in part A is approx within 4 weeks (C2D1) from the start of treatment in part A. The time frame for determining the tmax PK parameter in part B is within 24 hours of the start of treatment in part B.
Safety Issue:
Description:To determine the Pharmacokinetic (PK) parameters of tmax of free carboplatin in plasma. For part B, PK sampling will be performed on subset of patients only (6 patients).
Measure:Part A and part B: Pharmacokinetic (PK) parameters of Area under Curve (AUC) of Carboplatin
Time Frame:The time frame for determining the AUC PK parameter in part A is approx within 4 weeks (C2D1) from the start of treatment in part A. The time frame for determining the AUC PK parameter in part B is within 24 hours of the start of treatment in part B.
Safety Issue:
Description:To determine the Pharmacokinetic (PK) parameters of AUC of free carboplatin in plasma from zero (pre-dose) extrapolated to infinity. For part B, PK sampling will be performed on subset of patients only (6 patients).
Measure:Part A and part B: Pharmacokinetic (PK) parameters of Terminal Half Life (t1/2) of Carboplatin
Time Frame:The time frame for determining the t1/2 PK parameter in part A is approx within 4 weeks (C2D1) from the start of treatment in part A. The time frame for determining the t1/2 PK parameter in part B is within 24 hours of the start of treatment in part B.
Safety Issue:
Description:To determine the Pharmacokinetic (PK) parameters of terminal t1/2 of free carboplatin in plasma. For part B, PK sampling will be performed on subset of patients only (6 patients).
Measure:Part A and part B: Pharmacokinetic (PK) parameters of Maximum Plasma Concentration (Clast) of Carboplatin
Time Frame:The time frame for determining the Cmax PK parameter in part A is approx within 4 weeks (C2D1) from the start of treatment in part A. The time frame for determining the Cmax PK parameter in part B is within 24 hours of the start of treatment in part B.
Safety Issue:
Description:To determine the Pharmacokinetic (PK) parameters of Clast of free carboplatin in plasma. For part B, PK sampling will be performed on subset of patients only (6 patients).
Measure:Part A and part B: Pharmacokinetic (PK) parameters of Area under Curve (AUClast) of Carboplatin
Time Frame:The time frame for determining the AUClast PK parameter in part A is approx within 4 weeks (C2D1) from the start of treatment in part A. In part B it is within 24 hours of the start of treatment in part B.
Safety Issue:
Description:To determine the Pharmacokinetic (PK) parameters of AUClast of free carboplatin in plasma from zero (pre-dose) to the last quantifiable concentration. For part B, PK sampling will be performed on subset of patients only (6 patients).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:AstraZeneca

Trial Keywords

  • breast cancer

Last Updated

February 14, 2017